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Concept: Lewy body

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In retired professional association football (soccer) players with a past history of repetitive head impacts, chronic traumatic encephalopathy (CTE) is a potential neurodegenerative cause of dementia and motor impairments. From 1980 to 2010, 14 retired footballers with dementia were followed up regularly until death. Their clinical data, playing career, and concussion history were prospectively collected. Next-of-kin provided consent for six to have post-mortem brain examination. Of the 14 male participants, 13 were professional and 1 was a committed amateur. All were skilled headers of the ball and had played football for an average of 26 years. Concussion rate was limited in six cases to one episode each during their careers. All cases developed progressive cognitive impairment with an average age at onset of 63.6 years and disease duration of 10 years. Neuropathological examination revealed septal abnormalities in all six post-mortem cases, supportive of a history of chronic repetitive head impacts. Four cases had pathologically confirmed CTE; concomitant pathologies included Alzheimer’s disease (N = 6), TDP-43 (N = 6), cerebral amyloid angiopathy (N = 5), hippocampal sclerosis (N = 2), corticobasal degeneration (N = 1), dementia with Lewy bodies (N = 1), and vascular pathology (N = 1); and all would have contributed synergistically to the clinical manifestations. The pathological diagnosis of CTE was established in four individuals according to the latest consensus diagnostic criteria. This finding is probably related to their past prolonged exposure to repetitive head impacts from head-to-player collisions and heading the ball thousands of time throughout their careers. Alzheimer’s disease and TDP-43 pathologies are common concomitant findings in CTE, both of which are increasingly considered as part of the CTE pathological entity in older individuals. Association football is the most popular sport in the world and the potential link between repetitive head impacts from playing football and CTE as indicated from our findings is of considerable public health interest. Clearly, a definitive link cannot be established in this clinico-pathological series, but our findings support the need for further systematic investigation, including large-scale case-control studies to identify at risk groups of footballers which will justify for the implementation of protective strategies.

Concepts: Alzheimer's disease, Pathology, Parkinson's disease, Dementia, Lewy body, Autopsy, Cerebral amyloid angiopathy, Football

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To predict the risk of probable dementia with Lewy bodies (DLB) competing with Alzheimer disease (AD) dementia by hippocampal volume (HV) in patients with mild cognitive impairment (MCI) with impairments in amnestic or nonamnestic cognitive domains.

Concepts: Alzheimer's disease, Memory, Parkinson's disease, Hippocampus, Dementia, Lewy body, Dementia with Lewy bodies, Mild cognitive impairment

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The progressive aging of the world’s population makes a higher prevalence of neurodegenerative diseases inevitable. The necessity for an accurate, but at the same time, inexpensive and minimally invasive, diagnostic test is urgently required, not only to confirm the presence of the disease but also to discriminate between different types of dementia to provide the appropriate management and treatment. In this study, attenuated total reflection FTIR (ATR-FTIR) spectroscopy combined with chemometric techniques were used to analyze blood plasma samples from our cohort. Blood samples are easily collected by conventional venepuncture, permitting repeated measurements from the same individuals to monitor their progression throughout the years or evaluate any tested drugs. We included 549 individuals: 347 with various neurodegenerative diseases and 202 age-matched healthy individuals. Alzheimer’s disease (AD; n = 164) was identified with 70% sensitivity and specificity, which after the incorporation of apolipoprotein ε4 genotype (APOE ε4) information, increased to 86% when individuals carried one or two alleles of ε4, and to 72% sensitivity and 77% specificity when individuals did not carry ε4 alleles. Early AD cases (n = 14) were identified with 80% sensitivity and 74% specificity. Segregation of AD from dementia with Lewy bodies (DLB; n = 34) was achieved with 90% sensitivity and specificity. Other neurodegenerative diseases, such as frontotemporal dementia (FTD; n = 30), Parkinson’s disease (PD; n = 32), and progressive supranuclear palsy (PSP; n = 31), were included in our cohort for diagnostic purposes. Our method allows for both rapid and robust diagnosis of neurodegeneration and segregation between different dementias.

Concepts: Alzheimer's disease, Neurology, Neurodegenerative disorders, Parkinson's disease, Dementia, Progressive supranuclear palsy, Lewy body, Dementia with Lewy bodies

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Mechanisms of protein misfolding are of increasing interest in the aetiology of neurodegenerative diseases characterized by protein aggregation and tangles including Amyotrophic Lateral Sclerosis (ALS), Alzheimer’s disease (AD), Parkinson’s disease (PD), Lewy Body Dementia (LBD), and Progressive Supranuclear Palsy (PSP). Some forms of neurodegenerative illness are associated with mutations in genes which control assembly of disease related proteins. For example, the mouse sticky mutation sti, which results in undetected mischarging of tRNA(Ala) with serine resulting in the substitution of serine for alanine in proteins causes cerebellar Purkinje cell loss and ataxia in laboratory animals. Replacement of serine 422 with glutamic acid in tau increases the propensity of tau aggregation associated with neurodegeneration. However, the possibility that environmental factors can trigger abnormal folding in proteins remains relatively unexplored. We here report that a non-protein amino acid, β-N-methylamino-L-alanine (BMAA), can be misincorporated in place of l-serine into human proteins. We also report that this misincorporation can be inhibited by l-serine. Misincorporation of BMAA into human neuroproteins may shed light on putative associations between human exposure to BMAA produced by cyanobacteria and an increased incidence of ALS.

Concepts: Alzheimer's disease, Amino acid, Neurology, Amyotrophic lateral sclerosis, Neurodegenerative disorders, Parkinson's disease, Dementia, Lewy body

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Clinical trials using cells derived from embryonic ventral mesencephalon have shown that transplanted dopaminergic neurons can survive and function in the long term, as demonstrated by in vivo brain imaging using (18)F-fluorodopa and (11)C-raclopride positron emission tomography. Here we report the postmortem analysis of a patient with Parkinson’s disease who 24 y earlier underwent unilateral transplantation of embryonic dopaminergic neurons in the putamen and subsequently exhibited major motor improvement and recovery of striatal dopaminergic function. Histopathological analysis showed that a dense, near-normal graft-derived dopaminergic reinnervation of the putamen can be maintained for a quarter of a century despite severe host brain pathology and with no evidence of immune response. In addition, ubiquitin- and α-synuclein-positive inclusions were seen, some with the appearance of typical Lewy bodies, in 11-12% of the grafted dopaminergic neurons, reflecting the spread of pathology from the host brain to the transplants. Because the clinical benefits induced by transplantation in this patient were gradually lost after 14 y posttransplantation, our findings provide the first reported evidence, to our knowledge, that even a viable dopaminergic graft giving rise to extensive striatal reinnervation may lose its efficacy if widespread degenerative changes develop in the host brain.

Concepts: Alzheimer's disease, Nervous system, Pathology, Positron emission tomography, Parkinson's disease, Substantia nigra, Dopamine, Lewy body

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To investigate the efficacy and safety of zonisamide as an adjunct to levodopa therapy for parkinsonism in patients with dementia with Lewy bodies (DLB).

Concepts: Alzheimer's disease, Randomized controlled trial, Parkinson's disease, Dementia, Progressive supranuclear palsy, Alpha-synuclein, Lewy body, Dementia with Lewy bodies

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Inheritance of the ε4 allele of apolipoprotein E (APOE) increases a person’s risk of developing both Alzheimer’s disease (AD) and Lewy body dementia (LBD), yet the underlying mechanisms behind this risk are incompletely understood. The recent identification of reduced APOE DNA methylation in AD postmortem brains prompted this study to investigate APOE methylation in LBD.

Concepts: Alzheimer's disease, DNA, Death, Parkinson's disease, Apolipoprotein E, Dementia, Lewy body, Dementia with Lewy bodies

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Abstract Mutations in the gene encoding glucocerebrosidase (GBA1) cause Gaucher disease (GD), a lysosomal storage disease with recessive inheritance. Glucocerebrosidase (GCase) is a lysosomal lipid hydrolase that digests glycolipid substrates, such as glucosylceramide and glucosylsphingosine. GBA1 mutations have been implicated in Lewy body diseases (LBDs), such as Parkinson’s disease and dementia with Lewy bodies. Parkinsonism occurs more frequently in certain type of GD, and GBA1 mutation carriers are more likely to have LBDs than non-carriers. Furthermore, GCase is often found in Lewy bodies, which is composed of α-synuclein fibrils as well as a variety of proteins and vesicles. In this review, we discuss potential mechanisms of action of GBA1 mutations in LBDs with particular emphasis on α-synuclein aggregation by reviewing the current literature on the role of GCase in lysosomal functions and glycolipid metabolism.

Concepts: Alzheimer's disease, Lysosomal storage disease, Parkinson's disease, Alpha-synuclein, Lewy body, Dementia with Lewy bodies, Gaucher's disease, Glucocerebrosidase

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Parkinson’s disease is a highly debilitating neurodegenerative condition whose pathological hallmark is the presence in nerve cells of proteinacious deposits, known as Lewy bodies, composed primarily of amyloid fibrils of α-synuclein. Several missense mutations in the gene encoding α-synuclein have been associated with familial variants of Parkinson’s disease and have been shown to affect the kinetics of the aggregation of the protein. Using a combination of experimental and theoretical approaches, we present a systematic in vitro study of the influence of disease-associated single-point mutations on the individual processes involved in α-synuclein aggregation into amyloid fibrils. We find that lipid-induced fibril production and surface catalyzed fibril amplification are the processes most strongly affected by these mutations and show that familial mutations can induce dramatic changes in the crucial processes thought to be associated with the initiation and spreading of the aggregation of α-synuclein.

Concepts: Alzheimer's disease, Mutation, Parkinson's disease, In vitro, Point mutation, Alpha-synuclein, Lewy body, Dementia with Lewy bodies

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Misidentification delusions (MDs) are considered relatively rare psychopathologic phenomena that may occur within the context of psychiatric or neurological conditions. The purpose of this study was to assess the prevalence of MD in different types of dementia, correlate the presence of MD with demographic and clinical variables, and validate a specific questionnaire. We examined 146 subjects with Alzheimer disease, 21 with Lewy body dementia, 6 with frontotemporal dementia, and 13 with vascular dementia (subcortical type), who were consecutively enrolled in the study from 2 Memory Clinics. Patients had a mean age of 78.7±6.4 years and an Mini-Mental State Examination average score of 16.9±6.1. The Neuropsychiatric Inventory delusion subscale and a new Misidentification Delusion Questionnaire aimed at specific assessment of 11 delusional misidentification syndromes were administrated to the caregivers. On the basis of the Neuropsychiatric Inventory, MDs were present in 33.3% of the subjects, whereas according to the Misidentification Delusion Questionnaire they were present in 36.0% of the subjects. Specifically, 34.2% of Alzheimer disease, 52.4% of Lewy body dementia, and 46.1% of vascular dementia patients experienced at least 1 MD. None of the patients with frontotemporal dementia developed MD. The most frequent MD was house misidentification, followed by splitting of people and reduplicative paramnesia. Our self-administered questionnaire proved to be an accurate and specific tool for the detection of MD.

Concepts: Alzheimer's disease, Neurology, Parkinson's disease, Dementia, Psychiatry, Lewy body, Delusional misidentification syndrome, Frontotemporal lobar degeneration