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Sathyanarayana S, Pavese N, Ledingham D. The cholinergic system in dementia with Lewy bodies. HANDBOOK OF CLINICAL NEUROLOGY 2025; 211:231-245. [PMID: 40340064 DOI: 10.1016/b978-0-443-19088-9.00008-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/10/2025]
Abstract
Dementia with Lewy bodies (DLB) is a progressive neurodegenerative disorder pathologically characterized by the presence of neuronal intracytoplasmic inclusions known as Lewy bodies. Core clinical features include fluctuating cognitive impairment, recurrent visual hallucinations, REM sleep behavior disorder, and Parkinsonism. Cholinergic dysfunction is implicated in many of the symptoms of DLB, based on both pathologic and functional imaging studies, as well as the clear symptomatic response of cognitive and behavioral symptoms to drugs that modulate the cholinergic system. In this chapter, we will review and discuss the evidence for cholinergic dysfunction in DLB and its clinical and therapeutic implications.
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Affiliation(s)
- Sahana Sathyanarayana
- Clinical Ageing Research Unit, Newcastle University, Newcastle Upon Tyne, United Kingdom
| | - Nicola Pavese
- Clinical Ageing Research Unit, Newcastle University, Newcastle Upon Tyne, United Kingdom; Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Aarhus, Denmark
| | - David Ledingham
- Clinical Ageing Research Unit, Newcastle University, Newcastle Upon Tyne, United Kingdom; Royal Victoria Infirmary, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, United Kingdom.
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Xie C, Li T, Lin Y, Fu Z, Li N, Qi W, Yu X, Zhu L, Wang H. Prevalence and correlates of probable rapid eye movement sleep behavior disorder among middle-aged and older adults in a psychiatric outpatient clinic: A cross-sectional survey. Sleep Med 2024; 121:266-274. [PMID: 39032185 DOI: 10.1016/j.sleep.2024.07.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 07/11/2024] [Accepted: 07/12/2024] [Indexed: 07/22/2024]
Abstract
OBJECTIVE Rapid eye movement sleep behavior disorder (RBD) is often underdiagnosed among people living with mental disorders. The present study aimed to investigate the prevalence of probable RBD (pRBD) and its associated factors among middle-aged and older adults in a psychiatric outpatient clinic. METHODS We conducted a cross-sectional survey among 2907 people aged 45-80 years who visited the outpatient clinic between March 1 and August 31, 2022 in a psychiatric hospital. A cutoff score ≥5 on the RBD Screening Questionnaire (RBDSQ) was used to indicate the presence of probable RBD (pRBD). Potential factors associated with pRBD were also assessed with a structured checklist. The association between these factors and the presence of pRBD was examined with logistic regression. RESULTS The response rate was 64.3 %. Among 1868 respondents [age 58.5 ± 9.6 years, male n = 738 (39.5 %), female n = 1130 (60.5 %)], 15.9 % (95 % CI 14.2-17.6 %) screened positive for pRBD. Occupational exposure to chemicals; positive family history of psychotic disorders; a late start of mental health care; a medical history of autonomic dysfunction; mood problems; and use of antidepressants, hypnotics, and acetylcholinesterase inhibitors were associated with an increased likelihood of having pRBD (P < 0.05 for all). CONCLUSION pRBD is common among outpatients with mental disorders, especially in mental disorders due to neurological diseases and physical conditions, mood disorders and anxiety or somatoform disorders. The findings highlight the importance of identifying sleep behavior disorders among people living with mental disorders in clinical practice.
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Affiliation(s)
- Caixia Xie
- School of Mental Health, Wenzhou Medical University, Wenzhou, 325000, China.
| | - Tao Li
- Dementia Care and Research Center, Beijing Dementia Key Lab, Peking University Institute of Mental Health (Sixth Hospital), NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, 100191, China.
| | - Yongsheng Lin
- Shangrao Third People's Hospital, Shangrao, 334000, China.
| | - Zhiqiang Fu
- Shangrao Third People's Hospital, Shangrao, 334000, China.
| | - Nan Li
- Center of Clinical Epidemiology, Peking University Third Hospital, Beijing, 100191, China.
| | - Wei Qi
- Shangrao Third People's Hospital, Shangrao, 334000, China.
| | - Xin Yu
- Dementia Care and Research Center, Beijing Dementia Key Lab, Peking University Institute of Mental Health (Sixth Hospital), NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, 100191, China.
| | - Limao Zhu
- Shangrao Third People's Hospital, Shangrao, 334000, China.
| | - Huali Wang
- School of Mental Health, Wenzhou Medical University, Wenzhou, 325000, China; Dementia Care and Research Center, Beijing Dementia Key Lab, Peking University Institute of Mental Health (Sixth Hospital), NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, 100191, China.
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Prins ND, de Haan W, Gardner A, Blackburn K, Chu HM, Galvin JE, Alam JJ. Phase 2A Learnings Incorporated into RewinD-LB, a Phase 2B Clinical Trial of Neflamapimod in Dementia with Lewy Bodies. J Prev Alzheimers Dis 2024; 11:549-557. [PMID: 38706271 PMCID: PMC11061005 DOI: 10.14283/jpad.2024.36] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Accepted: 12/21/2023] [Indexed: 05/07/2024]
Abstract
BACKGROUND In an exploratory 91-participant phase 2a clinical trial (AscenD-LB, NCT04001517) in dementia with Lewy bodies (DLB), neflamapimod showed improvement over placebo on multiple clinical endpoints. To confirm those results, a phase 2b clinical study (RewinD-LB, NCT05869669 ) that is similar to AscenD-LB has been initiated. OBJECTIVES To optimize the choice of patient population, primary endpoint, and biomarker evaluations in RewinD-LB. DESIGN Evaluation of the efficacy results from AscenD-LB, the main results of which, and a re-analysis after stratification for absence or presence of AD co-pathology (assessed by plasma ptau181), have been published. In addition, the MRI data from a prior phase 2a clinical trial in Early Alzheimer's disease (AD), were reviewed. SETTING 22 clinical sites in the US and 2 in the Netherlands. PARTICIPANTS Probable DLB by consensus criteria and abnormal dopamine uptake by DaTscan™ (Ioflupane I123 SPECT). INTERVENTION Neflamapimod 40mg capsules or matching placebo capsules, twice-a-day (BID) or three-times-a-day (TID), for 16 weeks. MEASUREMENTS 6-test Neuropsychological Test Battery (NTB) assessing attention and executive function, Clinical Dementia Rating Sum-of-Boxes (CDR-SB), Timed Up and Go (TUG), International Shopping List Test (ISLT). RESULTS Within AscenD-LB, patients without evidence of AD co-pathology exhibited a neflamapimod treatment effect that was greater than that in the overall population and substantial (cohen's d effect size vs. placebo ≥ for CDR-SB, TUG, Attention and ISLT-recognition). In addition, the CDR-SB and TUG performed better than the cognitive tests to demonstrate neflamapimod treatment effect in comparison to placebo. Further, clinical trial simulations indicate with 160-patients (randomized 1:1), RewinD-LB conducted in patients without AD co-pathology has >95% (approaching 100%) statistical power to detect significant improvement over placebo on the CDR-SB. Preliminary evidence of positive treatment effects on beta functional connectivity by EEG and basal forebrain atrophy by MRI were obtained in AscenD-LB and the Early AD study, respectively. CONCLUSION In addition to use of a single dose regimen of neflamapimod (40mg TID), key distinctions between phase 2b and phase 2a include RewinD-LB (1) excluding patients with AD co-pathology, (2) having CDR-SB as the primary endpoint, and (3) having MRI studies to evaluate effects on basal forebrain atrophy.
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Affiliation(s)
- N D Prins
- John J. Alam, MD, CervoMed, Inc., 20 Park Plaza, Suite 424, Boston, MA 02116, , Tel: +1-617-948-2107
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Sadeghi S, Mohammadian F, Tehrani-Doost M, Gholami K, Mohebbi N. Evaluating the Effects of Rivastigmine on Decision-Making in Patients with Mild Cognitive Impairment by Cambridge Neuropsychological Test Automated Battery (CANTAB); A Randomized, Double-Blind, Placebo-Controlled Trial. IRANIAN JOURNAL OF PHARMACEUTICAL RESEARCH : IJPR 2023; 22:e138943. [PMID: 38444714 PMCID: PMC10912857 DOI: 10.5812/ijpr-138943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Revised: 09/04/2023] [Accepted: 09/09/2023] [Indexed: 03/07/2024]
Abstract
Background Decision-making is a complex process, and most studies showed that patients with mild cognitive impairment (MCI) make worse decisions than healthy people. Objectives This study aims to evaluate the effect of rivastigmine on the decision-making of MCI patients using the Cambridge Neuropsychological Test Automated Battery (CANTAB) tests. Methods The study was conducted at the Roozbeh Hospital neurology clinic, and 30 patients with mild cognitive impairment over 40 years old were randomly recruited to receive rivastigmine or placebo twice daily for 12 weeks. The initial dose of rivastigmine or placebo was 1.5 mg twice daily and was increased to 3 mg twice daily per patient compliance. A CANTAB test was conducted before and following the intervention. Results The mean age of patients in the rivastigmine group was 58.93 ± 10.88, and in the placebo group was 59.33 ± 10.34. The median MMSE (Mini-Mental State Examination) was 26 (IQR = 25 - 26) in both groups. Patients in the rivastigmine group showed significant differences in all subgroup tests of CGT, IST, and SST except in risk adjustment in the CGT test, discrimination in the IST test, and median correct RT on the go trial and SSRT in the SST test. The most commonly reported adverse effects were gastrointestinal complications. Conclusions According to the results, rivastigmine significantly improved the primary decision-making outcomes in comparison with placebo.
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Affiliation(s)
- Setayesh Sadeghi
- Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Mohammadian
- Department of Psychiatry, Roozbeh Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehdi Tehrani-Doost
- Research Center for Cognitive and Behavioral Sciences, Tehran University of Medial Sciences, Tehran, Iran
| | - Kheirollah Gholami
- Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- Research Center for Rational Use of Drugs, Tehran University of Medical Sciences, Tehran, Iran
| | - Niayesh Mohebbi
- Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- Research Center for Rational Use of Drugs, Tehran University of Medical Sciences, Tehran, Iran
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Preclinical and randomized clinical evaluation of the p38α kinase inhibitor neflamapimod for basal forebrain cholinergic degeneration. Nat Commun 2022; 13:5308. [PMID: 36130946 PMCID: PMC9492778 DOI: 10.1038/s41467-022-32944-3] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 08/23/2022] [Indexed: 12/14/2022] Open
Abstract
The endosome-associated GTPase Rab5 is a central player in the molecular mechanisms leading to degeneration of basal forebrain cholinergic neurons (BFCN), a long-standing target for drug development. As p38α is a Rab5 activator, we hypothesized that inhibition of this kinase holds potential as an approach to treat diseases associated with BFCN loss. Herein, we report that neflamapimod (oral small molecule p38α inhibitor) reduces Rab5 activity, reverses endosomal pathology, and restores the numbers and morphology of BFCNs in a mouse model that develops BFCN degeneration. We also report on the results of an exploratory (hypothesis-generating) phase 2a randomized double-blind 16-week placebo-controlled clinical trial (Clinical trial registration: NCT04001517/EudraCT #2019-001566-15) of neflamapimod in mild-to-moderate dementia with Lewy bodies (DLB), a disease in which BFCN degeneration is an important driver of disease expression. A total of 91 participants, all receiving background cholinesterase inhibitor therapy, were randomized 1:1 between neflamapimod 40 mg or matching placebo capsules (taken orally twice-daily if weight <80 kg or thrice-daily if weight >80 kg). Neflamapimod does not show an effect in the clinical study on the primary endpoint, a cognitive-test battery. On two secondary endpoints, a measure of functional mobility and a dementia rating-scale, improvements were seen that are consistent with an effect on BFCN function. Neflamapimod treatment is well-tolerated with no study drug associated treatment discontinuations. The combined preclinical and clinical observations inform on the validity of the Rab5-based pathogenic model of cholinergic degeneration and provide a foundation for confirmatory (hypothesis-testing) clinical evaluation of neflamapimod in DLB.
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Lin CL, Zheng TL, Tsou SH, Chang HM, Tseng LH, Yu CH, Hung CS, Ho YJ. Amitriptyline Improves Cognitive and Neuronal Function in a Rat Model that Mimics Dementia with Lewy Bodies. Behav Brain Res 2022; 435:114035. [PMID: 35926562 DOI: 10.1016/j.bbr.2022.114035] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 07/09/2022] [Accepted: 07/28/2022] [Indexed: 11/19/2022]
Abstract
Dementia with Lewy bodies (DLB), a highly prevalent neurodegenerative disorder, causes motor and cognitive deficits. The main pathophysiologies of DLB are glutamate excitotoxicity and accumulation of Lewy bodies comprising α-synuclein (α-syn) and β-amyloid (Aβ). Amitriptyline (AMI) promotes expression of glutamate transporter-1 and glutamate reuptake. In this study, we measured the effects of AMI on behavioral and neuronal function in a DLB rat model. We used rivastigmine (RIVA) as a positive control. To establish the DLB rat model, male Wistar rats were stereotaxically injected with recombinant adenoassociated viral vector with the SNCA gene (10μg/10μL) and Aβ (5μg/2.5μL) into the left ventricle and prefrontal cortex, respectively. AMI (10mg/kg/day, i.p.), RIVA (2mg/kg/day, i.p.), or saline was injected intraperitoneally after surgery. From the 29th day, behavioral tests were performed to evaluate the motor and cognitive functions of the rats. Immunohistochemical staining was used to assess neuronal changes. We measured the α-syn level, number of newborn cells, and neuronal density in the hippocampus and in the nigrostriatal dopaminergic system. The DLB group exhibited deficit in object recognition. Both the AMI and RIVA treatments reversed these deficits. Histologically, the DLB rats exhibited cell loss in the substantia nigra pars compacta and in the hippocampal CA1 area. AMI reduced this cell loss, but RIVA did not. In addition, the DLB rats exhibited a lower number of newborn cells and higher α-syn levels in the dentate gyrus (DG). AMI did not affect α-syn accumulation but recovered neurogenesis in the DG of the rats, whereas RIVA reversed the α-syn accumulation but did not affect neurogenesis in the rats. We suggest that AMI may have potential for use in the treatment of DLB.
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Affiliation(s)
- Chih-Li Lin
- Institute of Medicine, Department of Medical Research, Chung Shan Medical University Hospital, Chung Shan Medical University, Taichung 40201, Taiwan, ROC
| | - Ting-Lin Zheng
- Department of Psychology, Chung Shan Medical University Hospital, Chung Shan Medical University, Taichung 40201, Taiwan, ROC
| | - Sing-Hua Tsou
- Institute of Medicine, Department of Medical Research, Chung Shan Medical University Hospital, Chung Shan Medical University, Taichung 40201, Taiwan, ROC
| | - Hung-Ming Chang
- Department of Anantomy and Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan, ROC
| | - Li-Ho Tseng
- Graduate School of Environmental Management, Tajen University, Pingtung 907, Taiwan, ROC
| | - Ching-Han Yu
- Department of Pysiology, School of Medicine, Chung Shan Medical University Hospital, Chung Shan Medical University, Taichung 40201, Taiwan, ROC.
| | - Ching-Sui Hung
- Occupational Safety and Health Office, Taipei City Hospital, Taipei 10581, Taiwan, ROC.
| | - Ying-Jui Ho
- Department of Psychology, Chung Shan Medical University Hospital, Chung Shan Medical University, Taichung 40201, Taiwan, ROC.
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Phillips JR, Matar E, Ehgoetz Martens KA, Moustafa AA, Halliday GM, Lewis SJ. An adaptive measure of visuospatial impairment in Dementia with Lewy Bodies. Mov Disord Clin Pract 2022; 9:619-627. [PMID: 35844276 PMCID: PMC9274351 DOI: 10.1002/mdc3.13488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 03/07/2022] [Accepted: 03/26/2022] [Indexed: 11/13/2022] Open
Abstract
Background Dementia with Lewy bodies (DLB) is a common cause of dementia with poor prognosis and high hospitalization rates. DLB is frequently misdiagnosed, with clinical features that overlap significantly with other diseases including Parkinson's disease (PD). Clinical instruments that discriminate and track the progression of cognitive impairment in DLB are needed. Objectives The current study was designed to assess the utility of a mental rotation (MR) task for assessing visuospatial impairments in early DLB. Methods Accuracy of 22 DLB patients, 22 PD patients and 22 age‐matched healthy controls in the MR task were compared at comparing shapes with 0°, 45° and 90° rotations. Results Healthy controls and PD patients performed at similar levels while the DLB group were significantly impaired. Further, impairment in the visuospatial and executive function measures correlated with MR poor outcomes. Conclusion These findings support the MR task as an objective measure of visuospatial impairment with the ability to adjust difficulty to suit impairments in a DLB population. This would be a useful tool within clinical trials.
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Affiliation(s)
- Joseph R. Phillips
- Faculty of Medicine and Health Brain and Mind Centre and Central Clinical School, University of Sydney, Camperdown Sydney Australia
- School of Psychology & Marcs Institute for Brain and Behaviour Western Sydney University Sydney New South Wales Australia
| | - Elie Matar
- Faculty of Medicine and Health Brain and Mind Centre and Central Clinical School, University of Sydney, Camperdown Sydney Australia
- Dementia and Movement Disorders Laboratory, Brain and Mind Centre University of Sydney Sydney New South Wales Australia
| | - Kaylena A. Ehgoetz Martens
- Faculty of Medicine and Health Brain and Mind Centre and Central Clinical School, University of Sydney, Camperdown Sydney Australia
- Department of Kinesiology, Faculty of Health University of Waterloo Waterloo Ontario Canada
| | - Ahmed A. Moustafa
- Faculty of Medicine and Health Brain and Mind Centre and Central Clinical School, University of Sydney, Camperdown Sydney Australia
- School of Psychology & Marcs Institute for Brain and Behaviour Western Sydney University Sydney New South Wales Australia
| | - Glenda M. Halliday
- Faculty of Medicine and Health Brain and Mind Centre and Central Clinical School, University of Sydney, Camperdown Sydney Australia
- Dementia and Movement Disorders Laboratory, Brain and Mind Centre University of Sydney Sydney New South Wales Australia
| | - Simon J.G. Lewis
- Faculty of Medicine and Health Brain and Mind Centre and Central Clinical School, University of Sydney, Camperdown Sydney Australia
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Elder GJ, Colloby SJ, Firbank MJ, Taylor JP. Quantifying test-retest reliability of repeated objective attentional measures in Lewy body dementia. J Neurol 2022; 269:3605-3613. [PMID: 35084558 PMCID: PMC9217900 DOI: 10.1007/s00415-022-10977-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 01/12/2022] [Accepted: 01/18/2022] [Indexed: 11/29/2022]
Abstract
Objective cognitive impairment is a feature of Lewy body dementia (LBD), and computerised attentional tasks are commonly used as outcome measures in interventional trials. However, the reliability of these measures, in the absence of interventions, are unknown. This study examined the reliability of these attentional measures at short-term and longer-term follow-up stages. LBD patients (n = 36) completed computerised attentional tasks [simple and choice reaction time, and digit vigilance (SRT, CRT, DV)] at short-term (Day 0–Day 5) and longer-term (4 and 12 weeks) follow-up. Intra-class correlations (ICCs) were calculated to assess test–retest reliability. At short-term, the reciprocal SRT, CRT and DV mean reaction time to correct answers, the reciprocal DV coefficient of variation, and reciprocal power of attention (PoA) all showed excellent levels of reliability (all ICCs > 0.90). The reciprocal PoA showed the highest level of reliability (ICC = 0.978). At longer-term follow-up, only the reciprocal PoA had excellent levels of reliability (ICC = 0.927). Reciprocal SRT, CRT and DV reaction time to correct answers, and the CRT coefficient of variation values, showed good levels of test–retest reliability (ICCs ≥ 0.85). Contrary to expectations, most attentional measures demonstrated high levels of test–retest reliability at both short-term and longer-term follow-up time points. The reciprocal PoA composite measure demonstrated excellent levels of test–retest reliability, both in the short-term and long-term. This indicates that objective attentional tasks are suitable outcome measures in LBD studies and that the composite PoA measure may offer the highest levels of reliability.
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Affiliation(s)
- Greg J Elder
- Northumbria Sleep Research, Department of Psychology, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, NE1 8ST, UK. .,Translational and Clinical Research Institute, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, NE4 5PL, UK.
| | - Sean J Colloby
- Translational and Clinical Research Institute, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, NE4 5PL, UK
| | - Michael J Firbank
- Translational and Clinical Research Institute, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, NE4 5PL, UK
| | - John-Paul Taylor
- Translational and Clinical Research Institute, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, NE4 5PL, UK
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Patel B, Irwin DJ, Kaufer D, Boeve BF, Taylor A, Armstrong MJ. Outcome Measures for Dementia With Lewy Body Clinical Trials: A Review. Alzheimer Dis Assoc Disord 2022; 36:64-72. [PMID: 34393189 PMCID: PMC8847491 DOI: 10.1097/wad.0000000000000473] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 07/07/2021] [Indexed: 01/03/2023]
Abstract
BACKGROUND Dementia with Lewy bodies (DLB) is one of the most common degenerative dementias. Clinical trials for individuals with DLB are increasing. We aimed to identify commonly used outcome measures for trials in DLB. METHODS A pragmatic literature search of PubMed and clinicaltrials.gov identified interventional studies including populations with DLB. Studies were included if they enrolled participants with DLB and met the National Institutes of Health criteria for a clinical trial. Data were collected using standardized forms. Outcome measures were categorized according to core and supportive features of DLB. RESULTS After de-duplication, 58 trials were identified. The most common cognitive outcome measures were the Mini Mental State Examination (n=24) and Cognitive Drug Research computerized Assessment System (n=5). The Clinician's Assessment of Fluctuations was the most commonly used measure for fluctuations (n=4). Over half of studies used the Neuropsychiatric Inventory to assess behavioral symptoms (n=31). The Unified Parkinson's Disease Rating Scale was frequently used for motor assessment (n=23). CONCLUSIONS AND RELEVANCE Clinical trial outcomes used in DLB are rarely validated in this population and some lack face validity. There is a need to validate existing scales in DLB and develop DLB-specific outcome measures.
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Affiliation(s)
- Bhavana Patel
- Department of Neurology, University of Florida College of Medicine, McKnight Brain Institute
| | | | - Daniel Kaufer
- Departments of Neurology and Psychiatry, University of North Carolina
| | - Bradley F. Boeve
- Department of Neurology and Center for Sleep Medicine, Mayo Clinic Rochester
| | - Angela Taylor
- Lewy Body Dementia Association
- Comprehensive Center for Brain Health, Department of Neurology, University of Miami Miller School of Medicine
| | - Melissa J. Armstrong
- Department of Neurology, University of Florida College of Medicine, McKnight Brain Institute
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Lang FM, Kwon DY, Aarsland D, Boeve B, Tousi B, Harnett M, Mo Y, Noel Sabbagh M. An international, randomized, placebo-controlled, phase 2b clinical trial of intepirdine for dementia with Lewy bodies (HEADWAY-DLB). ALZHEIMER'S & DEMENTIA (NEW YORK, N. Y.) 2021; 7:e12171. [PMID: 34189249 PMCID: PMC8215076 DOI: 10.1002/trc2.12171] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 03/08/2021] [Accepted: 03/14/2021] [Indexed: 12/20/2022]
Abstract
INTRODUCTION A phase 2b clinical trial, HEADWAY-DLB, was performed to assess treatment with intepirdine, a serotonin receptor antagonist, in patients with dementia with Lewy bodies (DLB). METHODS HEADWAY-DLB was a multinational, double-blind, randomized, placebo-controlled study. Two hundred sixty-nine DLB patients were randomized to receive placebo, 70 mg/day intepirdine, or 35 mg/day intepirdine over 24 weeks. The primary endpoint was change from baseline to week 24 on the Unified Parkinson's Disease Rating Scale-Part III (UPDRS-III). RESULTS Both intepirdine groups did not demonstrate significant benefits over placebo at 24 weeks on the UPDRS-III (35 mg/day: P = .1580, 70 mg/day: P = .6069). All other endpoints were not significant. Intepirdine was well tolerated, with a slightly higher incidence of gastrointestinal adverse events observed in the intepirdine groups versus placebo. DISCUSSION Intepirdine treatment did not lead to improvements over placebo in patients with DLB. As one of the largest DLB studies to date, HEADWAY-DLB demonstrates that international trials for DLB are feasible within a reasonable timeframe.
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Affiliation(s)
- Frederick M. Lang
- Axovant SciencesNew YorkNew YorkUSA
- Roivant SciencesInc. (Roivant)New YorkNew YorkUSA
| | - Daniel Y. Kwon
- Axovant SciencesNew YorkNew YorkUSA
- Roivant SciencesInc. (Roivant)New YorkNew YorkUSA
| | - Dag Aarsland
- Centre for Age‐Related Medicine (SESAM)Stavanger University HospitalStavangerNorway
- Institute of PsychiatryPsychologyand NeuroscienceKing's College LondonLondonUK
| | - Brad Boeve
- Department of NeurologyMayo ClinicRochesterMinnesotaUSA
| | - Babak Tousi
- Cleveland ClinicLou Ruvo Center for Brain HealthClevelandOhioUSA
| | | | - Yi Mo
- Axovant SciencesNew YorkNew YorkUSA
| | - Marwan Noel Sabbagh
- Department of NeurologyUniversity of Nevada (NLV) and Cleveland Clinic Lou Ruvo Center for Brain HealthLas VegasNevadaUSA
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Abstract
Acute presentation of new movement disorders and acute decompensation of chronic movement disorders are uncommon but potentially life-threatening. Inadvertent or purposeful overdose of many psychiatric medications can result in acute life-threatening movement disorders including serotonin syndrome, neuroleptic malignant syndrome, and malignant catatonia. Early withdrawal of potentiating medications, treatment with benzodiazepines and other diagnosis-specific drugs, and providing appropriate supportive care including airway and breathing management, hemodynamic stabilization, fluid resuscitation, and renal support including possible hemodialysis are the mainstays of acute management. Many of these conditions require admission to the neurologic intensive care unit.
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Orlović I, Bartolović M, Marušić K, Vlahović D, Šiško Markoš I, Karlović D, Peitl V. THE ENIGMA OF LEWY BODY DEMENTIA: A CASE REPORT. Acta Clin Croat 2020; 59:771-776. [PMID: 34285451 PMCID: PMC8253061 DOI: 10.20471/acc.2020.59.04.27] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Accepted: 11/12/2019] [Indexed: 11/24/2022] Open
Abstract
Lewy body dementia is a progressive neurodegenerative disease and is considered to be the second most common cause of dementia in the elderly. Because of the complexity of clinical presentation, it is often misdiagnosed and mistaken for other dementias, which may result in administering inappropriate therapy, and thus worsening of the patient condition. We reviewed a case of a 71-year-old patient whose clinical presentation gradually occurred with complex visual hallucinations, atypical extrapyramidal motor symptoms, fluctuating cognitive impairments with delirious episodes, and oscillating syncope. Depressive mood, impaired daily functioning and sensitivity to antipsychotics were also noted. Extensive diagnostic workup was performed with neuropsychological testing and use of single-photon emission computerized tomography. Considering the clinical presentation and diagnostic procedures performed, the diagnosis of Lewy body dementia was set and pharmacotherapy was revised. We discuss the importance of taking overall clinical presentation and diagnostic treatment in consideration and applying appropriate therapy to slow down the progression of the disease and exacerbation of the patient's psychological functions.
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Affiliation(s)
- Ivona Orlović
- 1Department of Psychiatry, Sestre milosrdnice University Hospital Centre, Zagreb, Croatia; 2Department of Oncology and Nuclear Medicine, Sestre milosrdnice University Hospital Centre, Zagreb, Croatia; 3Catholic University of Croatia, Zagreb, Croatia; 4School of Dental Medicine, University of Zagreb, Zagreb, Croatia
| | - Matija Bartolović
- 1Department of Psychiatry, Sestre milosrdnice University Hospital Centre, Zagreb, Croatia; 2Department of Oncology and Nuclear Medicine, Sestre milosrdnice University Hospital Centre, Zagreb, Croatia; 3Catholic University of Croatia, Zagreb, Croatia; 4School of Dental Medicine, University of Zagreb, Zagreb, Croatia
| | - Katarina Marušić
- 1Department of Psychiatry, Sestre milosrdnice University Hospital Centre, Zagreb, Croatia; 2Department of Oncology and Nuclear Medicine, Sestre milosrdnice University Hospital Centre, Zagreb, Croatia; 3Catholic University of Croatia, Zagreb, Croatia; 4School of Dental Medicine, University of Zagreb, Zagreb, Croatia
| | - Darko Vlahović
- 1Department of Psychiatry, Sestre milosrdnice University Hospital Centre, Zagreb, Croatia; 2Department of Oncology and Nuclear Medicine, Sestre milosrdnice University Hospital Centre, Zagreb, Croatia; 3Catholic University of Croatia, Zagreb, Croatia; 4School of Dental Medicine, University of Zagreb, Zagreb, Croatia
| | - Ines Šiško Markoš
- 1Department of Psychiatry, Sestre milosrdnice University Hospital Centre, Zagreb, Croatia; 2Department of Oncology and Nuclear Medicine, Sestre milosrdnice University Hospital Centre, Zagreb, Croatia; 3Catholic University of Croatia, Zagreb, Croatia; 4School of Dental Medicine, University of Zagreb, Zagreb, Croatia
| | - Dalibor Karlović
- 1Department of Psychiatry, Sestre milosrdnice University Hospital Centre, Zagreb, Croatia; 2Department of Oncology and Nuclear Medicine, Sestre milosrdnice University Hospital Centre, Zagreb, Croatia; 3Catholic University of Croatia, Zagreb, Croatia; 4School of Dental Medicine, University of Zagreb, Zagreb, Croatia
| | - Vjekoslav Peitl
- 1Department of Psychiatry, Sestre milosrdnice University Hospital Centre, Zagreb, Croatia; 2Department of Oncology and Nuclear Medicine, Sestre milosrdnice University Hospital Centre, Zagreb, Croatia; 3Catholic University of Croatia, Zagreb, Croatia; 4School of Dental Medicine, University of Zagreb, Zagreb, Croatia
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Tahami Monfared AA, Desai M, Hughes R, Lucherini S, Yi Y, Perry R. Treatment Options for Dementia with Lewy Bodies: A Network Meta-Analysis of Randomised Control Trials. Neurol Ther 2020; 9:521-534. [PMID: 32495063 PMCID: PMC7606367 DOI: 10.1007/s40120-020-00198-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Indexed: 11/05/2022] Open
Abstract
INTRODUCTION Dementia with Lewy bodies (DLB) is the third most common type of dementia after Alzheimer's disease (AD) and vascular dementia. Treatment is targeted at specific disease manifestations/symptoms. While donepezil is approved for the treatment of DLB in Japan, to date no other treatment has been approved for this indication anywhere in the world. Notwithstanding, many of the medications that are approved for AD are widely used in the treatment of DLB with varying degrees of success. Consequently, clinical evidence is limited, and there is a need to understand the comparative efficacy and safety of currently used therapies for DLB. The aim of this study was to conduct a network meta-analysis (NMA) to evaluate the outcomes of the available treatment options based on currently used trial endpoints. METHODS Using data from a previously published systematic review, we conducted an NMA to investigate the efficacy and safety of treatments in patients with DLB. Networks were based on change from baseline of efficacy endpoints (Mini-Mental State Examination; Neuropsychiatric Inventory; Unified Parkinson's Disease Rating Scale) and rate of safety events (overall adverse events [AEs]; discontinuations; discontinuations due to AEs; psychiatric events). RESULTS Focused around a common treatment option of placebo, the NMA comprised studies on donepezil, rivastigmine, memantine and quetiapine. Donepezil 3 mg, 5 mg and 10 mg doses were compared against each other and placebo. Overall, donepezil consistently performed better than the alternative treatments when compared to placebo for all efficacy and safety endpoints. However, the small sample size and/or heterogeneity of the studies led to uncertainty, resulting in no statistically significant differences favouring any treatment above another or placebo. CONCLUSION Despite the lack of statistical significance, when assessing the efficacy and safety outcomes for each drug in the evidence network, donepezil appeared to have a more favourable overall benefit/risk profile for patients with DLB. Further comparative trials are required to improve understanding of the true difference between existing and potential future treatment options.
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Affiliation(s)
- Amir A Tahami Monfared
- Eisai Inc., Woodcliff Lake, NJ, USA.
- Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, QC, Canada.
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Luo M, Mu R, Liu JF, Bai FH. Novel computerized psychometric tests as primary screening tools for the diagnosis of minimal hepatic encephalopathy. World J Clin Cases 2020; 8:3377-3389. [PMID: 32913845 PMCID: PMC7457114 DOI: 10.12998/wjcc.v8.i16.3377] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 05/05/2020] [Accepted: 07/14/2020] [Indexed: 02/06/2023] Open
Abstract
Minimal hepatic encephalopathy (MHE) is a critical neurocognitive complication of decompensated liver cirrhosis and portosystemic shunting, which results in a wide range of cognitive deficits including impairments in working attention, psychomotor speed, and executive function. Current guidelines have recommended paper-and-pencil psychometric tests for the diagnosis of MHE. Most high-risk cirrhotic patients are required to be examined; however, paper-and-pencil psychometric tests are neither convenient nor rapid to perform in the clinic. Recently, novel computerized psychometric tests, including the inhibitory control test, EncephalApp Stroop App, and critical flicker frequency, have been proven to be rapid, effective, and convenient methods for screening MHE in clinical practice and for identifying high-risk cirrhotic patients for further validation using rigid neuropsychometric examinations. However, diagnostic accuracy of these tests is influenced by educational background, age, and cultural differences. This review summarizes clinical evidence of the application of novel computerized psychometric tests for screening MHE.
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Affiliation(s)
- Ming Luo
- Department of Gastroenterology, People’s Hospital of Ningxia Hui Autonomous Region, Yinchuan 750021, Ningxia Hui Autonomous Region, China
| | - Rui Mu
- Department of Gastroenterology, People’s Hospital of Ningxia Hui Autonomous Region, Yinchuan 750021, Ningxia Hui Autonomous Region, China
| | - Jian-Fang Liu
- Department of Gastroenterology, People’s Hospital of Ningxia Hui Autonomous Region, Yinchuan 750021, Ningxia Hui Autonomous Region, China
| | - Fei-Hu Bai
- Department of Gastroenterology, People’s Hospital of Ningxia Hui Autonomous Region, Yinchuan 750021, Ningxia Hui Autonomous Region, China
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Pask S, Dell'Olio M, Murtagh FEM, Boland JW. The Effects of Opioids on Cognition in Older Adults With Cancer and Chronic Noncancer Pain: A Systematic Review. J Pain Symptom Manage 2020; 59:871-893.e1. [PMID: 31678462 DOI: 10.1016/j.jpainsymman.2019.10.022] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Revised: 10/17/2019] [Accepted: 10/21/2019] [Indexed: 01/08/2023]
Abstract
CONTEXT Opioids are prescribed to manage moderate-to-severe pain and can be used with older adults; however, they may lead to several adverse effects, including cognitive impairment. OBJECTIVES To identify, appraise, and synthesize evidence on the impact of opioids on cognition in older adults with cancer/chronic noncancer pain, and screening tools/neuropsychological assessments used to detect opioid-induced cognitive impairment. METHODS A systematic literature review following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (international prospective register of systematic reviews registration: CRD42018092943). MEDLINE, EMBASE, PsycINFO, CINAHL, Cochrane Library, and Web of Science were searched up to December 2018. Randomized controlled trials, quasi-experimental studies, and observational studies of adults aged 65 years and older with cancer/chronic noncancer pain taking opioids were included. A narrative synthesis was conducted. RESULTS From 4036 records, 10 met inclusion criteria. Five studies used one screening tool, and five studies used a range of neuropsychological assessments; assessing 14 cognitive domains. Most studies demonstrated no effect of opioid use on cognitive domains, whereas four studies showed mixed effects. In particular, attention, language, orientation, psychomotor function, and verbal working/delayed episodic memory were worsened. Changes to cognitive function were predominantly observed in studies with higher mean doses of opioids (120-190.7mg oral morphine equivalent daily dose). CONCLUSION Both improvements and impairments to cognition were observed in studies with higher mean opioid doses. In clinical practice, a brief screening tool assessing attention, language, orientation, psychomotor function, and verbal working/delayed episodic memory may be beneficial to detect worsening cognition in older adults with chronic pain using opioids.
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Affiliation(s)
- Sophie Pask
- Wolfson Palliative Care Research Centre, Hull York Medical School, University of Hull, Hull, United Kingdom.
| | - Myriam Dell'Olio
- Academy of Primary Care, Hull York Medical School, University of Hull, Hull, United Kingdom
| | - Fliss E M Murtagh
- Wolfson Palliative Care Research Centre, Hull York Medical School, University of Hull, Hull, United Kingdom
| | - Jason W Boland
- Wolfson Palliative Care Research Centre, Hull York Medical School, University of Hull, Hull, United Kingdom
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Luo M, Ma P, Li L, Cao WK. Advances in psychometric tests for screening minimal hepatic encephalopathy: From paper-and-pencil to computer-aided assessment. TURKISH JOURNAL OF GASTROENTEROLOGY 2020; 30:398-407. [PMID: 31060994 DOI: 10.5152/tjg.2019.18226] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Minimal hepatic encephalopathy (MHE) is a major neuropsychiatric complication of liver cirrhosis and portosystemic shunting. Although MHE produces a spectrum of cognitive impairments in the domains of short-term attention, working memory, and executive function, it generally does not present with obvious clinical manifestation on conventional assessments. Paper-and-pencil psychometric tests, such as the psychometric hepatic encephalopathy score and the repeatable battery for the assessment of neuropsychological status, are recommended to diagnose MHE. However, these tests are neither rapid nor convenient to use in practice. To facilitate repeated testing in clinic and follow-up, computer-aided psychometric tests, such as the scan test, Cognitive Drug Research assessment battery, inhibitory control test, EncephalApp Stroop App, and critical flicker frequency, have been used to screen for MHE among patients with liver cirrhosis. The aim of this review was to describe the progression from the utility of paper-and-pencil to computer-aided psychometric tests for MHE screening in clinical practice.
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Affiliation(s)
- Ming Luo
- Department of Gastroenterology, Ningxia People's Hospital, Ningxia, China
| | - Ping Ma
- Department of Hepatology, Tianjin Second People's Hospital, Tianjin, China
| | - Lei Li
- Department of Hepatology, Tianjin Second People's Hospital, Tianjin, China
| | - Wu-Kui Cao
- Tianjin Liver Disease Institute, Tianjin Second People's Hospital, Tianjin, China
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Chabran E, Noblet V, Loureiro de Sousa P, Demuynck C, Philippi N, Mutter C, Anthony P, Martin-Hunyadi C, Cretin B, Blanc F. Changes in gray matter volume and functional connectivity in dementia with Lewy bodies compared to Alzheimer's disease and normal aging: implications for fluctuations. Alzheimers Res Ther 2020; 12:9. [PMID: 31907068 PMCID: PMC6945518 DOI: 10.1186/s13195-019-0575-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Accepted: 12/23/2019] [Indexed: 12/02/2022]
Abstract
BACKGROUND Fluctuations are one of the core clinical features characterizing dementia with Lewy bodies (DLB). They represent a determining factor for its diagnosis and strongly impact the quality of life of patients and their caregivers. However, the neural correlates of this complex symptom remain poorly understood. This study aimed to investigate the structural and functional changes in DLB patients, compared to Alzheimer's disease (AD) patients and healthy elderly subjects, and their potential links with fluctuations. METHODS Structural and resting-state functional MRI data were collected from 92 DLB patients, 70 AD patients, and 22 control subjects, who also underwent a detailed clinical examination including the Mayo Clinic Fluctuation Scale. Gray matter volume changes were analyzed using whole-brain voxel-based morphometry, and resting-state functional connectivity was investigated using a seed-based analysis, with regions of interest corresponding to the main nodes of the salience network (SN), frontoparietal network (FPN), dorsal attention network (DAN), and default mode network (DMN). RESULTS At the structural level, fluctuation scores in DLB patients did not relate to the atrophy of insular, temporal, and frontal regions typically found in this pathology, but instead showed a weak correlation with more subtle volume reductions in different regions of the cholinergic system. At the functional level, the DLB group was characterized by a decreased connectivity within the SN and attentional networks, while the AD group showed decreases within the SN and DMN. In addition, higher fluctuation scores in DLB patients were correlated to a greater connectivity of the SN with the DAN and left thalamus, along with a decreased connectivity between the SN and DMN, and between the right thalamus and both the FPN and DMN. CONCLUSIONS Functional connectivity changes, rather than significant gray matter loss, could play an important role in the emergence of fluctuations in DLB. Notably, fluctuations in DLB patients appeared to be related to a disturbed external functional connectivity of the SN, which may lead to less relevant transitions between different cognitive states in response to internal and environmental stimuli. Our results also suggest that the thalamus could be a key region for the occurrence of this symptom.
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Affiliation(s)
- Eléna Chabran
- ICube Laboratory UMR 7357 and FMTS (Fédération de Médecine Translationnelle de Strasbourg), Team IMIS, University of Strasbourg and CNRS, Strasbourg, France
| | - Vincent Noblet
- ICube Laboratory UMR 7357 and FMTS (Fédération de Médecine Translationnelle de Strasbourg), Team IMIS, University of Strasbourg and CNRS, Strasbourg, France
| | - Paulo Loureiro de Sousa
- ICube Laboratory UMR 7357 and FMTS (Fédération de Médecine Translationnelle de Strasbourg), Team IMIS, University of Strasbourg and CNRS, Strasbourg, France
| | - Catherine Demuynck
- CM2R (Research and Resources Memory Centre), Geriatrics Department, University Hospitals of Strasbourg, Geriatric Day Hospital and Neuropsychology Unit, Strasbourg, France
| | - Nathalie Philippi
- ICube Laboratory UMR 7357 and FMTS (Fédération de Médecine Translationnelle de Strasbourg), Team IMIS, University of Strasbourg and CNRS, Strasbourg, France
- CM2R (Research and Resources Memory Centre), Geriatrics Department, University Hospitals of Strasbourg, Geriatric Day Hospital and Neuropsychology Unit, Strasbourg, France
| | - Catherine Mutter
- INSERM Centre d’Investigation Clinique 1434, University Hospitals of Strasbourg, Strasbourg, France
| | - Pierre Anthony
- General Hospital Centre, Geriatrics Department, CM2R, Geriatric Day Hospital, Colmar, France
| | - Catherine Martin-Hunyadi
- CM2R (Research and Resources Memory Centre), Geriatrics Department, University Hospitals of Strasbourg, Geriatric Day Hospital and Neuropsychology Unit, Strasbourg, France
| | - Benjamin Cretin
- ICube Laboratory UMR 7357 and FMTS (Fédération de Médecine Translationnelle de Strasbourg), Team IMIS, University of Strasbourg and CNRS, Strasbourg, France
- CM2R (Research and Resources Memory Centre), Geriatrics Department, University Hospitals of Strasbourg, Geriatric Day Hospital and Neuropsychology Unit, Strasbourg, France
| | - Frédéric Blanc
- ICube Laboratory UMR 7357 and FMTS (Fédération de Médecine Translationnelle de Strasbourg), Team IMIS, University of Strasbourg and CNRS, Strasbourg, France
- CM2R (Research and Resources Memory Centre), Geriatrics Department, University Hospitals of Strasbourg, Geriatric Day Hospital and Neuropsychology Unit, Strasbourg, France
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Tahami Monfared AA, Meier G, Perry R, Joe D. Burden of Disease and Current Management of Dementia with Lewy Bodies: A Literature Review. Neurol Ther 2019; 8:289-305. [PMID: 31512165 PMCID: PMC6858913 DOI: 10.1007/s40120-019-00154-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Indexed: 11/12/2022] Open
Abstract
INTRODUCTION A significant proportion of dementia is concretely estimated to be attributable to dementia with Lewy bodies (DLB)-one of the most common types of progressive dementia; however, there is a paucity of literature on this disease. We aimed to examine available evidence to gain a better understanding of its treatment landscape, clinical management, and disease burden. METHODS A systematic literature review captured any DLB studies that report on randomised controlled trials (RCTs), epidemiology, disease progression, and economic data. An additional targeted literature review captured studies reporting on clinical management and quality of life (QoL) in this disease. Publication date was limited to 1 January 2007-26 March 2018, with the exception for RCTs, where no time restrictions were applied. FINDINGS Of the 3486 studies initially identified, 55 studies were eligible for inclusion. The studies were mainly from Europe (n = 29), the USA (n = 9), and Japan (n = 8). Mini-Mental State Examination and Neuropsychiatric Inventory scores were the most commonly reported clinical outcomes in RCTs (n = 14). The most frequently identified interventions reported in RCTs were donepezil and memantine. Patients with DLB typically reported worse outcomes in relation to efficacy and safety, cognitive impairment, survival, and QoL compared with those with Alzheimer's disease (AD). Additionally, patients with DLB were associated with higher hospitalisation rates and cost of care. Furthermore, there is a reliance on a small number of consensus guidelines. Of these, only one set of guidelines (DLB Consortium) was developed specifically for DLB. CONCLUSION The paucity of data indicates an unmet need in this therapy area. Although several studies look into the clinical and pathological aspects of DLB, consensus guidelines and studies on healthcare utilisation in patients with dementia have largely focused on AD. Additionally, most of the findings were made in comparison with AD. FUNDING Eisai Inc.
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Affiliation(s)
- Amir Abbas Tahami Monfared
- Eisai Inc., Woodcliff Lake, USA.
- Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Canada.
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Eldufani J, Blaise G. The role of acetylcholinesterase inhibitors such as neostigmine and rivastigmine on chronic pain and cognitive function in aging: A review of recent clinical applications. ALZHEIMER'S & DEMENTIA (NEW YORK, N. Y.) 2019; 5:175-183. [PMID: 31194017 PMCID: PMC6551376 DOI: 10.1016/j.trci.2019.03.004] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Chronic pain in patients with Alzheimer's disease or dementia is a complex issue in the medical field; these patients suffer from the common causes of chronic pain, especially in geriatric medicine. To ensure the correct type and level of given treatment, medical care should be taken to avoid the contribution of chronic pain and cognitive impairment in the elderly population. Acetylcholinesterase inhibitors (AChE-Is) have been proven as an efficient therapeutic resource for significant improvement in dementia of Alzheimer's disease and chronic pain due to the fact that cholinergic deficit is considered as an early finding in cognitive impairment and persisting pain. Some AChE-Is are investigated here in terms of treatment of dementia and chronic pain management. Neostigmine has been used as an adjunct analgesic in the postoperative period and in combination with other analgesic medications in an intrathecal approach. Rivastigmine has, over the past ten years, become the approved agent for the management of dementia of mild to moderate Alzheimer's disease and has gained approval for treating different types of non-Alzheimer's dementia. In this review, we will focus on the two types of AChE-Is (rivastigmine and neostigmine) in the development of their clinical use and their respective mechanisms of actions on improving cognitive function and managing chronic pain.
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Affiliation(s)
- Jabril Eldufani
- Department of Medicine, Montreal University, Montreal, Quebec, Canada
- Department of Medicine, Elmergib University, El-khums, Libya
| | - Gilbert Blaise
- Department of Medicine, Montreal University, Montreal, Quebec, Canada
- Department of Anesthesiology and Pain Management, University Hospital of Montreal (CHUM), Montreal, Quebec, Canada
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Moretti DV. Available and future treatments for atypical parkinsonism. A systematic review. CNS Neurosci Ther 2019; 25:159-174. [PMID: 30294976 PMCID: PMC6488913 DOI: 10.1111/cns.13068] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Revised: 09/01/2018] [Accepted: 09/05/2018] [Indexed: 01/02/2023] Open
Abstract
AIMS Success in treating patients with atypical parkinsonian syndromes, namely progressive supranuclear palsy (PSP), cortico-basal degeneration (CBD), multiple system atrophy (MSA), Parkinson's disease with dementia (PDD), and Lewy body dementia with (LBD), remains exceedingly low. The present work overviews the most influential research literature collected on MEDLINE, ISI Web of Science, Cochrane Library, and Scopus for available treatment in atypical parkinsonisms without time restriction. DISCUSSION Transdermal rotigotine, autologous mesenchymal stem cells, tideglusib, and coenzyme Q10 along with donepezil, rivastigmine, memantine, and the deep brain stimulation have shown some benefits in alleviating symptoms in APS. Moreover, many new clinical trials are ongoing testing microtubule stabilizer, antitau monoclonal antibody, tau acetylation inhibition, cell replacement, selective serotonin reuptake inhibitor, active immunization, inhibition of toxic α-synuclein oligomers formation, and inhibition of microglia. CONCLUSION A detailed knowledge of the pathological mechanism underlying the disorders is needed, and disease-modifying therapies are required to offer better therapeutic options to physician and caregivers of APS patients.
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Elder GJ, Colloby SJ, Firbank MJ, McKeith IG, Taylor JP. Consecutive sessions of transcranial direct current stimulation do not remediate visual hallucinations in Lewy body dementia: a randomised controlled trial. Alzheimers Res Ther 2019; 11:9. [PMID: 30658705 PMCID: PMC6339360 DOI: 10.1186/s13195-018-0465-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Accepted: 12/27/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND Complex visual hallucinations are common in Lewy body dementia (LBD) and can cause significant patient and caregiver distress. Current treatments are primarily pharmacological in nature and have limited efficacy and associated side effects. The objective of this study was to assess the effects of consecutive sessions of transcranial direct current stimulation (tDCS) on visual hallucination frequency and severity in LBD, at short-term and long-term follow-up stages. METHODS The study was a randomised, double-blind, placebo-controlled trial involving 40 participants with LBD (Mage = 75.52 years, SDage = 8.69 years) which was conducted at a single site between November 2013 and December 2017. Participants received two consecutive 20-min sessions of active (0.048 mA/cm2) or placebo tDCS, separated by a 30-min break, over 5 consecutive days. The anodal electrode was applied to the right parietal cortex (P4) and the cathodal electrode was applied to the occipital cortex (Oz). The primary outcome measure was the Neuropsychiatric Inventory (NPI) hallucinations subscale, as completed by a caregiver/informant at baseline and day 5 (short-term) follow-up, and month 1 and month 3 (long-term) follow-up. Secondary outcome measures included visual cortical excitability, as measured using transcranial magnetic stimulation, computerised attentional and visuoperceptual tasks, and measures of global cognition and cognitive fluctuations. RESULTS Complete study data were obtained from 36 participants. There was an overall improvement in visual hallucinations (NPI) for both groups at day 5 relative to baseline, with a medium-to-large effect size; however, compared to placebo, active tDCS did not result in any improvements in visual hallucinations (NPI) at day 5 relative to baseline, or at month 1 or month 3 follow-up time points. Additionally, comparisons of secondary outcome measures showed that active tDCS did not result in any improvements on any measure (visual cortical excitability, attentional and visuoperceptual tasks or cognitive measures) at any time point. CONCLUSIONS Repeated consecutive sessions of parietal anodal tDCS, and occipital cathodal tDCS, do not improve visual hallucinations or visuoperceptual function, or alter visual cortical excitability in LBD. TRIAL REGISTRATION ISRCTN, ISRCTN40214749 . Registered on 25 October 2013.
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Affiliation(s)
- Greg J. Elder
- Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, NE4 5PL UK
- Department of Psychology, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, NE1 8ST UK
| | - Sean J. Colloby
- Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, NE4 5PL UK
| | - Michael J. Firbank
- Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, NE4 5PL UK
| | - Ian G. McKeith
- Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, NE4 5PL UK
| | - John-Paul Taylor
- Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, NE4 5PL UK
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Meng YH, Wang PP, Song YX, Wang JH. Cholinesterase inhibitors and memantine for Parkinson's disease dementia and Lewy body dementia: A meta-analysis. Exp Ther Med 2018; 17:1611-1624. [PMID: 30783428 PMCID: PMC6364145 DOI: 10.3892/etm.2018.7129] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Accepted: 11/30/2018] [Indexed: 12/01/2022] Open
Abstract
Recently, several randomized controlled trials on the use of cholinesterase inhibitors or memantine as treatments for cognitive impairment in Parkinson's disease (CIND-PD), Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB) were completed. The present study provided a meta-analysis of these studies to evaluate the efficacy of cholinesterase inhibitors and memantine on CIND-PD, PDD and DLB. The Cochrane Library, Pubmed, Embase and Web of Science databases were searched to retrieve eligible studies. As primary efficacy outcomes, cognitive function, global impression, behavioral symptoms and motor function were selected, while falling and adverse events were regarded as safety outcomes. Of note, domain-specific cognitive function was assessed as a primary efficacy outcome and falling as a safety outcome, which, to the best of our knowledge, has not been studied previously in CIND-PD, PDD and DLB. A total of 15 trials were included in the present meta-analysis. The results revealed that treatment with cholinesterase inhibitors resulted in improvements in cognitive function, the clinician's global impression, behavioral symptoms and motor function, in accordance with the results of previous studies. Furthermore, it was revealed that cholinesterase inhibitors had a significant effect on attention, processing speed, executive functions, memory and language; however, they did not improve visuospatial cognition compared with placebos. Memantine had a significant effect on attention, processing speed and executive functions. In addition, cholinesterase inhibitors and memantine did not significantly reduce falling. It was demonstrated that an increased number of adverse events occurred in the pooled cholinesterase inhibitors and memantine group, compared with that in the placebo group (risk ratio (RR)=1.09; 95% confidence interval (CI): 1.04–1.16; P=0.001); however, in the subgroup analysis, only the rivastigmine group experienced significantly more adverse events than the placebo group (85 vs. 73%; RR=1.18; 95% CI: 1.08–1.29; P=0.0001), but donepezil and memantine did not produce any significant adverse events. In conclusion, cholinesterase inhibitors and memantine have an effect not only on global cognitive function and motor function, but also on attention, processing speed, executive functions, memory and language. However, careful monitoring of the side effects of rivastigmine may be required. Further clinical trials are required to verify these conclusions.
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Affiliation(s)
- Yan-Hong Meng
- Department of Graduate School, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China.,Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
| | - Pan-Pan Wang
- Department of Graduate School, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China.,Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
| | - Ya-Xue Song
- Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China.,Department of Graduate School, Hebei North University, Zhangjiakou, Hebei 075000, P.R. China
| | - Jian-Hua Wang
- Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
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Vasenina EE, Gankina OA, Levin OS. The addition of memantine to galantamine increases treatment efficacy in patients with moderate dementia with Lewy bodies. Zh Nevrol Psikhiatr Im S S Korsakova 2018; 118:32-36. [DOI: 10.17116/jnevro201811806232] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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Watson R, Colloby SJ, Blamire AM, Wesnes KA, Wood J, O'Brien JT. Does attentional dysfunction and thalamic atrophy predict decline in dementia with Lewy bodies? Parkinsonism Relat Disord 2017; 45:69-74. [DOI: 10.1016/j.parkreldis.2017.10.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Revised: 09/27/2017] [Accepted: 10/08/2017] [Indexed: 11/25/2022]
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Mak E, Su L, Williams GB, Firbank MJ, Lawson RA, Yarnall AJ, Duncan GW, Mollenhauer B, Owen AM, Khoo TK, Brooks DJ, Rowe JB, Barker RA, Burn DJ, O'Brien JT. Longitudinal whole-brain atrophy and ventricular enlargement in nondemented Parkinson's disease. Neurobiol Aging 2017; 55:78-90. [PMID: 28431288 PMCID: PMC5454799 DOI: 10.1016/j.neurobiolaging.2017.03.012] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2016] [Revised: 03/05/2017] [Accepted: 03/08/2017] [Indexed: 11/28/2022]
Abstract
We investigated whole-brain atrophy and ventricular enlargement over 18 months in nondemented Parkinson's disease (PD) and examined their associations with clinical measures and baseline CSF markers. PD subjects (n = 100) were classified at baseline into those with mild cognitive impairment (MCI; PD-MCI, n = 36) and no cognitive impairment (PD-NC, n = 64). Percentage of whole-brain volume change (PBVC) and ventricular expansion over 18 months were assessed with FSL-SIENA and ventricular enlargement (VIENA) respectively. PD-MCI showed increased global atrophy (-1.1% ± 0.8%) and ventricular enlargement (6.9 % ± 5.2%) compared with both PD-NC (PBVC: -0.4 ± 0.5, p < 0.01; VIENA: 2.1% ± 4.3%, p < 0.01) and healthy controls. In a subset of 35 PD subjects, CSF levels of tau, and Aβ42/Aβ40 ratio were correlated with PBVC and ventricular enlargement respectively. The sample size required to demonstrate a 20% reduction in PBVC and VIENA was approximately 1/15th of that required to detect equivalent changes in cognitive decline. These findings suggest that longitudinal MRI measurements have potential to serve as surrogate markers to complement clinical assessments for future disease-modifying trials in PD.
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Affiliation(s)
- Elijah Mak
- Department of Psychiatry, University of Cambridge, Cambridgeshire, UK
| | - Li Su
- Department of Psychiatry, University of Cambridge, Cambridgeshire, UK
| | - Guy B Williams
- Wolfson Brain Imaging Centre, University of Cambridge, Cambridgeshire, UK
| | - Michael J Firbank
- Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK
| | - Rachael A Lawson
- Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK
| | - Alison J Yarnall
- Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK
| | - Gordon W Duncan
- Medicine of the Elderly, Western General Hospital, Edinburgh, UK
| | - Brit Mollenhauer
- Paracelsus-Elena-Klinik, Kassel, Germany; University Medical Center Goettingen, Institute of Neuropathology, Goettingen, Germany
| | - Adrian M Owen
- Brain and Mind Institute, University of Western Ontario, London, Canada; Department of Psychology, University of Western Ontario, London, Canada
| | - Tien K Khoo
- Menzies Health Institute, Queensland and School of Medicine, Griffith University, Gold Coast, Australia
| | - David J Brooks
- Division of Neuroscience, Imperial College London, London, UK; Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - James B Rowe
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK; Medical Research Council, Cognition and Brain Sciences Unit, Cambridge, UK; Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK
| | - Roger A Barker
- John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK
| | - David J Burn
- Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK
| | - John T O'Brien
- Department of Psychiatry, University of Cambridge, Cambridgeshire, UK.
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Dissanayaka NNW, Lawson RA, Yarnall AJ, Duncan GW, Breen DP, Khoo TK, Barker RA, Burn DJ. Anxiety is associated with cognitive impairment in newly-diagnosed Parkinson's disease. Parkinsonism Relat Disord 2017; 36:63-68. [PMID: 28108263 PMCID: PMC5338650 DOI: 10.1016/j.parkreldis.2017.01.001] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Revised: 11/18/2016] [Accepted: 01/03/2017] [Indexed: 11/25/2022]
Abstract
Introduction Anxiety and mild cognitive impairment (MCI) are prevalent non-motor manifestations of Parkinson's disease (PD). While few studies have demonstrated a possible link between cognitive dysfunction and anxiety in PD, to our knowledge, no studies have directly examined the association between them. This study investigated the association between anxiety and cognitive deficits in newly diagnosed PD patients. Methods Patients with newly diagnosed PD (N = 185) were recruited from community and outpatient clinics. Anxiety was assessed using the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) clinician rated anxiety item, which has previously been validated against a standardized criteria for the diagnosis of anxiety disorders in PD. Participants scoring ≥2 were classified as anxious. A threshold of 1 SD below normative values (obtained from controls) was used to define cognitive impairment. Impairments in specific cognitive domains were identified as being >1 SD below controls in ≥1 test per domain. Results After controlling for age, education and motor severity, patients with anxiety were three times more likely to have cognitive impairment compared to those without anxiety (OR = 3.0, 95% CI = 1.2–7.3, p < 0.05). Patients with anxiety were more than twice as likely to be classified as having cognitive impairment due to impairment in the memory domain compared with PD without anxiety (OR = 2.3, 95% CI = 1.0–5.1, p < 0.05), whilst no associations were found between anxiety and performance on other cognitive domains. Conclusion This study shows an association between anxiety and cognitive impairment (specifically memory impairment). Examining the neural basis of this association warrants future research in this developing field.
Anxiety was associated with mild cognitive impairment (MCI) in PD. Patients with anxiety were three times more likely to have cognitive impairment. Anxiety was specifically associated with impairments in the memory domain.
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Affiliation(s)
- Nadeeka N W Dissanayaka
- The University of Queensland, UQ Centre for Clinical Research, Brisbane, Australia; Department of Neurology, Royal Brisbane & Women's Hospital, Brisbane, Australia; School of Psychology, The University of Queensland, Brisbane, Australia.
| | - Rachael A Lawson
- Institute of Neuroscience, Newcastle University, Newcastle Upon Tyne, UK
| | - Alison J Yarnall
- Institute of Neuroscience, Newcastle University, Newcastle Upon Tyne, UK
| | - Gordon W Duncan
- Institute of Neuroscience, Newcastle University, Newcastle Upon Tyne, UK; Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
| | - David P Breen
- John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK
| | - Tien K Khoo
- School of Medicine & Menzies Health Institute Queensland, Griffith University, Australia
| | - Roger A Barker
- John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK
| | - David J Burn
- Institute of Neuroscience, Newcastle University, Newcastle Upon Tyne, UK
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27
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Sleeman I, Aspray T, Lawson R, Coleman S, Duncan G, Khoo TK, Schoenmakers I, Rochester L, Burn D, Yarnall A. The Role of Vitamin D in Disease Progression in Early Parkinson's Disease. JOURNAL OF PARKINSON'S DISEASE 2017; 7:669-675. [PMID: 28984616 PMCID: PMC5676984 DOI: 10.3233/jpd-171122] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Accepted: 09/11/2017] [Indexed: 12/18/2022]
Abstract
BACKGROUND Previous cross-sectional studies have shown that Parkinson's disease (PD) patients have lower serum 25-hydroxy vitamin D (25(OH)D) concentrations than controls. Vitamin D deficiency was associated with increased disease severity and cognitive impairment in prevalent PD patients. OBJECTIVE The aim of the study was to determine 25(OH)D in newly diagnosed PD and age-matched controls and to assess if there was an association with clinical outcomes (disease severity, cognition and falls) over the 36-month follow up period. METHODS A prospective observational study of newly diagnosed PD patients in the North East of England with age-matched controls (PD, n = 145; control, n = 94). Serum 25(OH)D was assessed at baseline and 18 months. Participants underwent clinical assessment at baseline, 18 and 36 months. One hundred and ten participants with PD also took part in a prospective falls study. RESULTS Mean serum 25(OH)D concentrations were lower in PD than control participants at baseline (44.1±21.7 vs. 52.2±22.1 nmol/L, p < 0.05) and 18 months (44.2±23.6 vs. 55.7±28.8 nmol/L, p < 0.05). Baseline serum 25(OH)D concentration, age, motor score and dosage of dopaminergic medication were significant predictors of variance of motor severity at 36 months ((ΔR2 = 0.039, F = 6.6, p < 0.01). Serum 25(OH)D was not associated with cognition or falls during the follow up period. CONCLUSIONS Patients with incident PD had significantly lower serum 25(OH)D concentrations than age-matched controls, which may have implications in terms of bone health and fracture risk. There was a small but significant association between vitamin D status at baseline and disease motor severity at 36 months.
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Affiliation(s)
- Isobel Sleeman
- Clinical Ageing Research Unit, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK
| | - Terry Aspray
- Bone Clinic, Freeman Hospital, Freeman Road, Newcastle upon Tyne, UK
| | - Rachael Lawson
- Clinical Ageing Research Unit, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK
| | - Shirley Coleman
- Industrial Statistics Research Unit, Herschel Building, Newcastle University, Newcastle upon Tyne, UK
| | - Gordon Duncan
- Department of Geriatric Medicine, University of Edinburgh, Edinburgh, UK
| | - Tien K. Khoo
- School of Medicine and Menzies Health Institute Queensland, Griffith University, QLD, Australia
| | - Inez Schoenmakers
- Department of Medicine, Faculty of Medicine and Health Sciences, University of East Anglia, Norwich Research Park, Norwich, UK
- MRC Human Nutrition Research, Cambridge, UK
| | - Lynn Rochester
- Institute of Neuroscience, Newcastle University, Clinical Ageing Research Unit, Campus for Ageing and Vitality, UK
| | - David Burn
- Institute of Neuroscience, The Medical School, Newcastle University, UK
| | - Alison Yarnall
- Institute of Neuroscience, The Medical School, Newcastle University, UK
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Rinne JO, Wesnes K, Cummings JL, Hakulinen P, Hallikainen M, Hänninen J, Murphy M, Riordan H, Scheinin M, Soininen H, Rouru J. Tolerability of ORM-12741 and effects on episodic memory in patients with Alzheimer's disease. ALZHEIMERS & DEMENTIA-TRANSLATIONAL RESEARCH & CLINICAL INTERVENTIONS 2016; 3:1-9. [PMID: 29067315 PMCID: PMC5651366 DOI: 10.1016/j.trci.2016.11.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Introduction ORM-12741 is a novel selective antagonist of alpha-2C adrenoceptors. This trial evaluated the safety and efficacy of ORM-12741 in patients with Alzheimer's disease (AD). Methods A randomized, double-blind, placebo-controlled, exploratory phase 2a trial was conducted in 100 subjects with AD and neuropsychiatric symptoms. Participants were randomized to receive one of two flexible doses of ORM-12741 (30–60 mg or 100–200 mg) or placebo b.i.d. for 12 weeks in addition to standard therapy with cholinesterase inhibitors. Efficacy was assessed primarily with the Cognitive Drug Research (CDR) computerized assessment system and secondarily with the Neuropsychiatric Inventory (NPI). Results A statistically significant treatment effect was seen in one of the four primary CDR system end points, Quality of Episodic Memory (P = .030; not adjusted for multiple comparisons), favoring ORM-12741 over placebo. NPI caregiver distress scores also favored ORM-12741 (P = .034). ORM-12741 was well tolerated. Discussion This is the first clinical trial providing evidence on an acceptable safety profile for ORM-12741 in patients with AD and neuropsychiatric symptoms. In addition, the trial provided hints of potential therapeutic benefit, primarily on episodic memory, in this patient population.
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Affiliation(s)
- Juha O Rinne
- Turku PET Centre, Turku, Finland.,Turku University Hospital, Turku, Finland
| | - Keith Wesnes
- Bracket Global, Goring-on-Thames, UK.,Department of Psychology, Northumbria University, Newcastle, UK.,Centre for Human Psychopharmacology, Swinburne University, Melbourne, Australia
| | | | | | | | | | | | | | - Mika Scheinin
- Turku University Hospital, Turku, Finland.,University of Turku, Turku, Finland
| | | | - Juha Rouru
- Orion Corporation Orion Pharma, R&D, Turku, Finland
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Zhang J, Zhang L, Sun X, Yang Y, Kong L, Lu C, Lv G, Wang T, Wang H, Fu F. Acetylcholinesterase Inhibitors for Alzheimer's Disease Treatment Ameliorate Acetaminophen-Induced Liver Injury in Mice via Central Cholinergic System Regulation. J Pharmacol Exp Ther 2016; 359:374-382. [PMID: 27535978 DOI: 10.1124/jpet.116.233841] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Accepted: 08/12/2016] [Indexed: 01/30/2023] Open
Abstract
Acetaminophen (APAP) is widely used as an analgesic and antipyretic agent, but it may induce acute liver injury at high doses. Alzheimer's disease patients, while treated with acetylcholinesterase inhibitor (AChEI), may take APAP when they suffer from cold or pain. It is generally recognized that inhibiting acetylcholinesterase activity may also result in liver injury. To clarify whether AChEI could deteriorate or attenuate APAP hepatotoxicity, the effects of AChEI on APAP hepatotoxicity were investigated. Male C57BL/6J mice were administrated with the muscarinic acetylcholine receptor (mAChR) blocker atropine (Atr), or classic α7 nicotine acetylcholine receptor (α7nAChR) antagonist methyllycaconitine (MLA) 1 hour before administration of AChEIs-donepezil (4 mg/kg), rivastigmine (2 mg/kg), huperzine A (0.2 mg/kg), or neostigmine (0.15 mg/kg)-followed by APAP (300 mg/kg). Eight hours later, the mice were euthanized for histopathologic examination and biochemical assay. The results demonstrated that the tested AChEIs, excluding neostigmine, could attenuate APAP-induced liver injury, accompanied by reduced reactive oxygen species formation, adenosine triphosphate and cytochrome C loss, c-Jun N-terminal kinase 2 (JNK2) phosphorylation, and cytokines. However, Atr or MLA significantly weakened the protective effect of AChEI by affecting mitochondrial function or JNK2 phosphorylation and inflammation response. These results suggest that central mAChR and α7nAChR, which are activated by accumulated acetylcholine resulting from AChEI, were responsible for the protective effect of AChEIs on APAP-induced liver injury. This indicates that Alzheimer's patients treated with AChEI could take APAP, as AChEI is unlikely to deteriorate the hepatotoxicity of APAP.
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Affiliation(s)
- Jianqiao Zhang
- Key Laboratory of Molecular Pharmacology and Drug Evaluation (Ministry of Education of China), School of Pharmacy, Yantai University, Yantai, People's Republic of China
| | - Leiming Zhang
- Key Laboratory of Molecular Pharmacology and Drug Evaluation (Ministry of Education of China), School of Pharmacy, Yantai University, Yantai, People's Republic of China
| | - Xue Sun
- Key Laboratory of Molecular Pharmacology and Drug Evaluation (Ministry of Education of China), School of Pharmacy, Yantai University, Yantai, People's Republic of China
| | - Yanting Yang
- Key Laboratory of Molecular Pharmacology and Drug Evaluation (Ministry of Education of China), School of Pharmacy, Yantai University, Yantai, People's Republic of China
| | - Liang Kong
- Key Laboratory of Molecular Pharmacology and Drug Evaluation (Ministry of Education of China), School of Pharmacy, Yantai University, Yantai, People's Republic of China
| | - Chengwen Lu
- Key Laboratory of Molecular Pharmacology and Drug Evaluation (Ministry of Education of China), School of Pharmacy, Yantai University, Yantai, People's Republic of China
| | - Guangyao Lv
- Key Laboratory of Molecular Pharmacology and Drug Evaluation (Ministry of Education of China), School of Pharmacy, Yantai University, Yantai, People's Republic of China
| | - Tian Wang
- Key Laboratory of Molecular Pharmacology and Drug Evaluation (Ministry of Education of China), School of Pharmacy, Yantai University, Yantai, People's Republic of China
| | - Hongbo Wang
- Key Laboratory of Molecular Pharmacology and Drug Evaluation (Ministry of Education of China), School of Pharmacy, Yantai University, Yantai, People's Republic of China
| | - Fenghua Fu
- Key Laboratory of Molecular Pharmacology and Drug Evaluation (Ministry of Education of China), School of Pharmacy, Yantai University, Yantai, People's Republic of China
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30
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Wesnes KA, McNamara C, Annas P. Norms for healthy adults aged 18-87 years for the Cognitive Drug Research System: An automated set of tests of attention, information processing and memory for use in clinical trials. J Psychopharmacol 2016; 30:263-72. [PMID: 26755546 DOI: 10.1177/0269881115625116] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The Cognitive Drug Research (CDR) System is a set of nine computerized tests of attention, information processing, working memory, executive control and episodic memory which was designed for repeated assessments in research projects. The CDR System has been used extensively in clinical trials involving healthy volunteers for over 30 years, and a database of 7751 individuals aged 18-87 years has been accumulated for pre-treatment data from these studies. This database has been analysed, and the relationships between the various scores with factors, including age, gender and years of full-time education, have been identified. These analyses are reported in this paper, along with tables of norms for the various key measures from the core tasks stratified by age and gender. These norms can be used for a variety of purposes, including the determination of eligibility for participation in clinical trials and the everyday relevance of research findings from the system. In addition, these norms provide valuable information on gender differences and the effects of normal ageing on major aspects of human cognitive function.
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Affiliation(s)
- Keith A Wesnes
- Wesnes Cognition Ltd, Streatley on Thames, UK Department of Psychology, Northumbria University, Newcastle upon Tyne, UK Centre for Human Psychopharmacology, Swinburne University, Melbourne, VIC, Australia Medicinal Plant Research Group, Newcastle University, Newcastle upon Tyne, UK
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Verbalis JG, Ellison H, Hobart M, Krasa H, Ouyang J, Czerwiec FS. Tolvaptan and Neurocognitive Function in Mild to Moderate Chronic Hyponatremia: A Randomized Trial (INSIGHT). Am J Kidney Dis 2016; 67:893-901. [PMID: 26874645 DOI: 10.1053/j.ajkd.2015.12.024] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Accepted: 12/28/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND This trial assessed the effect of tolvaptan on cognition, gait, and postural stability in adult patients with mild to moderate asymptomatic hyponatremia. STUDY DESIGN Phase 3b, multicenter, randomized, double-blind, placebo-controlled, parallel-group pilot study. SETTING & PARTICIPANTS 57 men and women 50 years or older with chronic asymptomatic euvolemic or hypervolemic hyponatremia (serum sodium concentration >120-<135 mEq/L) at 16 sites. INTERVENTION Patients were randomly assigned 1:1 to receive tolvaptan or matching placebo beginning at a dose of 15mg/d, with titration to 30 or 60mg/d based on change in serum sodium concentration and tolerance. OUTCOMES Primary: change from baseline in the neurocognitive composite score of speed domains. Secondary: changes from baseline in individual neurocognitive domain scores, overall neurocognitive composite score, gait and postural stability test results, and serum sodium concentrations. RESULTS Mean serum sodium concentration increased from 129 to 136 mEq/L in the tolvaptan group and from 130 to 132 mEq/L in the placebo group (P<0.001). There was no difference in overall neurocognitive composite scores of speed domains between groups, except for the psychomotor speed domain, which was statistically improved following hyponatremia correction with tolvaptan (treatment effect, 0.27; 95% CI, 0.04-0.51; P=0.03). LIMITATIONS There were some imbalances between treatment groups in baseline neurocognitive function scores and some baseline test results were near normal, leaving little opportunity for improvement. Formal sample size calculations were not performed because this was a pilot study. The study population was small (n=57) and treatment was of short duration (3 weeks). The primary end point of the study was not significant; thus, subgroup analyses are subject to errors of multiplicity and should be regarded as hypothesis generating. CONCLUSIONS Tolvaptan was effective in reversing chronic hyponatremia, and this correlated with improvements in results of a variety of neurocognition tests, particularly rapid motor movements, which tended to reverse following return to a low baseline serum sodium concentration after treatment withdrawal.
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Affiliation(s)
- Joseph G Verbalis
- Division of Endocrinology and Metabolism, Georgetown University, Washington, DC.
| | | | - Mary Hobart
- Otsuka Pharmaceutical Development and Commercialization, Inc, Rockville, MD
| | - Holly Krasa
- Otsuka Pharmaceutical Development and Commercialization, Inc, Rockville, MD
| | - John Ouyang
- Otsuka Pharmaceutical Development and Commercialization, Inc, Rockville, MD
| | - Frank S Czerwiec
- Otsuka Pharmaceutical Development and Commercialization, Inc, Rockville, MD
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32
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Elder GJ, Firbank MJ, Kumar H, Chatterjee P, Chakraborty T, Dutt A, Taylor JP. Effects of transcranial direct current stimulation upon attention and visuoperceptual function in Lewy body dementia: a preliminary study. Int Psychogeriatr 2016; 28:341-7. [PMID: 26250473 PMCID: PMC4720143 DOI: 10.1017/s1041610215001180] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2015] [Revised: 06/12/2015] [Accepted: 06/27/2015] [Indexed: 11/20/2022]
Abstract
BACKGROUND Individuals with Lewy body dementia (LBD) typically exhibit impairments in attentional and executive function. Current pharmacological treatments have limited efficacy, with associated side effects. Transcranial direct current stimulation (tDCS) may represent an alternative treatment, as cognitive improvements have been demonstrated in healthy individuals. However, no studies to date have assessed the feasibility of tDCS in an LBD population. The aim of this preliminary study, therefore, was to assess the tolerability of tDCS, as well as its effects upon attentional and visuoperceptual performance, in LBD patients. METHODS Thirteen participants completed attentional (simple reaction time, choice reaction time, and digit vigilance) and forced-choice visuoperceptual (angle and motion perception) tasks before and after one 20-min session of active tDCS (0.08 mA/cm2). The anodal electrode was applied to the left dorsolateral prefrontal cortex and the cathodal electrode was applied to the right deltoid. Attentional (task accuracy and reaction time to correct answers) and visuoperceptual (task accuracy and difficulty) outcome measures were compared using paired t-tests. RESULTS All participants tolerated stimulation and did not report any side effects during or immediately after stimulation. Post-stimulation improvements were observed in the choice reaction time (increased percentage of correct answers; p = 0.01) and digit vigilance (reduced mean reaction time to correct answers; p = 0.02) attention tasks. Visuoperceptual task performance did not improve (all p-values > 0.05). CONCLUSIONS Attentional, but not visuoperceptual, improvements were observed following stimulation in LBD patients. Larger-scale, placebo-controlled trials are needed to confirm whether tDCS is a useful treatment option for attentional deficits in LBD.
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Affiliation(s)
- Greg J. Elder
- Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne NE4 5PL, UK
| | - Michael J. Firbank
- Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne NE4 5PL, UK
| | - Hrishikesh Kumar
- Institute of Neurosciences Kolkata, AJC Bose Road, Kolkata 700017, West Bengal, India
| | - Payel Chatterjee
- Institute of Neurosciences Kolkata, AJC Bose Road, Kolkata 700017, West Bengal, India
| | - Titas Chakraborty
- Institute of Neurosciences Kolkata, AJC Bose Road, Kolkata 700017, West Bengal, India
| | - Alakananda Dutt
- Institute of Neurosciences Kolkata, AJC Bose Road, Kolkata 700017, West Bengal, India
| | - John-Paul Taylor
- Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne NE4 5PL, UK
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Finkelstein DI, Hare DJ, Billings JL, Sedjahtera A, Nurjono M, Arthofer E, George S, Culvenor JG, Bush AI, Adlard PA. Clioquinol Improves Cognitive, Motor Function, and Microanatomy of the Alpha-Synuclein hA53T Transgenic Mice. ACS Chem Neurosci 2016; 7:119-29. [PMID: 26481462 DOI: 10.1021/acschemneuro.5b00253] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
The abnormal accumulation of alpha-synuclein (α-syn) has been linked to a number of neurodegenerative disorders, the most noteworthy of which is Parkinson's disease. Alpha-synuclein itself is not toxic and fulfills various physiological roles in the central nervous system. However, specific types of aggregates have been shown to be toxic, and metals have been linked to the assembly of these toxic aggregates. In this paper, we have characterized a transgenic mouse that overexpresses the A53T mutation of human α-syn, specifically assessing cognition, motor performance, and subtle anatomical markers that have all been observed in synucleinopathies in humans. We hypothesized that treatment with the moderate-affinity metal chelator, clioquinol (CQ), would reduce the interaction between metals and α-syn to subsequently improve the phenotype of the A53T animal model. We showed that CQ prevents an iron-synuclein interaction, the formation of urea-soluble α-syn aggregates, α-syn-related substantia nigra pars compacta cell loss, reduction in dendritic spine density of hippocampal and caudate putamen medium spiny neurons, and the decline in motor and cognitive function. In conclusion, our data suggests that CQ is capable of mitigating the pathological metal/α-syn interactions, suggesting that the modulation of metal ions warrants further study as a therapeutic approach for the synucleinopathies.
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Affiliation(s)
- David I. Finkelstein
- The
Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3052, Australia
| | - Dominic J. Hare
- The
Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3052, Australia
- Elemental
Bio-imaging Facility, University of Technology Sydney, Broadway, New South Wales 2007, Australia
- Senator
Frank R. Lautenberg Environmental Science Laboratory, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
| | - Jessica L. Billings
- The
Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3052, Australia
| | - Amelia Sedjahtera
- The
Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3052, Australia
| | - Milawaty Nurjono
- The
Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3052, Australia
| | - Elisa Arthofer
- The
Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3052, Australia
- Department
of Physiology and Pharmacology, Karolinska Institut, Stockholm SE-171 77, Sweden
| | - Sonia George
- School
of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria 3052, Australia
| | - Janetta G. Culvenor
- School
of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria 3052, Australia
| | - Ashley I. Bush
- The
Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3052, Australia
| | - Paul A. Adlard
- The
Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3052, Australia
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van Erp TGM, Preda A, Turner JA, Callahan S, Calhoun VD, Bustillo JR, Lim KO, Mueller B, Brown GG, Vaidya JG, McEwen S, Belger A, Voyvodic J, Mathalon DH, Nguyen D, Ford JM, Potkin SG. Neuropsychological profile in adult schizophrenia measured with the CMINDS. Psychiatry Res 2015; 230:826-34. [PMID: 26586142 PMCID: PMC4692593 DOI: 10.1016/j.psychres.2015.10.028] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2015] [Revised: 10/19/2015] [Accepted: 10/24/2015] [Indexed: 12/21/2022]
Abstract
Schizophrenia neurocognitive domain profiles are predominantly based on paper-and-pencil batteries. This study presents the first schizophrenia domain profile based on the Computerized Multiphasic Interactive Neurocognitive System (CMINDS(®)). Neurocognitive domain z-scores were computed from computerized neuropsychological tests, similar to those in the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB), administered to 175 patients with schizophrenia and 169 demographically similar healthy volunteers. The schizophrenia domain profile order by effect size was Speed of Processing (d=-1.14), Attention/Vigilance (d=-1.04), Working Memory (d=-1.03), Verbal Learning (d=-1.02), Visual Learning (d=-0.91), and Reasoning/Problem Solving (d=-0.67). There were no significant group by sex interactions, but overall women, compared to men, showed advantages on Attention/Vigilance, Verbal Learning, and Visual Learning compared to Reasoning/Problem Solving on which men showed an advantage over women. The CMINDS can readily be employed in the assessment of cognitive deficits in neuropsychiatric disorders; particularly in large-scale studies that may benefit most from electronic data capture.
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Affiliation(s)
- Theo G M van Erp
- Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, CA 92617, USA.
| | - Adrian Preda
- Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, CA 92617, USA
| | - Jessica A Turner
- Departments of Psychology and Neuroscience, Georgia State University, Atlanta, GA 30303, USA; Mind Research Network, Albuquerque, NM 87106, USA
| | - Shawn Callahan
- Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, CA 92617, USA
| | - Vince D Calhoun
- Mind Research Network, Albuquerque, NM 87106, USA; Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque, NM 97106, USA; Departments of Psychiatry & Neuroscience, University of New Mexico, Albuquerque, NM 87131, USA
| | - Juan R Bustillo
- Departments of Psychiatry & Neuroscience, University of New Mexico, Albuquerque, NM 87131, USA
| | - Kelvin O Lim
- Department of Psychiatry, University of Minnesota, Minneapolis, MN 55454, USA
| | - Bryon Mueller
- Department of Psychiatry, University of Minnesota, Minneapolis, MN 55454, USA
| | - Gregory G Brown
- VA San Diego Healthcare System and Department of Psychiatry, University of California San Diego, CA 92161, USA
| | - Jatin G Vaidya
- Department of Psychiatry, University of Iowa, Iowa City, IA 52242, USA
| | - Sarah McEwen
- Department of Psychology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Aysenil Belger
- Departments of Psychiatry and Psychology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - James Voyvodic
- Brain Imaging and Analysis Center, Duke University Medical Center, Durham, NC 27710, USA
| | - Daniel H Mathalon
- Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Dana Nguyen
- Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, CA 92617, USA
| | - Judith M Ford
- Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Steven G Potkin
- Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, CA 92617, USA
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35
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Pyle A, Brennan R, Kurzawa-Akanbi M, Yarnall A, Thouin A, Mollenhauer B, Burn D, Chinnery PF, Hudson G. Reduced cerebrospinal fluid mitochondrial DNA is a biomarker for early-stage Parkinson's disease. Ann Neurol 2015; 78:1000-4. [PMID: 26343811 DOI: 10.1002/ana.24515] [Citation(s) in RCA: 102] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Revised: 08/24/2015] [Accepted: 08/24/2015] [Indexed: 01/09/2023]
Abstract
The identification of cell-free circulating mitochondrial DNA (ccf-mtDNA) in early-stage Alzheimer's disease (AD) raised the possibility that the same neurodegenerative effect could be observed in Parkinson's disease (PD). Here, and for the first time, we investigated the role of ccf-mtDNA in PD, identifying a significant reduction of ccf-mtDNA in PD patient cerebrospinal fluid (CSF) when compared to controls. Our data demonstrates that CSF ccf-mtDNA is not only a powerful biomarker for PD, but, given that the effect is also observed in AD, is likely a biomarker for neurodegeneration.
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Affiliation(s)
- Angela Pyle
- Mitochondrial Research Group, University of Newcastle Upon Tyne, Newcastle Upon Tyne, United Kingdom
| | - Rebecca Brennan
- Mitochondrial Research Group, University of Newcastle Upon Tyne, Newcastle Upon Tyne, United Kingdom
| | - Marzena Kurzawa-Akanbi
- Mitochondrial Research Group, University of Newcastle Upon Tyne, Newcastle Upon Tyne, United Kingdom
| | - Alison Yarnall
- Insitutute of Neuroscience, University of Newcastle Upon Tyne, Newcastle Upon Tyne, United Kingdom
| | - Anais Thouin
- Insitutute of Neuroscience, University of Newcastle Upon Tyne, Newcastle Upon Tyne, United Kingdom
| | - Brit Mollenhauer
- Institute for Neuropathology, University of Goettingen, Goettingen, Germany
| | - David Burn
- Insitutute of Neuroscience, University of Newcastle Upon Tyne, Newcastle Upon Tyne, United Kingdom
| | - Patrick F Chinnery
- Mitochondrial Research Group, University of Newcastle Upon Tyne, Newcastle Upon Tyne, United Kingdom
| | - Gavin Hudson
- Mitochondrial Research Group, University of Newcastle Upon Tyne, Newcastle Upon Tyne, United Kingdom
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36
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Mak E, Su L, Williams GB, Firbank MJ, Lawson RA, Yarnall AJ, Duncan GW, Owen AM, Khoo TK, Brooks DJ, Rowe JB, Barker RA, Burn DJ, O'Brien JT. Baseline and longitudinal grey matter changes in newly diagnosed Parkinson's disease: ICICLE-PD study. Brain 2015; 138:2974-86. [PMID: 26173861 PMCID: PMC4671477 DOI: 10.1093/brain/awv211] [Citation(s) in RCA: 190] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Revised: 05/12/2015] [Accepted: 06/05/2015] [Indexed: 12/12/2022] Open
Abstract
Mild cognitive impairment in Parkinson's disease is associated with progression to dementia (Parkinson's disease dementia) in a majority of patients. Determining structural imaging biomarkers associated with prodromal Parkinson's disease dementia may allow for the earlier identification of those at risk, and allow for targeted disease modifying therapies. One hundred and five non-demented subjects with newly diagnosed idiopathic Parkinson's disease and 37 healthy matched controls had serial 3 T structural magnetic resonance imaging scans with clinical and neuropsychological assessments at baseline, which were repeated after 18 months. The Movement Disorder Society Task Force criteria were used to classify the Parkinson's disease subjects into Parkinson's disease with mild cognitive impairment (n = 39) and Parkinson's disease with no cognitive impairment (n = 66). Freesurfer image processing software was used to measure cortical thickness and subcortical volumes at baseline and follow-up. We compared regional percentage change of cortical thinning and subcortical atrophy over 18 months. At baseline, cases with Parkinson's disease with mild cognitive impairment demonstrated widespread cortical thinning relative to controls and atrophy of the nucleus accumbens compared to both controls and subjects with Parkinson's disease with no cognitive impairment. Regional cortical thickness at baseline was correlated with global cognition in the combined Parkinson's disease cohort. Over 18 months, patients with Parkinson's disease with mild cognitive impairment demonstrated more severe cortical thinning in frontal and temporo-parietal cortices, including hippocampal atrophy, relative to those with Parkinson's disease and no cognitive impairment and healthy controls, whereas subjects with Parkinson's disease and no cognitive impairment showed more severe frontal cortical thinning compared to healthy controls. At baseline, Parkinson's disease with no cognitive impairment converters showed bilateral temporal cortex thinning relative to the Parkinson's disease with no cognitive impairment stable subjects. Although loss of both cortical and subcortical volume occurs in non-demented Parkinson's disease, our longitudinal analyses revealed that Parkinson's disease with mild cognitive impairment shows more extensive atrophy and greater percentage of cortical thinning compared to Parkinson's disease with no cognitive impairment. In particular, an extension of cortical thinning in the temporo-parietal regions in addition to frontal atrophy could be a biomarker in therapeutic studies of mild cognitive impairment in Parkinson's disease for progression towards dementia.
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Affiliation(s)
- Elijah Mak
- 1 Department of Psychiatry, University of Cambridge, UK
| | - Li Su
- 1 Department of Psychiatry, University of Cambridge, UK
| | - Guy B Williams
- 2 Wolfson Brain Imaging Centre, University of Cambridge, UK
| | | | - Rachael A Lawson
- 3 Institute of Neuroscience, Newcastle University, Newcastle, UK
| | - Alison J Yarnall
- 3 Institute of Neuroscience, Newcastle University, Newcastle, UK
| | - Gordon W Duncan
- 4 Medicine of the Elderly, Western General Hospital, Edinburgh, UK
| | - Adrian M Owen
- 5 Brain and Mind Institute, University of Western Ontario, London, Canada 6 Department of Psychology, University of Western Ontario, London, Canada
| | - Tien K Khoo
- 7 Griffith Health Institute and School of Medicine, Griffith University, Gold Coast, Australia
| | - David J Brooks
- 8 Division of Brain Sciences, Imperial College London, London, UK 9 Department of Clinical Medicine, Positron Emission Tomography Centre, Aarhus University, Denmark
| | - James B Rowe
- 10 Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK 11 Medical Research Council, Cognition and Brain Sciences Unit, Cambridge, UK 12 Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK
| | - Roger A Barker
- 13 John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK
| | - David J Burn
- 3 Institute of Neuroscience, Newcastle University, Newcastle, UK
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37
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Duncan GW, Firbank MJ, Yarnall AJ, Khoo TK, Brooks DJ, Barker RA, Burn DJ, O'Brien JT. Gray and white matter imaging: A biomarker for cognitive impairment in early Parkinson's disease? Mov Disord 2015. [PMID: 26202802 DOI: 10.1002/mds.26312] [Citation(s) in RCA: 118] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND The aim of this work was to investigate the cortical and white matter changes that underlie cognitive impairment in patients with incident Parkinson's disease (PD) disease using voxel-based morphometry and diffusion tensor imaging. METHODS Newly diagnosed nondemented PD (n = 125) and control subjects (n = 50) were recruited from the Incidence of Cognitive Impairment in Cohorts with Longitudinal Evaluation in Parkinson's Disease Study and completed cognitive assessments and 3T structural and diffusion tensor MR imaging. Voxel-based morphometry was performed to investigate the relationship between gray matter volume and cognitive ability. Microstructural white matter changes were assessed with diffusion tensor imaging measures of fractional anisotropy and mean diffusivity using tract-based spatial statistics. RESULTS Increased mean diffusivity was observed bilaterally in subjects with PD, relative to controls (P = 0.019). Increased mean diffusivity was associated with performance on the semantic fluency and Tower of London tasks in frontal and parietal white matter tracts, including the cingulum, superior longitudinal fasciculus, inferior longitudinal fasciculus, and inferior fronto-occipital fasciculus. There was no difference in total gray matter volume between groups; however, bilateral reductions in frontal and parietal gray matter volume were associated with reduced performance on measures of executive function in PD subjects. CONCLUSIONS At the earliest stages of PD, regionally specific increases in central white matter mean diffusivity are present and suggest early axonal damage. Such changes are not accompanied by significant gray matter volume loss and are consistent with proposed models of pathological progression of the disease. Structural MRI, especially diffusion tensor imaging analysis, offers potential as a noninvasive biomarker reflecting cognitive impairment in PD.
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Affiliation(s)
- Gordon W Duncan
- Institute of Neuroscience, Newcastle University, Newcastle, United Kingdom.,Medicine of the Elderly, Western General Hospital, Edinburgh, United Kingdom
| | - Michael J Firbank
- Institute of Neuroscience, Newcastle University, Newcastle, United Kingdom
| | - Alison J Yarnall
- Institute of Neuroscience, Newcastle University, Newcastle, United Kingdom
| | - Tien K Khoo
- School of Medicine and Griffith Health Institute, Griffith University, Gold Coast, Australia
| | - David J Brooks
- Aarhus University, Aarhus, Denmark and Imperial College, London, United Kingdom
| | - Roger A Barker
- John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, United Kingdom
| | - David J Burn
- Institute of Neuroscience, Newcastle University, Newcastle, United Kingdom
| | - John T O'Brien
- Institute of Neuroscience, Newcastle University, Newcastle, United Kingdom.,Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
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38
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Lavon O, Eisenkraft A, Blanca M, Raveh L, Ramaty E, Krivoy A, Atsmon J, Grauer E, Brandeis R. Is rivastigmine safe as pretreatment against nerve agents poisoning? A pharmacological, physiological and cognitive assessment in healthy young adult volunteers. Neurotoxicology 2015; 49:36-44. [DOI: 10.1016/j.neuro.2015.05.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2015] [Revised: 05/04/2015] [Accepted: 05/11/2015] [Indexed: 01/02/2023]
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Moretti DV. Are there treatments for atypical parkinsonism? An update on actual options. Rev Neurosci 2015; 26:547-53. [PMID: 26098698 DOI: 10.1515/revneuro-2015-0008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2015] [Accepted: 04/19/2015] [Indexed: 11/15/2022]
Abstract
Success in treating patients with atypical parkinsonism remains exceedingly low. It is particularly important for both neurologists and general practicians to have a guideline in the actual possible cure options. This study reviews the limited available literature reporting treatment trials about treatment in parkinsonism. Various therapeutical approaches have been tried with rasagiline, immunoglobulin, autologous mesenchymal stem cells, davunetide, lithium, and tideglusib. Recently, the transdermal rotigotine has been proposed for the treatment of atypical parkinsonism, as well as deep brain stimulation (DBS) of the peduncolopontine nucleus alone or combined with globus pallidus internus stimulation. The outcomes reviewed here highlight the need for the development of randomized, placebo-controlled trials to validate outcomes about rotigotine, DBS, and all other new therapies directed at altering the underlying biological mechanisms involved in the disease process.
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40
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Carbutt S, Duff J, Yarnall A, Burn DJ, Hudson G. Variation in complement protein C1q is not a major contributor to cognitive impairment in Parkinson's disease. Neurosci Lett 2015; 594:66-9. [PMID: 25817358 PMCID: PMC4407898 DOI: 10.1016/j.neulet.2015.03.048] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2014] [Revised: 03/17/2015] [Accepted: 03/24/2015] [Indexed: 01/20/2023]
Abstract
Cognitive decline is a strong hallmark of PD. Genetic variation in C1Q – does not account for the cognitive decline seen in PD. Genetic variation in C1Q – is unlikely to contribute to PD aetiology. Traditional dogma regarding the brain as an immune exempt organ has changed in recent years. New research has highlighted the role of the classical complement cascade in both synaptic elimination and function, driven largely by the role of the pathway initiating protein C1q. Given the links between C1q and cognitive function we assessed the genetic variability of the C1q encoding genes: C1QA, C1QB and C1QC between PD patients and matched controls. Despite a strong link between C1Q/cognitive decline and PD/cognitive decline we were unable to find a link between common C1Q variation and PD. We conclude that common C1Q-A/B/C genetic variation is unlikely to contribute to cognitive decline or the missing heritability in PD.
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Affiliation(s)
- Sophia Carbutt
- Mitochondrial Research Group, University of Newcastle Upon Tyne, United Kingdom
| | - Jennifer Duff
- Mitochondrial Research Group, University of Newcastle Upon Tyne, United Kingdom
| | - Alison Yarnall
- Institute for Ageing and Health, University of Newcastle Upon Tyne, United Kingdom
| | - David J Burn
- Institute for Ageing and Health, University of Newcastle Upon Tyne, United Kingdom
| | - Gavin Hudson
- Mitochondrial Research Group, University of Newcastle Upon Tyne, United Kingdom.
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Wesnes KA, Aarsland D, Ballard C, Londos E. Memantine improves attention and episodic memory in Parkinson's disease dementia and dementia with Lewy bodies. Int J Geriatr Psychiatry 2015; 30:46-54. [PMID: 24737460 DOI: 10.1002/gps.4109] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2013] [Accepted: 03/04/2014] [Indexed: 11/09/2022]
Abstract
OBJECTIVE In both dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), attentional dysfunction is a core clinical feature together with disrupted episodic memory. This study evaluated the cognitive effects of memantine in DLB and PDD using automated tests of attention and episodic memory. METHODS A randomised double-blind, placebo-controlled, 24-week three centre trial of memantine (20 mg/day) was conducted in which tests of attention (simple and choice reaction time) and word recognition (immediate and delayed) from the CDR System were administered prior to dosing and again at 12 and 24 weeks. Although other results from this study have been published, the data from the CDR System tests were not included and are presented here for the first time. RESULTS Data were available for 51 patients (21 DLB and 30 PDD). In both populations, memantine produced statistically significant medium to large effect sized improvements to choice reaction time, immediate and delayed word recognition. CONCLUSIONS These are the first substantial improvements on cognitive tests of attention and episodic recognition memory identified with memantine in either DLB or PDD.
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Affiliation(s)
- Keith A Wesnes
- Wesnes Cognition Ltd, Streatley on Thames, UK; Department of Psychology, Northumbria University, Newcastle, UK; Centre for Human Psychopharmacology, Swinburne University, Melbourne, Australia
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Camicioli R, Gauthier S. Clinical Trials in Parkinson's Disease Dementia and Dementia with Lewy Bodies. Can J Neurol Sci 2014; 34 Suppl 1:S109-17. [PMID: 17469693 DOI: 10.1017/s0317167100005679] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB) are pathological overlapping and important causes of dementia for which clinical trials are in their infancy. Cholinesterase inhibitors may be of benefit in DLB and PDD, as suggested by placebo-controlled clinical trials of rivastigmine and donepezil. The anti-psychotic agent clozapine has been of benefit in PD and PDD, but other agents, such as quetiapine, require adequate assessment. Barriers to trials include pathological overlap that can lead to inaccuracies in clinical diagnosis, unavailability of a consensus definition for PDD, unanswered questions regarding natural history and the paucity of validated outcome measures. Motor impairment must be considered in patients with PDD and DLB; conversely, cognitive impairment should be assessed in trials targeting motor impairment in advanced PD. Potential targets for treatment include onset of dementia, cognitive impairment, behavioral impairment, functional decline, falls, nursing home placement, mortality, quality of life and economic impact. Biomarkers including neuroimaging and cerebrospinal fluid markers are not currently established. At present PDD and DLB are distinct entities by definition. Future studies, including clinical trials and biomarker studies, will help to further define the clinical and therapeutic implications of this distinction.
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Ripley DL, Morey CE, Gerber D, Harrison-Felix C, Brenner LA, Pretz CR, Cusick C, Wesnes K. Atomoxetine for attention deficits following traumatic brain injury: Results from a randomized controlled trial. Brain Inj 2014; 28:1514-22. [DOI: 10.3109/02699052.2014.919530] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Affiliation(s)
- David L. Ripley
- Department of Physical Medicine and Rehabilitation, Northwestern University Feinberg School of Medicine, Rehabilitation Institute of Chicago
Chicago, ILUSA
| | - Clare E. Morey
- Department of Physical Medicine and Rehabilitation, University of Colorado School of Medicine
Aurora, COUSA
| | - Don Gerber
- Department of Physical Medicine and Rehabilitation, University of Colorado School of Medicine
Aurora, COUSA
| | - Cynthia Harrison-Felix
- Department of Physical Medicine and Rehabilitation, University of Colorado School of Medicine
Aurora, COUSA
| | - Lisa A. Brenner
- Department of Physical Medicine and Rehabilitation, University of Colorado School of Medicine
Aurora, COUSA
- Departments of Psychiatry, Neurology, and Physical Medicine and Rehabilitation, University of Colorado, School of Medicine
Aurora, COUSA
| | - Christopher R. Pretz
- Department of Physical Medicine and Rehabilitation, University of Colorado School of Medicine
Aurora, COUSA
| | - Chris Cusick
- Department of Physical Medicine and Rehabilitation, University of Colorado School of Medicine
Aurora, COUSA
| | - Keith Wesnes
- Bracket Global, Goring-on-ThamesUK
- Centre for Human Psychopharmacology, Swinburne University of Technology
MelbourneAustralia
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44
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Magnetic resonance spectroscopy in the diagnosis of dementia with Lewy bodies. BIOMED RESEARCH INTERNATIONAL 2014; 2014:809503. [PMID: 25110697 PMCID: PMC4109391 DOI: 10.1155/2014/809503] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/25/2014] [Revised: 05/21/2014] [Accepted: 06/20/2014] [Indexed: 01/03/2023]
Abstract
Dementia with Lewy bodies (DLB) is considered to be the second most frequent primary degenerative dementing illness after Alzheimer's disease (AD). DLB, together with Parkinson's disease (PD), Parkinson's disease with dementia (PDD) belong to α-synucleinopathies—a group of neurodegenerative diseases associated with pathological accumulation of the α-synuclein protein. Dementia due to PD and DLB shares clinical symptoms and neuropsychological profiles. Moreover, the core features and additional clinical signs and symptoms for these two very similar diseases are largely the same. Neuroimaging seems to be a promising method in differential diagnosis of dementia studies. The development of imaging methods or other objective measures to supplement clinical criteria for DLB is needed and a method which would accurately facilitate diagnosis of DLB prior to death is still being searched. Proton magnetic resonance spectroscopy (1H-MRS) provides a noninvasive method of assessing an in vivo biochemistry of brain tissue. This review summarizes the main results obtained from the application of neuroimaging techniques in DLB cases focusing on 1H-MRS.
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45
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Tsai RM, Boxer AL. Clinical trials: past, current, and future for atypical Parkinsonian syndromes. Semin Neurol 2014; 34:225-34. [PMID: 24963682 DOI: 10.1055/s-0034-1381739] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
There are currently no effective Food and Drug Administration-approved treatments for atypical parkinsonian disorders such as progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies, or multiple system atrophy. Previous treatment trials for these disorders were focused on symptomatic support and did not affect disease progression. Recent breakthroughs in neuropathology and pathophysiology have allowed a new understanding of these disorders and investigation into potentially disease modifying therapies. Randomized, placebo-controlled clinical trials of these disorders will be reviewed here. Suggestions for future therapeutic targets and clinical trial design (with a focus on progressive supranuclear palsy) will also be provided.
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Affiliation(s)
- Richard M Tsai
- Department of Neurology, University of California San Francisco, San Francisco, California
| | - Adam L Boxer
- Department of Neurology, University of California San Francisco, San Francisco, California
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Wesnes KA, Annas P, Basun H, Edgar C, Blennow K. Performance on a pattern separation task by Alzheimer's patients shows possible links between disrupted dentate gyrus activity and apolipoprotein E ∈4 status and cerebrospinal fluid amyloid-β42 levels. ALZHEIMERS RESEARCH & THERAPY 2014; 6:20. [PMID: 24735568 PMCID: PMC4054957 DOI: 10.1186/alzrt250] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/09/2013] [Accepted: 03/25/2014] [Indexed: 12/30/2022]
Abstract
INTRODUCTION Emerging evidence suggests that decreased adult hippocampal neurogenesis represents an early critical event in the course of Alzheimer's disease (AD). In mice, adult neurogenesis is reduced by knock-in alleles for human apolipoprotein E (ApoE) ∈4. Decreased dentate gyrus (DG) neural progenitor cells proliferation has been observed in the triple-transgenic mouse model of AD (3xTg-AD); this reduction being directly associated with the presence of amyloid-β (Aβ) plaques and an increase in the number of Aβ-containing neurons in the hippocampus. Cognitive tasks involving difficult pattern separations have been shown to reflect DG activity and thus potentially neurogenesis in both animals and man. This study involved the administration of a pattern separation paradigm to Alzheimer's patients to investigate relationships between task performance and both ApoE status and cerebrospinal fluid (CSF) Aβ42 levels. METHODS The CDR System pattern separation task involves the presentation of pictures that must later be discriminated from closely similar pictures. This paper presents pattern separation data from 66 mild to moderate AD patients, of which 50 were genotyped and 65 in whom CSF Aβ42 was measured. RESULTS ApoE ∈4 homozygotes were not compromised on the easy pattern separations compared with the other patients, but they were statistically significantly poorer at the difficult separations. In all patients CSF Aβ42 correlated significantly with the ability to make the difficult discriminations, but not easier discriminations. Pattern separation speed correlated negatively with CSF Aβ42, and thus the association was not due to increased impulsivity. CONCLUSIONS These are, to our knowledge, the first human pattern separation data to suggest a possible genetic link to poor hippocampal neurogenesis in AD, as well as a relationship to Aβ42. Therapies which target neurogenesis may thus be useful in preventing the early stages of AD, notably in ApoE ∈4 homocygotes.
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Affiliation(s)
- Keith A Wesnes
- Wesnes Cognition Ltd., Little Paddock, Streatley Hill, Streatley on Thames RG8 9RD, UK ; Department of Psychology, Northumbria University, Newcastle, UK ; Centre for Human Psychopharmacology, Swinburne University, Melbourne, VIC, Australia
| | | | - Hans Basun
- BioArctic Neuroscience AB, Stockholm, Sweden
| | - Chris Edgar
- Formerly, Bracket, Goring on Thames RG8 9RD, UK
| | - Kaj Blennow
- Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
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Relkin NR. Beyond symptomatic therapy: a re-examination of acetylcholinesterase inhibitors in Alzheimer’s disease. Expert Rev Neurother 2014; 7:735-48. [PMID: 17561789 DOI: 10.1586/14737175.7.6.735] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Acetylcholinesterase inhibitors (AChEIs) are generally regarded as palliative treatments for Alzheimer's disease that slow the progression of dementia symptoms without altering Alzheimer's disease's underlying pathogenic mechanisms. This concept is based on inference rather than evidence, and has limited the scope and persistence of AChEI use in clinical practice. Recent preclinical studies demonstrate that AChEIs exhibit a number of biological effects in addition to cholinesterase inhibition. A broader understanding of the possible mechanisms of action of AChEIs in Alzheimer's disease could result in more effective use and assist in the development of new and improved therapies. The available evidence brings into question the prevailing view that AChEIs are exclusively symptomatic treatments and supports the use of these agents persistently throughout the course of Alzheimer's disease.
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Affiliation(s)
- Norman R Relkin
- Joan and Sanford I. Weill Medical College of Cornell University, 428 East 72nd Street, Suite 500, NY 10017, USA.
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48
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Larner AJ. Cholinesterase inhibitors: beyond Alzheimer’s disease. Expert Rev Neurother 2014; 10:1699-705. [DOI: 10.1586/ern.10.105] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Yarnall AJ, Breen DP, Duncan GW, Khoo TK, Coleman SY, Firbank MJ, Nombela C, Winder-Rhodes S, Evans JR, Rowe JB, Mollenhauer B, Kruse N, Hudson G, Chinnery PF, O'Brien JT, Robbins TW, Wesnes K, Brooks DJ, Barker RA, Burn DJ. Characterizing mild cognitive impairment in incident Parkinson disease: the ICICLE-PD study. Neurology 2013; 82:308-16. [PMID: 24363137 DOI: 10.1212/wnl.0000000000000066] [Citation(s) in RCA: 328] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
OBJECTIVE To describe the frequency of mild cognitive impairment (MCI) in Parkinson disease (PD) in a cohort of newly diagnosed incident PD cases and the associations with a panel of biomarkers. METHODS Between June 2009 and December 2011, 219 subjects with PD and 99 age-matched controls participated in clinical and neuropsychological assessments as part of a longitudinal observational study. Consenting individuals underwent structural MRI, lumbar puncture, and genotyping for common variants of COMT, MAPT, SNCA, BuChE, EGF, and APOE. PD-MCI was defined with reference to the new Movement Disorder Society criteria. RESULTS The frequency of PD-MCI was 42.5% using level 2 criteria at 1.5 SDs below normative values. Memory impairment was the most common domain affected, with 15.1% impaired at 1.5 SDs. Depression scores were significantly higher in those with PD-MCI than the cognitively normal PD group. A significant correlation was found between visual Pattern Recognition Memory and cerebrospinal β-amyloid 1-42 levels (β standardized coefficient = 0.350; p = 0.008) after controlling for age and education in a linear regression model, with lower β-amyloid 1-42 and 1-40 levels observed in those with PD-MCI. Voxel-based morphometry did not reveal any areas of significant gray matter loss in participants with PD-MCI compared with controls, and no specific genotype was associated with PD-MCI at the 1.5-SD threshold. CONCLUSIONS In a large cohort of newly diagnosed PD participants, PD-MCI is common and significantly correlates with lower cerebrospinal β-amyloid 1-42 and 1-40 levels. Future longitudinal studies should enable us to determine those measures predictive of cognitive decline.
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Affiliation(s)
- Alison J Yarnall
- From the Institute for Ageing and Health (A.J.Y., G.W.D., M.J.F., D.J.B.), Industrial Statistics Research Unit (S.Y.C.), and Institute of Genetic Medicine (G.H., P.F.C.), Newcastle University; John van Geest Centre for Brain Repair (D.P.B., J.R.E., R.A.B.), Department of Clinical Neurosciences (C.N., S.W.-R., J.B.R.), Behavioural and Clinical Neuroscience Institute (C.N., S.W.-R., J.B.R., T.W.R.), MRC Cognition and Brain Sciences Unit (C.N., S.W.-R., J.B.R.), Departments of Psychiatry (J.T.O.) and Psychology (T.W.R.), University of Cambridge, UK; School of Medicine (T.K.K.), Griffith University, Australia; Paracelsus-Elena-Klinik (B.M.), Kassel, and Göttingen University; Institute for Neuropathology (N.K.), Prion and Dementia Research Unit, University Medical Centre Göttingen, Germany; Centre for Human Psychopharmacology (K.W.), Swinburne University, Melbourne, Australia; and Department of Medicine (D.J.W.), Imperial College London, UK
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Taylor JP, Colloby SJ, McKeith IG, O'Brien JT. Covariant perfusion patterns provide clues to the origin of cognitive fluctuations and attentional dysfunction in dementia with Lewy bodies. Int Psychogeriatr 2013; 25:1917-28. [PMID: 24148774 PMCID: PMC3819183 DOI: 10.1017/s1041610213001488] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2013] [Revised: 07/24/2013] [Accepted: 07/24/2013] [Indexed: 01/19/2023]
Abstract
BACKGROUND Fluctuating cognition (FC), particularly in attention, is a core and defining symptom in dementia with Lewy bodies (DLB) but is seen much less frequently in Alzheimer's dementia (AD). However, its neurobiological origin is poorly understood. The aim of our study was therefore to characterize perfusion patterns in DLB patients that are associated with the severity and frequency of FC as measured both clinically and using objective neuropsychological assessments. METHODS Spatial covariance analyses were applied to data derived from single photon emission computed tomography (SPECT) HMPAO brain imaging in 19 DLB and 23 AD patients. Patients underwent clinical assessment of their FC and cognitive function as well as objective testing of their attention. RESULTS Covariant perfusion principal components (PCs) were not associated with either FC or cognitive or attentional measures in AD. However, in DLB patients, the second PC (defined as DLB-cognitive motor pattern, DLB-PCI2) which was characterized by bilateral relative increases in cerebellum, basal ganglia, and supplementary motor areas and widespread bilateral decreases in parietal regions, positively correlated with poorer cognitive function, increased FC and worse attentional function measured both clinically and neurophysiologically (p < 0.05) as well as with the severity of bradykinesia (p = 0.04). CONCLUSIONS FC in DLB appears distinct from those seen in AD, and likely to be driven by internal neurobiological perturbations in brain circuitry as evidenced using spatial covariance analyses of cerebral perfusion. FC and certain aspects of attentional dysfunction in DLB may, in part, depend upon both distributed motor and non-motor networks.
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Affiliation(s)
- John-Paul Taylor
- Institute for Ageing and Health, Campus for Aging and Vitality, Newcastle University, Newcastle upon Tyne, UK
| | - Sean J. Colloby
- Institute for Ageing and Health, Campus for Aging and Vitality, Newcastle University, Newcastle upon Tyne, UK
| | - Ian G. McKeith
- Institute for Ageing and Health, Campus for Aging and Vitality, Newcastle University, Newcastle upon Tyne, UK
| | - John T. O'Brien
- Institute for Ageing and Health, Campus for Aging and Vitality, Newcastle University, Newcastle upon Tyne, UK
- Department of Psychiatry, University of Cambridge, Addenbrooke's Hospital, UK
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