Primary Neurodegenerative Dementia Research Articles

Multiple Roles of Paeoniflorin in Alzheimer's Disease.

Alzheimer's disease (AD) is a geriatric disease with the morbidity and mortality continuing to grow, partly due to the aging of the world population. As one of the most common types of primary neurodegenerative dementia, it is mainly due to environmental, epigenetic, immunological, and genetic factors. Paeoniflorin (PF), the main component of paeony extract, plays a more and more important role in the prevention and treatment of AD, including regulating protein, anti-inflammation, antioxidation, and antiapoptosis, protecting glial cells, regulating neurotransmitters and related enzymes and receptors, and inhibiting or activating related signal pathways. This article summarizes the latest researches on the multiple effects and the mechanisms of PF in the treatment to cure AD, providing new insights and research basis for further clinical application of traditional Chinese medicine (TCM) in the treatment of AD.

Case fatality of COVID-19 in patients with neurodegenerative dementia

IntroductionThe elderly population is the group most threatened by COVID-19, with the highest mortality rates. This study aims to analyse the case fatality of COVID-19 in a cohort of patients with degenerative dementia. MethodsWe conducted a descriptive case-control study of a sample of patients diagnosed with primary neurodegenerative dementia. ResultsTwenty-four of the 88 patients with COVID-19 included in the study died: 10/23 (43.4%) patients diagnosed with dementia and 14/65 (21.5%) controls; this difference was statistically significant. DiscussionOur results suggest that case fatality of COVID-19 is significantly higher among patients with primary degenerative dementia than in other patients with similar mean ages and comorbidities.

Análisis de letalidad por COVID-19 en pacientes con demencia neurodegenerativa

IntroductionThe elderly population is the group most threatened by COVID-19, with the highest mortality rates. This study aims to analyse the case fatality of COVID-19 in a cohort of patients with degenerative dementia. MethodsWe conducted a descriptive case-control study of a sample of patients diagnosed with primary neurodegenerative dementia. ResultsTwenty-four of the 88 patients with COVID-19 included in the study died: 10/23 (43.4%) patients diagnosed with dementia and 14/65 (21.5%) controls; this difference was statistically significant. DiscussionOur results suggest that case fatality of COVID-19 is significantly higher among patients with primary degenerative dementia than in other patients with similar mean ages and comorbidities.

Frontotemporal dementia-related gene mutations in clinical dementia patients from a Chinese population.

Alzheimer's disease (AD) and frontotemporal dementia (FTD) are two common forms of primary neurodegenerative dementia that show overlapping clinical symptoms. The aim of this study was to perform genetic analyses on GRN, VCP, CHMP2B, FUS, TARDBP, C9orf72 and MAPT genes in Chinese AD and FTD patients. We performed gene sequencing of the GRN, VCP, CHMP2B, FUS, TARDBP, MAPT and C9orf72 genes in 61 clinical AD and 38 FTD Chinese patients. We identified a known mutation of MAPT (p.Pro301Leu, c.902C>T) in four patients from an autosomal dominant FTD family with behavioral variant FTD (bvFTD) and progressive nonfluent aphasia (PNFA) phenotypes, and a novel mutation in MAPT (p.Leu48Val, c.142 G>C) in a sporadic progressive supranuclear palsy patient. Two novel variations in VCP (p.Thr127Ala, c. 379A>G; p.Asn401Ser, c.1202A>G) were present in both a sporadic FTD and an AD case, and a novel deletion in GRN (560del p.Leufs) was found in a sporadic primary progressive aphasia patient. Mutations of VCP, GRN and MAPT genes are present in Chinese FTD cases. In the case of the MAPT mutation, the family presented with both bvFTD and PNFA phenotypes, while the VCP mutation was also related to an early-onset AD phenotype.

Homocysteine, antioxidant vitamins and lipids as biomarkers of neurodegeneration in Alzheimer's disease versus non-Alzheimer's dementia.

Evidence for the benefit of antioxidants' based therapeutic intervention in dementia are inconsistent. Parallel studies in disease forms of dementia different than Alzheimer's are even less conclusive. In this study, the role of serum levels of homocysteine (tHcy), lipids and antioxidants in predicting the risk of cognitive decline in Alzheimer's disease (AD) versus non-Alzheimer's dementias (n-AD). The objective was to add to the ongoing cumulative research to establish the biochemical baseline for potential nutri-therapeutic intervention in different forms of dementia. 65 participants with dementia (DP-s) were divided into two groups: ADP--patients with Alzheimer's disease and n-ADP--patients with dementia of a different etiology than primary neurodegenerative dementia in the course of Alzheimer's disease. Cognitive function was assessed by Mini-Mental State Examination (MMSE) and related to plasma levels of tHcy, folate, vitamins B-6, B-12, lipids and vitamins A and E for both groups. Also examined were associations between cognitive impairment and several variables (age, education, duration of dementia) that might confound nutrition-cognition associations. A significant reduction in serum vitamin A levels and elevation of total cholesterol levels were shown for the DP-s group compared to those in the control group. Moreover, significant differences were found in MMSE data and serum vitamin E and tHcy levels between patients with ADP and n-ADP. The scores for MMSE showed a correlation with the vitamin E levels and duration of dementia in the ADP group and/or correlation with tHcy, levels of vitamins A and/or E, and duration of dementia in the n-ADP group. The results obtained suggest that elevated serum tHcy and decreased levels of vitamins A and E are associated with an increased risk of non-Alzheimer's dementias, although further studies involving a larger cohort are now needed to verify these results.

Clinical and Neuroimaging Characterization of Chinese Dementia Patients with PSEN1 and PSEN2 Mutations

Background: Alzheimer's disease (AD) and frontotemporal dementia (FTD) are two common forms of primary neurodegenerative dementia. Mutations in 3 genes (PSEN1, PSEN2, and APP) have been identified in patients with early-onset AD. Methods: We performed gene sequencing in PSEN1, PSEN2, and APP in 61 AD and 35 FTD Chinese patients. Amyloid load using ¹¹C-labeled Pittsburgh compound B (¹¹C-PIB) positron emission tomography (PET) and cerebral glucose metabolism using ¹⁸F-fludeoxyglucose PET were evaluated in patients carrying mutations. Results: We identified 1 known pathogenic PSEN1 (p.His163Arg, c.488A>G) mutation and 3 novel PSEN2 mutations in 6 patients. The novel mutation PSEN2 (p.His169Asn, c.505C>A) was identified in 1 patient with familial late-onset AD and in 1 sporadic FTD patient. The PSEN2 (p.Val214Leu, c.640G>T; p.Lys82Arg, c.245A>G) mutations were identified in 2 early-onset AD patients and 1 early-onset AD patient, respectively. Three patients with PSEN2 mutations were observed to have PIB retention on the cortex and striatum. One patient with the FTD phenotype was not observed to have PIB retention. Conclusion: PSEN2 mutations are common in the Chinese Han population with a history of AD and FTD. Pathogenic mutations or risk variants in the PSEN2 gene can influence both FTD and AD phenotypic traits and show variations in neuroimaging characterization. © 2014 S. Karger AG, Basel

Associations of physical activity, insomnia and cognitive impairment in older adults

primary neurodegenerative dementia, and vascular mild cognitive impairment (vMCI). We investigated the prevalence of VCI and its subtypes in a Korean elderly population.Methods: This study was a part of the Korean Longitudinal Study on Health and Aging (KLoSHA) which had been conducted on the residents aged 65 years or older in Seongnam, Korea from September 2005 to August 2006. A simple random sample (N1⁄41118) was drawn from the roster of 61,730 persons aged 65 years or older. Standardized clinical interviews, neurological and physical examinations and comprehensive neuropsychological assessments were administered. Diagnosis of vascular dementia was made according to NINDS-AIREN criteria. Diagnosis of mixed dementia was made according to DSM-IV-TR criteria. And, diagnosis of vMCI was made according to the MCI criteria proposed by the InternationalWorking Groupwith vascular risk factors (Modified Hachinski ischemic scale 4). Results: Ageand sex-standardized prevalence rate of VCI was 4.4% (95% CI1⁄42.9%-5.9%). Ageand sex-standardized prevalence of VD or mixed dementia was 1.4% (95% CI1⁄40.6%-2.3%), and that of vMCI was 3.0% (95% CI1⁄41.8%-4.3%). The prevalence of VCI increased with advancing age (2.3% in 65-69, 5.1% in 70-74, and 6.8% in 75 or older). Gender and educational level had no significant influence on the prevalence of VCI. Conclusions: The prevalence of VCI in Korean elders was comparable to other western countries (5% in Canada, 6.6% inUK) and older age was significantly associated with an increased risk of developing VCI. As operational criteria of VCI is still variable between studies, it is warranted to establish uniform operational criteria for VCI for ensuring validity and comparability in future researches.

Brain biopsy in dementia: clinical indications and diagnostic approach

Brain biopsy may be performed to make a definitive diagnosis in patients with rapidly progressive dementia. To assess the value of this procedure, we previously studied 90 consecutive cerebral biopsies performed in the tertiary referral centre of the National Hospital for Neurology and Neurosurgery, Queen Square between 1989 and 2003 (6 biopsies/year). Fifty-seven percent of all biopsies were diagnostic with Alzheimer's disease (18%), Creutzfeldt-Jakob disease (CJD) (12%) and inflammatory disorders (9%) being the most frequent. In the non-diagnostic group and for the series as a whole non-specific gliosis was the commonest diagnosis (37%). Treatment was altered because of information obtained from neuropathological findings in 11% of cases. To identify changes in practice that may have occurred due to recent advances in clinical assessment and improved histopathological techniques, we performed a follow-up study of 19 brain biopsies (approximately 3 cases/year) carried out for a dementing illness in the same centre between 2004 and 2009. These data suggest that brain biopsy may be less frequently used to help clinical diagnosis whilst its diagnostic yield increased from 57 to 74%. The commonest diagnosis was CJD, mostly suspected during life. Amongst the diagnoses, there were two cases of vasculitis and two cases of primary neurodegenerative dementia. These data suggest that improved clinical selection criteria supported by advances in diagnostic testing may result in brain biopsy being less frequently required, although it may still provide useful diagnostic information in difficult cases. We propose algorithms to aid the clinician in selecting appropriate patients for a biopsy and the neuropathologist in assessing a biopsy specimen.

Invited Article: The Alzheimer disease–frontotemporal lobar degeneration spectrum

Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD) are two frequent forms of primary neurodegenerative dementias. Despite distinctive clinical diagnostic criteria for both brain disorders, differential diagnosis is often complicated by overlapping symptomatology. As we learn more about brain pathology and genetic makeup underlying these dementia disorders, evidence is accumulating for a clinical, pathologic, and genetic spectrum of neurodegenerative brain diseases in which AD and FTLD occur along one continuum. This has important implications for molecular diagnostic testing and genetic counseling of patients with dementia. In this light, we review the molecular genetics of AD and FTLD assessing how AD genes can be implicated in FTLD and conversely FTLD genes in AD, by modifying disease susceptibility. Herein, we focus on recent exciting findings providing further support for an AD-FTLD spectrum.

Association of GSK3B With Alzheimer Disease and Frontotemporal Dementia

Deposits of abnormally hyperphosphorylated tau are a hallmark of several dementias, including Alzheimer disease (AD), and about 10% of familial frontotemporal dementia (FTD) cases are caused by mutations in the tau gene. As a known tau kinase, GSK3B is a promising candidate gene in the remaining cases of FTD and in AD, for which tau mutations have not been found. To examine the promoter of GSK3B and all 12 exons, including the surrounding intronic sequence, in patients with FTD, patients with AD, and aged healthy subjects to identify single-nucleotide polymorphisms associated with disease. Single-nucleotide polymorphism frequency was examined in a case-control cohort of 48 patients with probable AD, 102 patients with FTD, 38 patients with primary progressive aphasia, and 85 aged healthy subjects. Results were followed up in 2 independent AD family samples consisting of 437 multiplex families with AD (National Institute of Mental Health Genetics Initiative AD Study) or 150 sibships discordant for AD (Consortium on Alzheimer's Genetics Study). Several rare sequence variants in GSK3B were identified in the case-control study. An intronic polymorphism (IVS2-68G>A) occurred at more than twice the frequency among patients with FTD (10.8%) and patients with AD (14.6%) than in aged healthy subjects (4.1%). The polymorphism showed association with disease in both follow-up samples independently, although only the Consortium on Alzheimer's Genetics sample showed the same direction of association as the case-control sample. To our knowledge, this is the first evidence that a gene known to be involved in tau phosphorylation, GSK3B, is associated with risk for primary neurodegenerative dementias. This supports previous work in animal models suggesting that such genes are therapeutic targets.

The prevalence of oligoclonal bands in the CSF of patients with primary neurodegenerative dementia.

Recent guidelines from the United States and Europe on the diagnosis and management of dementia include advice that younger patients with dementia should undergo CSF examination, which frequently includes analysis for oligoclonal bands (OCB). The presence of CNS specific OCB has traditionally been considered suggestive of an inflammatory aetiology, although the interpretation of such a finding in the presence of a normal CSF white cell count and protein is more difficult. We reviewed retrospectively the prevalence of OCB, determined using agarose isoelectric focusing, in a series of 131 well characterised patients with a final diagnosis of a degenerative dementia who had undergone CSF examination. The mean age of the patients was 60.0 (SD 8.4) years. Seventy (53%) patients had Alzheimer's disease (AD), forty seven (36 %) had frontotemporal lobar degeneration (FTLD), seven (5%) had Dementia with Lewy bodies and the remaining seven (5%) patients had other rarer neurodegenerative dementias. Neuropathological examination had been performed in fifteen (11%) patients. CNS specific OCB were present in nine (7%) patients in this cohort, all of whom had normal CSF white cell counts: four AD patients (a prevalence of 6%), four FTLD patients (a prevalence of 9%), and one patient with Creutzfeldt-Jakob disease (a prevalence of 25%). Investigation of these patients, including two with neuropathologically verified AD and one with post-mortem confirmed CJD, did not reveal an alternative aetiology for their dementia. A central immune response can occur in primary neurodegenerative dementias, albeit uncommonly.

Transglutaminase‐mediated crosslinking of neural proteins in Alzheimer's disease and other primary dementias

AbstractThe formation of insoluble protein deposits is a common hallmark of most neurodegenerative diseases. The disease‐specific lesions arise from pathogenic modifications of proteins or defects of their breakdown. Transglutaminases posttranslationally modify proteins by transamidation of specific protein‐bound glutamines to specific protein‐bound lysines. This action results in the formation of covalent crosslinks between proteins, a modification likely to have profound effects on nerve cell function. Crosslinking of proteins via Nϵ(γ‐glutamyl)lysine bonds by transglutaminases has been described in in vitro and animal models of neuron loss. Recent findings provided evidence that dysregulation of transglutaminase activity may contribute to the pathology of various neurodegenerative diseases, including polyglutamine expansion diseases and primary neurodegenerative dementias, the prototype of which is Alzheimer's disease (AD). Transglutaminase activity and expression was shown to be elevated in AD and Huntington's disease (HD) compared to age‐matched controls by several studies. Further, crosslinks have been found to colocalize with neurofibrillary tangles characteristic of Alzheimer's pathology by immunocytochemistry. Recent data showed increased crosslink concentrations in the cerebrospinal fluid of HD patients. A series of studies from our laboratory showed that elevated crosslink concentrations in cerebrospinal fluid are characteristic of AD as well as other related dementias associated with the formation of intraneural inclusions. Although many issues remain to be addressed to establish a definitive model for the formation of specific histopathological lesions, crosslinking proteins by transglutaminases offers a plausible explanation for the stabilization of noxious protein aggregates and may reveal a common pathogenic mechanism in various primary neurodegenerative diseases. Drug Dev. Res. 56:458–472, 2002. © 2002 Wiley‐Liss, Inc.

A novel approach to the determination and characterization of HIV dementia.

Neuropsychological studies of the pattern and extent of cognitive impairment in HIV-infected patients have mostly used deviations from control values and/or cut-off scores as criteria for classification of dementia. There is, however, no agreement as to how to define impairment, and classification is imprecise. The current study used a dementia classification matrix, developed with a step-wise linear discriminant analysis of neuropsychological data from patients with primary neurodegenerative dementias, to classify symptomatic HIV patients as demented or non-demented, and further to differentiate cortical and subcortical dementia patterns. Thirty-two male and 2 female patients (mean age 39 +/- 2) with symptomatic HIV disease (mean absolute CD4 count 195 +/- 41) participated in the study. Thirty-five per cent of patients were classified as demented. Of these, 83% showed a subcortical pattern and 17% a cortical profile of deficits. Significant differences between patients classified as subcortically demented and those categorized as normal on neuropsychological measures associated with subcortical integrity further validated the classification. Measures of psychiatric status between subgroups were similar. Since certain treatments may delay or reverse cognitive deficits, the use of an objective classification method based on discriminant analysis may help to identify patients who may benefit from therapy.