Search

α-Synuclein (α-syn) phosphorylation at serine 129 (pS129–α-syn) is substantially increased in Lewy body disease, such as Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). However, the pathogenic relevance of pS129–α-syn remains controversial, so we sought to identify when pS129 modification occurs during α-syn aggregation and its role in initiation, progression and cellular toxicity of disease. Using diverse aggregation assays, including real-time quaking-induced conversion (RT-QuIC) on brain homogenates from PD and DLB cases, we demonstrated that pS129–α-syn inhibits α-syn fibril formation and seeded aggregation. We also identified lower seeding propensity of pS129–α-syn in cultured cells and correspondingly attenuated cellular toxicity. To build upon these findings, we developed a monoclonal antibody (4B1) specifically recognizing nonphosphorylated S129–α-syn (WT–α-syn) and noted that S129 residue is more efficiently phosphorylated when the protein is aggregated. Using this antibody, we characterized the time-course of α-syn phosphorylation in organotypic mouse hippocampal cultures and mice injected with α-syn preformed fibrils, and we observed aggregation of nonphosphorylated α-syn followed by later pS129–α-syn. Furthermore, in postmortem brain tissue from PD and DLB patients, we observed an inverse relationship between relative abundance of nonphosphorylated α-syn and disease duration. These findings suggest that pS129–α-syn occurs subsequent to initial protein aggregation and apparently inhibits further aggregation. This could possibly imply a potential protective role for pS129–α-syn, which has major implications for understanding the pathobiology of Lewy body disease and the continued use of reduced pS129–α-syn as a measure of efficacy in clinical trials.

Please modify the Abstract as follows:Here we tested if the reactivity of posterior resting-state electroencephalographic (rsEEG) alpha rhythms from the eye-closed to the eyes-open condition may differ in patients with dementia due to Lewy Bodies (DLB) and Alzheimer's disease (ADD) as a functional probe of the dominant neural synchronization mechanisms regulating the vigilance in posterior visual systems.We used clinical, demographical, and rsEEG datasets in 28 older adults (Healthy), 42 DLB, and 48 ADD participants. The eLORETA freeware was used to estimate cortical rsEEG sources.Results showed a substantial (> -10%) reduction in the posterior alpha activities during the eyes-open condition in 24 Healthy, 26 ADD, and 22 DLB subjects. There were lower reductions in the posterior alpha activities in the ADD and DLB groups than in the Healthy group. That reduction in the occipital region was lower in the DLB than in the ADD group.These results suggest that DLB patients may suffer from a greater alteration in the neural synchronization mechanisms regulating vigilance in occipital cortical systems compared to ADD patients. H2020 Marie S. Curie ITN-ETN project Italian Ministry of Health to the IRCCS SDN of Naples, IRCCS OASI of Troina, and IRCCS San Raffaele Pisana of Rome

The selection of appropriate outcome measures is fundamental to the design of any successful clinical trial. Although dementia with Lewy bodies (DLB) is one of the most common neurodegenerative conditions, assessment of therapeutic benefit in clinical trials often relies on tools developed for other conditions, such as Alzheimer's or Parkinson's disease. These may not be sufficiently valid or sensitive to treatment changes in DLB, decreasing their utility. In this review, we discuss the limitations and strengths of selected available tools used to measure DLB-associated outcomes in clinical trials and highlight the potential roles for more specific objective measures. We emphasize that the existing outcome measures require validation in the DLB population and that DLB-specific outcomes need to be developed. Finally, we highlight how the selection of outcome measures may vary between symptomatic and disease-modifying therapy trials.

Hannu Laaksovirta konsortion jäsenenä. The Genomics England Research Consortium, The International ALS/FTD Genomics Consortium (iAFGC), The International FTD Genetics Consortium (IFGC), The International LBD Genomics Consortium (iLBDGC), The NYGC ALS Consortium, The PROSPECT Consortium,17 James B. Rowe,17 Luisa Benussi,18 Giuliano Binetti,18,19 Roberta Ghidoni,18 Edwin Jabbari,20,21 Coralie Viollet,22 Jonathan D. Glass,23 Andrew B. Singleton,24 Vincenzo Silani,25,26 Owen A. Ross,27 Mina Ryten,8,28,29 Ali Torkamani,30 Toshiko Tanaka,31 Luigi Ferrucci,31 Susan M. Resnick,32 We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered. We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.

A cerebrospinal fluid (CSF) Alzheimer’s disease (AD) profile, that is, decreased amyloid-β1-42 (Aβ42) and increased total tau protein (t-tau) and/or phosphorylated tau at threonine-181 (p-tau),1 has been identified in a substantial number of dementia with Lewy bodies (DLB) patients, and it has been related to a more rapid cognitive decline.1 We investigated the association between AD CSF biomarkers and DLB core clinical features to better understand in vivo how AD pathology influences DLB clinical presentation. We included 171 subjects with a clinical diagnosis of probable DLB2 3 from the European DLB consortium (E-DLB). The centres involved are summarised in online supplementary table 1. Clinical examination was performed as previously reported.1 Dopamine transporter (DAT) single-photon emission CT scans (123I-FP-CIT-SPECT) were performed in 80 patients.### Supplementary data [jnnp-2019-320980supp001.pdf] CSF samples were collected at each centre according to the procedures detailed in online supplementary table 1. An AD CSF profile was defined as low Aβ42 combined with high t-tau or p-tau.1 Information about pharmacological treatments of patients were not available at each centre. Statistical analyses were performed using SPSS V.24. Association between CSF biomarkers (normal or abnormal), and each core features (present or absent), were tested with χ2 test. Associations between single CSF biomarkers and groups of subjects with different core clinical features’ number (1–4) were tested with Armitage test for trend. Local ethics committees approved the study. All patients gave their written consent for the use of their …

Background Dementia with Lewy bodies (DLB) is the second most common form of dementia. Current symptomatic treatment with medications remains inadequate. Deep brain stimulation of the nucleus basalis of Meynert (NBM DBS) has been proposed as a potential new treatment option in dementias. Objective To assess the safety and tolerability of low frequency (20 Hz) NBM DBS in DLB patients and explore its potential effects on both clinical symptoms and functional connectivity in underlying cognitive networks. Methods We conducted an exploratory randomised, double-blind, crossover trial of NBM DBS in six DLB patients recruited from two UK neuroscience centres. Patients were aged between 50 and 80 years, had mild-moderate dementia symptoms and were living with a carer-informant. Patients underwent image guided stereotactic implantation of bilateral DBS electrodes with the deepest contacts positioned in the Ch4i subsector of NBM. Patients were subsequently assigned to receive either active or sham stimulation for six weeks, followed by a two week washout period, then the opposite condition for six weeks. Safety and tolerability of both the surgery and stimulation were systematically evaluated throughout. Exploratory outcomes included the difference in scores on standardised measurements of cognitive, psychiatric and motor symptoms between the active and sham stimulation conditions, as well as differences in functional connectivity in discrete cognitive networks on resting state fMRI. Results Surgery and stimulation were well tolerated by all six patients (five male, mean age 71.33 years). One serious adverse event occurred: one patient developed antibiotic-associated colitis, prolonging his hospital stay by two weeks. No consistent improvements were observed in exploratory clinical outcome measures, but the severity of neuropsychiatric symptoms reduced with NBM DBS in 3/5 patients. Active stimulation was associated with functional connectivity changes in both the default mode network and the frontoparietal network. Conclusion Low frequency NBM DBS can be safely conducted in DLB patients. This should encourage further exploration of the possible effects of stimulation on neuropsychiatric symptoms and corresponding changes in functional connectivity in cognitive networks. Trial registration number NCT02263937.

Mild cognitive impairment has gained recognition as a construct and a potential prodromal stage to dementia in both Alzheimer's disease and Parkinson's disease (PD). Although mild cognitive impairment has been recognized in the Alzheimer's disease field, it is a relatively more recent topic of interest in PD. Recent advances include the development of diagnostic criteria for PD mild cognitive impairment to provide more uniform definitions for clinical and research use. Studies reveal that mild cognitive impairment in PD is frequent, but also heterogeneous, with variable clinical presentations, differences in its progression to dementia, and likely differences in underlying pathophysiology. Application of the International Parkinson and Movement Disorder Society PD Mild Cognitive Impairment Task Force diagnostic criteria has provided insights regarding cognitive measures, functional assessments, and other key topics that may require additional refinement. Furthermore, it is important to consider definitions of PD mild cognitive impairment in the landscape of other related Lewy body disorders, such as dementia with Lewy bodies, and in the context of prodromal and early-stage PD. This article examines the evolution of mild cognitive impairment in concept and definition, particularly in PD, but also in related disorders such as Alzheimer's disease and dementia with Lewy bodies; the development and application of International Parkinson and Movement Disorder Society PD Mild Cognitive Impairment diagnostic criteria; and insights and future directions for the field of PD mild cognitive impairment. © 2018 International Parkinson and Movement Disorder Society.

OBJECTIVE: To define a practice guideline for biological treatment of dementias for general practitioners in primary care. METHODS: This paper is a short and practical summary of the World Federation of Biological Psychiatry (WFSBP) guidelines for the Biological treatment of Alzheimer's disease and other dementias for treatment in primary care ( Ihl et al. 2011 ). The recommendations were developed by a task force of international experts in the field and are based on randomized controlled studies. RESULTS: Anti-dementia medications neither cure, nor arrest, or alter the course of the disease. The type of dementia, the individual symptom constellation and the tolerability and evidence for efficacy should determine what medications should be used. In treating neuropsychiatric symptoms, psychosocial intervention should be the treatment of first choice. For neuropsychiatric symptoms, medications should only be considered when psychosocial interventions are not adequate and after cautious risk-benefit analysis. CONCLUSIONS: Depending on the diagnostic entity and clinical presentation different anti-dementia drugs can be recommended. These guidelines provide a practical approach for general practitioners managing dementias.

Objective:To conduct a validation study of 123I-N-fluoropropyl-2b-carbomethoxy-3b-(4-iodophenyl) nortropane (123I-FP-CIT) SPECT dopaminergic imaging in the clinical diagnosis of dementia with Lewy bodies (DLB) with autopsy as the gold standard.Methods:Patients >60 years of age with dementia who had undergone 123I-FP-CIT imaging in research studies and who had donated their brain tissue to the Newcastle Brain Tissue Resource were included. All had structured clinical research assessments, and clinical diagnoses were applied by consensus panels using international diagnostic criteria. All underwent 123I-FP-CIT imaging at baseline, and scans were rated as normal or abnormal by blinded raters. Patients were reviewed in prospective studies and after death underwent detailed autopsy assessment, and neuropathologic diagnoses were applied with the use of standard international criteria.Results:Fifty-five patients (33 with DLB and 22 with Alzheimer disease) were included. Against autopsy diagnosis, 123I-FP-CIT had a balanced diagnostic accuracy of 86% (sensitivity 80%, specificity 92%) compared with clinical diagnosis, which had an accuracy of 79% (sensitivity 87%, specificity 72%). Among patients with DLB, 10% (3 patients) met pathologic criteria for Lewy body disease but had normal 123I-FP-CIT imaging.Conclusions:This large autopsy analysis of 123I-FP-CIT imaging in dementia demonstrates that it is a valid and accurate biomarker for DLB, and the high specificity compared with clinical diagnosis (20% higher) is clinically important. The results need to be replicated with patients recruited from a wider range of settings, including movement disorder clinics and general practice. While an abnormal 123I-FP-CIT scan strongly supports Lewy body disease, a normal scan does not exclude DLB with minimal brainstem involvement.Classification of evidence:This study provides Class I evidence that 123I-FP-CIT dopaminergic neuroimaging accurately identifies patients with DLB.

Caring for people with dementia incurs significant stress for carers. Stress has been related to the duration of caring role, the number of weekly hours provided and severity of cognitive impairment. What remains less clear is the impact of neuropsychiatric symptoms and subtype of dementia on carer stress and this study aimed to examine these.Dementia carers were recruited for people with a range of dementia subtypes. Carers were interviewed using the Neuropsychiatric Inventory with the Carer Distress Scale. Cognitive fluctuations were assessed using the Dementia Cognitive Fluctuations Scale. All patients were also examined with The Cambridge Assessment for mental disorders in the elderly.Dementia diagnostic subtype, the presence of cognitive fluctuations and some neuropsychiatric symptoms (psychosis and mood disturbance) did predict carer stress (all at p 0.01) but age, gender and severity of cognitive impairment did not (all p 0.33). Carers of people with dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) experienced more stress than those caring for patients with Alzheimer's disease and vascular dementia. Carer stress was associated with higher levels of psychosis, mood disturbances, daytime sleep and cognitive fluctuations in the person with dementia.This study identified the significant impact on carers of providing care for people with DLB and PDD dementia subtypes and also highlighted the significant impact of providing care for patients with high levels of psychosis, mood disturbances and cognitive fluctuations.

Dementia with Lewy bodies (DLB) is the second most common cause of neurodegenerative dementia in older people, accounting for 10–15% of all cases. It occupies part of a spectrum that includes Parkinson's disease and primary autonomic failure, all of which share a neuritic pathology based upon abnormal aggregation of the synaptic protein alpha-synuclein. It is important to identify DLB patients accurately because they have specific symptoms, impairments and functional disabilities that differ from those of other common dementia syndromes, including Alzheimer's disease, vascular cognitive impairment and frontotemporal dementia. Clinical diagnostic criteria for DLB have been validated against autopsy but fail to detect a substantial minority of cases with atypical presentations that are often due to the presence of mixed pathology. Newly developed rating scales for the core features of DLB (fluctuation, visual hallucinations and parkinsonism) should improve clinical diagnostic accuracy, as should the use of structural and functional neuroimaging. DLB patients frequently have severe neuroleptic sensitivity reactions, which are associated with significantly increased morbidity and mortality. Cholinesterase inhibitor treatment is usually well tolerated and substantially improves cognitive and neuropsychiatric symptoms. Virtually unrecognized 20 years ago, DLB could within this decade be one of the most treatable neurodegenerative disorders of late life.

A new online tool allows mapping of the different classifications of mild cognitive impairment.

To compare the acceptability and feasibility of computerized and pencil-and-paper tests of cognitive function in 85-year-old people.Group comparison of participants randomly allocated to pencil-and-paper (Wechsler Adult Intelligence and Memory Scales) or computerized (Cognitive Drug Research) tests of verbal memory and attention.The Newcastle 85+ Pilot Study was the precursor to the Newcastle 85+ Study a United Kingdom Medical Research Council/Biotechnology and Biological Sciences Research Council cohort study of health and aging in the oldest-old age group.Eighty-one community-dwelling individuals aged 85.Participant and researcher acceptability, completion rates, time taken, validity as cognitive measures, and psychometric utility.Participants randomized to computerized tests were less likely to rate the cognitive function tests as difficult (odds ratio (OR)=0.16, 95% confidence interval (CI)=0.07-0.39), stressful (OR=0.18, 95% CI=0.07-0.45), or unacceptable (OR=0.18, 95% CI=0.08-0.48) than those randomized to pencil-and-paper tests. Researchers were also less likely to rate participants as being distressed in the computer test group (OR=0.19, 95% CI=0.07-0.46). Pencil-and-paper tasks took participants less time to complete (mean+/-standard deviation 18+/-4 minutes vs 26+/-4 minutes) but had fewer participants who could complete all tasks (91% vs 100%). Both types of task were equally good measures of cognitive function.Computerized and pencil-and-paper tests are both feasible and useful means of assessing cognitive function in the oldest-old age group. Computerized tests are more acceptable to participants and administrators.

Dementia with Lewy bodies (DLB) is the second commonest cause of neurodegenerative dementia in older people. It is part of the range of clinical presentations that share a neuritic pathology based on abnormal aggregation of the synaptic protein alpha-synuclein. DLB has many of the clinical and pathological characteristics of the dementia that occurs during the course of Parkinson's disease. Here we review the current state of scientific knowledge on DLB. Accurate identification of patients is important because they have specific symptoms, impairments, and functional disabilities that differ from those of other common types of dementia. Severe neuroleptic sensitivity reactions are associated with significantly increased morbidity and mortality. Treatment with cholinesterase inhibitors is well tolerated by most patients and substantially improves cognitive and neuropsychiatric symptoms. Clear guidance on the management of DLB is urgently needed. Virtually unrecognised 20 years ago, DLB could within this decade be one of the most treatable neurodegenerative disorders of late life.

Objective: Analysis of AD has revealed that the apolipoprotein E locus ( APOE ) cannot account for all of the genetic risk associated with AD. Whole genome scanning in AD families suggests that a chromosome 12 locus may contribute significantly to disease development. The α2-macroglobulin gene ( A2M ) has been suggested as a candidate locus for AD based on analysis of familial AD. Method: We determined, in 195 neuropathologically verified AD cases and 107 age-matched control subjects, the association of two common polymorphisms in A2M (a pentanucleotide deletion 5′ to the bait domain exon, and a valine-1000-isoleucine polymorphism in the thiolester site of the protein). Results: Evidence was observed for linkage disequilibrium between the deletion and Ile1000 polymorphisms. No evidence was observed for an association between the thiolester polymorphism and AD alone or when accounting for the APOE -e4 allele. No alteration in the frequency of the bait domain deletion was observed, although a small excess (4%) of deletion homozygotes was found in the AD group, which were absent in the control population. Conclusions: The A2M deletion polymorphism at most accounts for a small fraction of the genetic contribution toward AD, and this is small compared with APOE . Furthermore, reverse transcriptase PCR of A2M RNA from the brains of patients homozygous for the deletion polymorphism showed that the bait domain exon still is present in the RNA. This suggests that the A2M deletion polymorphism may be nonfunctional and that the chromosome 12 AD locus is situated elsewhere.

Background Although incidence of dementia is known to vary between nations, variation within country has not been explored because most incidence studies are single site or have insufficient numbers to compare sites. Few countries have conducted multisite incidence studies in order to facilitate national comparisons. This study aims to provide robust measures of the variation of the incidence of dementia across sites within England and Wales and produce overall estimates by age and sex. Methods and Findings The Medical Research Council Cognitive Function and Ageing Study used identical methodology in five diverse sites across the United Kingdom, each with different risk patterns and mortality rates. Incidence has been estimated using likelihood-based methods between the first two waves of interviews. Incidence rates rise with age, particularly above the age of 75 y, from 7.4 (95% confidence interval, 3.6–16.1) per 1,000 person years at age 65–69 y to 84.9 (95% confidence interval, 63.0–107.8) per 1,000 person years at age 85 y and above. The rate of increase for both sexes is marked, and continues into the oldest age groups. Hence, it is estimated that approximately 180,000 new cases of dementia occur in England and Wales each year. There is no convincing evidence of variation across sites, and incidence rates do not reflect the variations in the prevalence of possible risk factors in these sites. Conclusion There is no evidence, within England and Wales, of variation in dementia incidence across sites. Dementia incidence rates do not tail off at the oldest ages., No evidence for variation in dementia incidence between areas with different vascular disease risk or between men and women, nor for reduced indidence amongst oldest age groups.