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Amyloid beta (Aβ) is thought to play a critical role in the pathogenesis of Alzheimer's disease (AD). Prion-like Aβ polymorphs, or "strains", can have varying pathogenicity and may underlie the phenotypic heterogeneity of the disease. In order to develop effective AD therapies, it is critical to identify the strains of Aβ that might arise prior to the onset of clinical symptoms and understand how they may change with progressing disease. Down syndrome (DS), as the most common genetic cause of AD, presents promising opportunities to compare such features between early and advanced AD. In this work, we evaluate the neuropathology and Aβ strain profile in the post-mortem brain tissues of 210 DS, AD, and control individuals. We assayed the levels of various Aβ and tau species and used conformation-sensitive fluorescent probes to detect differences in Aβ strains among individuals and populations. We found that these cohorts have some common but also some distinct strains from one another, with the most heterogeneous populations of Aβ emerging in subjects with high levels of AD pathology. The emergence of distinct strains in DS at these later stages of disease suggests that the confluence of aging, pathology, and other DS-linked factors may favor conditions that generate strains that are unique from sporadic AD.

Formalin‐fixed paraffin‐embedded (FFPE) brain tissue held in tissue banks constitutes a valuable research resource, especially when associated with clinical annotations and longitudinal psychometric testing. Apolipoprotein‐E (APOE) genotyping is important to fully characterise this resource, however older FFPE tissue may not be suitable for genotyping. We performed polymerase chain reaction restriction fragment length polymorphism (PCR‐RFLP) assays on DNA extracted from post‐mortem FFPE brain tissue ranging from 2‐19 years old. A maximum of three years in paraffin was determined for robust APOE genotyping of FFPE tissue using PCR‐RFLP which may suggest prolonged storage of fixed tissue as FFPE blocks may have deleterious effects on DNA. [ABSTRACT FROM AUTHOR]

Background: Corticobasal syndrome is a clinical diagnosis and common pathological causes are corticobasal degeneration, progressive supranuclear palsy and Alzheimer's disease. Objectives: We would like to highlight a rare but important differential of corticobasal syndrome. Methods: A 78‐year‐old female had a 4‐year history of predominantly right‐hand rest tremor, worsening of handwriting but no change in cognition. The clinical examination showed right upper limb postural and kinetic tremor, mild wrist rigidity and reduced amplitude of right‐sided finger tapping. She was initially diagnosed as idiopathic Parkinson's disease. Five years after onset of symptoms, she demonstrated bilateral myoclonic jerks and right upper limb dystonic posturing. She could not copy movements with the right hand. The magnetic resonance imaging (MRI) revealed disproportionate atrophy in the parietal lobes bilaterally. The clinical diagnosis was changed to probable corticobasal syndrome. She passed away 11 years from onset of symptoms at the age of 85 years. She underwent a post‐mortem. Results: The anterior and posterior frontal cortex, anterior cingulate, temporal neocortex, hippocampus and amygdaloid complex demonstrated considerable tau‐related pathology consisting of a dense background of neuropil threads, and rounded, paranuclear neuronal inclusions consistent with Pick bodies. The immunostaining for three microtubule binding domain repeats (3R) tau performed on sections from the frontal and temporal lobes, basal ganglia and midbrain highlighted several inclusions whilst no 4R tau was observed. She was finally diagnosed with Pick's disease. Conclusions: Pick's disease can rarely present with clinical features of corticobasal syndrome. [ABSTRACT FROM AUTHOR]

Background: While mid-life hypertension represents a risk factor for the development of Alzheimer's disease (AD), the risk after the age of 65 is less certain. Establishing relationships between late life hypertension and the pathological changes of AD could be crucial in understanding the relevance of blood pressure as a risk factor for this disorder. Objective: We investigated associations between self-reported late-life hypertension, cognitive status and AD pathology at death. The impact of antihypertensive medication was also examined. Methods: Using the Cornell Medical Index questionnaire, we ascertained whether participants had ever reported hypertension. We also noted use of antihypertensive medication. The donated brains of 108 individuals were assessed for AD pathology using consensus guidelines. Statistical analysis aimed to elucidate relationships between hypertension and AD pathology. Results: We found no associations between self-reported hypertension and cognitive impairment at death. However, those with hypertension were significantly more likely to exhibit lower levels of AD pathology as measured by Thal phase, Braak stage, CERAD score, and NIA-AA criteria—even after controlling for sex, level of education and presence of APOEɛ4 allele(s). No significant associations could be found when examining use of antihypertensive medications. Conclusions: Our findings suggest that late-life hypertension is associated with less severe AD pathology. We postulate that AD pathology may be promoted by reduced cerebral blood flow. [ABSTRACT FROM AUTHOR]

This article explores how the immunoreactivity of phosphorylated TDP-43 (pTDP-43) in fixed post-mortem brain tissue can be affected by factors such as long-term storage and prolonged formalin fixation. The study reveals that extended fixation and long-term storage can weaken the immunoreactivity of pTDP-43, but it remains detectable for diagnostic purposes. These findings have implications for the use of brain tissue stored in brain banks for scientific research. The study also found that other proteins, such as amyloid-β and phosphorylated α-synuclein, are not affected by extended fixation or long-term storage, suggesting that existing tissue samples in brain banks can still be used for research, even if they have been stored for many years. [Extracted from the article]

Pathological tau accumulates in the brain in tauopathies such as Alzheimer's disease, Pick's disease, progressive supranuclear palsy and corticobasal degeneration, and forms amyloid-like filaments incorporating various post-translational modifications (PTMs). Cryo-electron microscopic (cryo-EM) studies have demonstrated that tau filaments extracted from tauopathy brains are characteristic of the disease and share a common fold(s) in the same disease group. Furthermore, the tau PTM profile changes during tau pathology formation and disease progression, and disease-specific PTMs are detected in and around the filament core. In addition, templated seeding has been suggested to trigger pathological tau amplification and spreading in vitro and in vivo , although the molecular mechanisms are not fully understood. Recently, we reported that the cryo-EM structures of tau protofilaments in SH-SY5Y cells seeded with patient-derived tau filaments show a core structure(s) resembling that of the original seeds. Here, we investigated PTMs of tau filaments accumulated in the seeded cells by liquid chromatography/tandem mass spectrometry and compared them with the PTMs of patient-derived tau filaments. Examination of insoluble tau extracted from SH-SY5Y cells showed that numerous phosphorylation, deamidation and oxidation sites detected in the fuzzy coat in the original seeds were well reproduced in SH-SY5Y cells. Moreover, templated tau filament formation preceded both truncation of the N-/C-terminals of tau and PTMs in and around the filament core, indicating these PTMs may predominantly be introduced after the degradation of the fuzzy coat. [ABSTRACT FROM AUTHOR]

The formation of amyloid filaments through templated seeding is believed to underlie the propagation of pathology in most human neurodegenerative diseases. A widely used model system to study this process is to seed amyloid filament formation in cultured cells using human brain extracts. Here, we report the electron cryo‐microscopy structures of tau filaments from undifferentiated seeded SH‐SY5Y cells that transiently expressed N‐terminally HA‐tagged 1N3R or 1N4R human tau, using brain extracts from individuals with Alzheimer's disease or corticobasal degeneration. Although the resulting filament structures differed from those of the brain seeds, some degrees of structural templating were observed. Studying templated seeding in cultured cells, and determining the structures of the resulting filaments, can thus provide insights into the cellular aspects underlying neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

We investigated the cerebral folate system in post-mortem brains and matched cerebrospinal fluid (CSF) samples from subjects with definite Alzheimer's disease (AD) (n = 21) and neuropathologically normal brains (n = 21) using immunohistochemistry, Western blot and dot blot. In AD the CSF showed a significant decrease in 10-formyl tetrahydrofolate dehydrogenase (FDH), a critical folate binding protein and enzyme in the CSF, as well as in the main folate transporter, folate receptor alpha (FRα) and folate. In tissue, we found a switch in the pathway of folate supply to the cerebral cortex in AD compared to neurologically normal brains. FRα switched from entry through FDH-positive astrocytes in normal, to entry through glial fibrillary acidic protein (GFAP)-positive astrocytes in the AD cortex. Moreover, this switch correlated with an apparent change in metabolic direction to hypermethylation of neurons in AD. Our data suggest that the reduction in FDH in CSF prohibits FRα-folate entry via FDH-positive astrocytes and promotes entry through the GFAP pathway directly to neurons for hypermethylation. This data may explain some of the cognitive decline not attributable to the loss of neurons alone and presents a target for potential treatment. [ABSTRACT FROM AUTHOR]

Background: Early diagnosis of Alzheimer's disease (AD) provides an opportunity for early intervention. Cognitive testing has proven to be a reliable way to identify individuals who may be at risk of AD. The Telephone Assessment for Cognitive Screening (TICS) is proficient in screening for cognitive impairment. However, its ability to identify those at risk of developing AD pathology is unknown.Objective: We aim to investigate associations between TICS scores, collected over a period of 13 years, and the cognitive status of participants at death. We also examine relationships between TICS scores and neuropathological indices of AD (CERAD score, Thal phase, and Braak stage).Methods: Between 2004 and 2017, participants from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age underwent cognitive assessment using TICS. Scores from four time points were available for analysis. Cognitive impairment and AD pathology at death was evaluated in 101 participants.Results: TICS scores at time points 2, 3, and 4 were significantly lower in those cognitively impaired at death compared to those considered cognitively normal. There were significant negative correlations between TICS scores and CERAD score and Braak stage at time points 2 and 4. No correlations between Thal phase and TICS were found.Conclusion: Findings indicate that TICS could be used not only to screen for cognitive impairment, but also to identify individuals at risk of developing AD pathology, many years before any overt symptoms occur. Once identified, 'at risk' individuals could be targeted for early interventions which could attenuate the progression of the disease. [ABSTRACT FROM AUTHOR]

Tauopathies are a subset of neurodegenerative diseases characterized by abnormal tau inclusions. Specifically, three-repeat tau and four-repeat tau in Alzheimer's disease, three-repeat tau in Pick's disease (PiD) and four-repeat tau in progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) form amyloid-like fibrous structures that accumulate in neurons and/or glial cells. Amplification and cell-to-cell transmission of abnormal tau based on the prion hypothesis are believed to explain the onset and progression of tauopathies. Recent studies support not only the self-propagation of abnormal tau, but also the presence of conformationally distinct tau aggregates, namely tau strains. Cryogenic electron microscopy analyses of patient-derived tau filaments have revealed disease-specific ordered tau structures. However, it remains unclear whether the ultrastructural and biochemical properties of tau strains are inherited during the amplification of abnormal tau in the brain. In this study, we investigated template-dependent amplification of tau aggregates using a cellular model of seeded aggregation. Tau strains extracted from human tauopathies caused strain-dependent accumulation of insoluble filamentous tau in SH-SY5Y cells. The seeding activity towards full-length four-repeat tau substrate was highest in CBD-tau seeds, followed by PSP-tau and Alzheimer's disease (AD)-tau seeds, while AD-tau seeds showed higher seeding activity than PiD-tau seeds towards three-repeat tau substrate. Abnormal tau amplified in cells inherited the ultrastructural and biochemical properties of the original seeds. These results strongly suggest that the structural differences of patient-derived tau strains underlie the diversity of tauopathies, and that seeded aggregation and filament formation mimicking the pathogenesis of sporadic tauopathy can be reproduced in cultured cells. Our results indicate that the disease-specific conformation of tau aggregates determines the tau isoform substrate that is recruited for templated amplification, and also influences the prion-like seeding activity. [ABSTRACT FROM AUTHOR]

Objectives: Early diagnosis of Alzheimer's disease (AD) is essential for early interventions. Symptoms of depression could represent a prodromal stage of AD. Very early mood alterations may help to stratify those at highest risk of late-life AD. We aim to investigate associations between baseline/longitudinal scores for depression, presence of cognitive impairment and/or AD pathology at death.Methods/design: Between 1991 and 2015, participants from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age underwent 10 waves of assessment using the Geriatric Depression Scale (GDS). AD pathology at death was evaluated in 106 eligible cases. Analyses aimed to examine associations between GDS scores, cognitive status and AD pathology (as measured by Braak stage, Thal phase and CERAD).Results: Baseline GDS scores were significantly higher for those cognitively impaired at death than those cognitively normal. Significantly higher baseline GDS scores were found for those with greater Consortium to Establish a Registry for Alzheimer's Disease (CERAD) scores than those with lower CERAD scores. Similarly, significantly higher baseline GDS scores were found for those with a greater Braak stage than those with lower tau burden. These correlations remained after controlling for age at death, education and APOE ε4, but were less robust. Mean longitudinal GDS scores associated with cognition but not pathology.Conclusions: GDS scores collected approximately 20 years before death were associated with cognitive status and AD pathology at death. We postulate that early AD-related pathological change produces raised GDS scores due to an overlapping neural basis with depression, and that this may be considered as an early diagnostic marker for AD. [ABSTRACT FROM AUTHOR]

Background: An early symptom of Alzheimer's disease (AD) is a disturbance of the circadian rhythm that is associated with disrupted sleep/wake cycles.Objective: To investigate if BMAL1, a key gene that drives the circadian cycle, is epigenetically regulated in brains in relation to longitudinal changes in cognition, sleep quality, and AD neuropathology.Methods: Frontal cortex tissues were acquired from the Manchester Brain Bank (N = 96). DNA methylation at six CpG sites at the promoter of BMAL1, determined using bisulfite pyrosequencing, was tested for associations with Braak stage, CERAD score and Thal phase, longitudinal changes in cognition, sleep measurements and cross-section measures of depressive symptoms (BDI score).Results: Methylation across all the CpGs strongly correlated with each other. We found increased CpG2 methylation with higher Braak (t(92), p = 0.015) and CERAD (t(94), p = 0.044) stages. No significance was found between longitudinal fluid intelligence, processing speed and memory tests, but methylation at CpG1 (r = 0.20, p = 0.05) and CpG4 (r = 0.20, p = 0.05) positively correlated with vocabulary. CpG2 positively correlated with cross-sectional fluid intelligence (r = 0.20 p = 0.05) and vocabulary (r = 0.22 p = 0.03). Though longitudinal analysis revealed no significance between sleep duration, midsleep and efficiency for any of the CpG sites, CpG3 (B = 0.03, 95% CI, p = 0.03) and CpG5 (B = 0.04, 95% CI, p = 0.01) significantly correlated with night wake. CpG4 correlated with depressive symptoms (B = -0.27, 95% CI, p = 0.02).Conclusion: Methylation of BMAL1 associated with tau pathology, changes in cognitive measures, a measure of sleep and depressive symptoms, suggesting an involvement of the circadian cycle. [ABSTRACT FROM AUTHOR]

Background: The pathological features of Alzheimer's disease (AD) are well described but little is known as to how both neurodegeneration and vascular changes might interact in causing cognitive impairment.Objective: The present study aims to investigate relationships between vascular and AD pathology in cognitively healthy and cognitively impaired individuals with a particular emphasis on those at intermediate Braak tau stages.Methods: We investigated the interplay between Braak tau stage and measures of vascular pathology as described by the vascular cognitive impairment neuropathology guidelines (VCING) in 185 brains from the Brains for Dementia Research programme and The University of Manchester Longitudinal Study of Cognition in Healthy Old Age. VCING asserts that at least one large (>10 mm) infarct, moderate/severe occipital leptomeningeal cerebral amyloid angiopathy, and moderate/severe arteriosclerosis in occipital white matter accurately predicts the contribution of cerebrovascular pathology to cognitive impairment.Results: We found that the extent of arteriosclerosis in the occipital white matter did not differ between cognitive groups at intermediate (III-IV) Braak stages whereas moderate/severe leptomeningeal occipital cerebral amyloid angiopathy was greater in cognitively impaired than normal individuals at Braak stage III-IV. This finding remained significant after controlling for effects of age, sex, CERAD score, Thal phase, presence/severity of primary age-related tauopathy, presence/severity of limbic-predominant age-related TDP43 encephalopathy and small vessel disease in basal ganglia.Conclusion: Interventions targeting cerebral amyloid angiopathy may contribute to delay the onset of cognitive impairment in individuals with intermediate Alzheimer's type pathology. [ABSTRACT FROM AUTHOR]

If later time points had been available, a more severe decline in MC scores in AD compared to possible/definite PART would have been anticipated as the rate of both A and tau pathology accelerates compared to PART. This early detectable difference in cognition however is transient, being overcome by onset and progression of A and tau pathology in AD and possible PART, and tau pathology in definite PART. AD pathology, as measured by Braak stage, Thal phase and CERAD score, also correlated with MC test scores at time point 2. [Extracted from the article]

In the present study, we have characterized and compared individuals whose brains were donated as part of The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age (UoM) with those donated through the Manchester arm of the UK Brains for Dementia Research (BDR) program. The aim of this study was to investigate how differences in study recruitment may affect final pathological composition of cohort studies. The UoM cohort was established as a longitudinal study of aging and cognition whereas the BDR program was established, prima facie, to collect brains from both demented and non-demented individuals for the purpose of building a tissue research resource. Consequently, the differences in recruitment patterns generated differences in demographic, clinical, and neuropathological characteristics. There was a higher proportion of recruits with dementia [mostly Alzheimer's disease (AD)] within the BDR cohort than in the UoM cohort. In pathological terms, the BDR cohort was more 'polarized', being more composed of demented cases with high Braak pathology scores and non-demented cases with low Braak scores, and fewer non-AD pathology cases, than the UoM cohort. In both cohorts, cerebral amyloid angiopathy tended to be greater in demented than non-demented individuals. Such observations partly reflect the recruitment of demented and non-demented individuals into the BDR cohort, and also that insufficient study time may have elapsed for disease onset and development in non-demented individuals to take place. Conversely, in the UoM cohort, where there had been nearly 30 years of study time, a broader spread of AD-type pathological changes had 'naturally' evolved in the brains of both demented and non-demented participants. [ABSTRACT FROM AUTHOR]

Objectives: Head injury with loss of consciousness (HI-LOC) is a common occurrence. Some studies have linked such injuries with an increased risk of Alzheimer disease (AD). However, recent large clinicopathologic studies have failed to find a clear relationship between HI-LOC and the pathological changes associated with AD. The present study aims to further investigate the relationship between HI-LOC and AD pathology in the elderly.Methods/design: History of HI-LOC in participants in the University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age was ascertained. The donated brains of 110 of these individuals were assessed for AD pathology using consensus guidelines. Analyses aimed to elucidate relationships between HI-LOC and AD pathology.Results: No associations were found between incidence of HI-LOC and regional AD pathology or any of the three established measures of the neuropathology associated with AD: CERAD score, Thal phase, or Braak stage.Conclusions: Single incidences of HI-LOC may not be sufficient to cause the pathology associated with late-stage AD. Other routes of damage, such as diffuse axonal injury or Lewy body pathology, may play a greater role in causing cognitive impairment associated with head injury. [ABSTRACT FROM AUTHOR]

Background: Brain-derived neurotrophic factor (BDNF) is essential for neurogenesis and has been implicated in Alzheimer's disease (AD). However, few studies have investigated together the epigenetic, transcriptional, and translational regulation of this peptide in the brain in relation to AD.Objective: To investigate mechanisms underlying how BDNF is possibly dysregulated in the brain in relation to aging and AD neuropathology.Methods: Prefrontal cortex tissues were acquired from the Manchester Brain Bank (N = 67). BDNF exon I, and exon IV-containing transcripts and total long 3' transcript gene expression were determined by quantitative PCR and bisulfite pyrosequencing was used to quantify DNA methylation within promoters I and IV. Protein concentrations were quantified via ELISA.Results: BDNF exon IV and total long 3' isoform gene expression levels negatively associated with donor's age at death (IV: r = -0.291, p = 0.020; total: r = -0.354, p = 0.004). Expression of BDNF exon I- containing isoform was significantly higher in Met-carriers of the rs6265 variant, compared to Val-homozygotes, when accounting for donor ages (F = 6.455, p = 0.014). BDNF total long 3' transcript expression was significantly lower in those with early AD neuropathology, compared to those without any neuropathology (p = 0.021). There were no associations between BDNF promoter I and IV methylation or protein levels with ages, rs6265 genotype or AD neuropathology status.Conclusion: Prefrontal cortex BDNF gene expression is associated with aging, rs6265 carrier status, and AD neuropathology in a variant-specific manner that seems to be independent of DNA methylation influences. [ABSTRACT FROM AUTHOR]

The neuropathological changes responsible for cognitive impairment and dementia remain incompletely understood. Longitudinal studies with a brain donation end point allow the opportunity to examine relationships between cognitive status and neuropathology. We report on the first 97 participants coming to autopsy with sufficient clinical information from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age. This study began in 1983 and recruited 6,542 healthy individuals between 1983 and 1994, 312 of whom consented to brain donation. Alzheimer-type pathology was common throughout the cohort and generally correlated well with cognitive status. However, there was some overlap between cognitive status and measures of Alzheimer pathology with 26% of cognitively intact participants reaching either CERAD B or C, 11% reaching Thal phase 4 or 5, and 29% reaching Braak stage III- VI. Cerebral amyloid angiopathy(CAA), α-synuclein, and TDP-43 pathology was less common, but when present correlated well with cognitive status. Possession of APOEɛ4 allele(s) was associated with more severe Alzheimer-type and CAA pathology and earlier death, whereas possession of APOEɛ2 allele(s) had no effect on pathology but was more common in cognitively intact individuals. The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age cohort is pathologically representative when compared with similar studies. Cognitive impairment in life correlates strongly with all pathologies examined and the APOE status of an individual can affect pathology severity and longevity. [ABSTRACT FROM AUTHOR]

Background: Community- or population-based longitudinal studies of cognitive ability with a brain donation end point offer an opportunity to examine relationships between pathology and cognitive state prior to death. Discriminating the earliest signs of dementing disorders, such as Alzheimer disease (AD), is necessary to undertake early interventions and treatments. Methods: The neuropathological profile of brains donated from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age, including CERAD (Consortium to Establish a Registry for Alzheimer’s Disease) and Braak stage, was assessed by immunohistochemistry. Cognitive test scores collected 20 years prior to death were correlated with the extent of AD pathology present at death. Results: Baseline scores from the Memory Circle test had the ability to distinguish between individuals who developed substantial AD pathology and those with no, or low, AD pathology. Predicted test scores at the age of 65 years also discriminated between these pathology groups. The addition of APOE genotype further improved the discriminatory ability of the model. Conclusions: The results raise the possibility of identifying individuals at future risk of the neuropathological changes associated with AD over 20 years before death using a simple cognitive test. This work may facilitate early interventions, therapeutics and treatments for AD by identifying at-risk and minimally affected (in pathological terms) individuals. [ABSTRACT FROM AUTHOR]

Aims: Microglia-driven neuroinflammation can play an important role in the pathophysiology of neurodegenerative disorders. In this study, we sought to characterize the distribution of microglial cell activation in 2 neurodegenerative dementias with distinct protein signatures, Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD) of the TDP subtype, and to determine if there was an anatomical correlation with the phenotypes most commonly associated with these conditions. Methods: The distribution and extent of microglial cell activation was assessed semiquantitatively in the hippocampal formation, cortical gray matter, and subcortical white matter of CD68-immunostained sections of the frontal, temporal, parietal, and occipital cortices from 15 pathologically confirmed cases of AD, 13 cases of FTLD, and 18 controls. Results: Significantly higher levels of microglial cell activation occurred in the subiculum in AD and FTLD than in controls. Additionally, AD had higher microglial activation in the CA1 and FTLD in the hippocampal white matter than the controls. Microglial activation was greater in the dentate gyrus molecular layer in AD than in FTLD. In the cortical regions, the 2 pathological groups differed only in frontal white matter, with the FTLD group showing higher microglial scores. FTLD showed higher microglial activation in the white matter compared to the respective gray matter in the entorhinal, temporal, and frontal regions. Conclusions: Our work expands the knowledge of the distribution and magnitude of microglial activation in these disorders. Additionally, we found some microglial circuit-specific patterns that could help to explain some of the clinical overlap between AD and FTLD-TDP, namely in memory deficits. [ABSTRACT FROM AUTHOR]

Objectives To compare the psychometric performance of the Dementia Knowledge Assessment Scale ( DKAS) and the Alzheimer's Disease Knowledge Scale ( ADKS) when administered to a large international cohort before and after online dementia education. Design Comparative psychometric analysis with pre- and posteducation scale responses. Setting The setting for this research encompassed 7,909 individuals from 124 countries who completed the 9-week Understanding Dementia Massive Open Online Course ( MOOC). Participants Volunteer respondents who completed the DKAS and ADKS before (n = 3,649) and after (n = 878) completion of the Understanding Dementia MOOC. Measurements Assessment and comparison of the DKAS and ADKS included evaluation of scale development procedures, interscale correlations, response distribution, internal consistency, and construct validity. Results The DKAS had superior internal consistency, wider response distribution with less ceiling effect, and better discrimination between pre- and posteducation scores and occupational cohorts than the ADKS. Conclusion The 27-item DKAS is a reliable and preliminarily valid measure of dementia knowledge that is psychometrically and conceptually sound, overcomes limitations of existing instruments, and can be administered to diverse cohorts to measure baseline understanding and knowledge change. [ABSTRACT FROM AUTHOR]

Introduction Frontotemporal lobar degeneration ( FTLD) is classified mainly into FTLD-tau and FTLD- TDP according to the protein present within inclusion bodies. While such a classification implies only a single type of protein should be present, recent studies have demonstrated dual tau and TDP-43 proteinopathy can occur, particularly in inherited FTLD. Methods We therefore investigated 33 patients with FTLD-tau (including 9 with MAPT mutation) for TDP-43 pathological changes, and 45 patients with FTLD- TDP (including 12 with hexanucleotide expansion in C9ORF72 and 12 with GRN mutation), and 23 patients with motor neurone disease (3 with hexanucleotide expansion in C9ORF72), for tauopathy. Results TDP-43 pathological changes, of the kind seen in many elderly individuals with Alzheimer's disease, were seen in only two FTLD-tau cases - a 70-year-old male with exon 10 + 13 mutation in MAPT, and a 73-year-old female with corticobasal degeneration. Such changes were considered to be secondary and probably reflective of advanced age. Conversely, there was generally only scant tau pathology, usually only within hippocampus and/or entorhinal cortex, in most patients with FTLD- TDP or MND. The extent of tau pathology in FTLD- TDP and MND, as with amyloid β protein, may relate to increased age and possession of Apolipoprotein ε4 allele. Conclusion We find no predilection or predisposition towards an accompanying TDP-43 pathology in patients with FTLD-tau, irrespective of presence or absence of MAPT mutation, or that genetic changes associated with FTLD- TDP predispose towards excessive tauopathy. Where the two processes coexist, this is limited and probably causatively independent of each other. [ABSTRACT FROM AUTHOR]

Aims Pathological heterogeneity within patients with frontotemporal lobar degeneration ( FTLD) in general precludes the accurate assignment of diagnostic subtype in life. The aim of this study was to assess the extent of microglial cell activation in FTLD in order to determine whether it might be possible to employ this as a diagnostic marker in vivo using PET ligand [11 C]( R)- PK11195 in order to differentiate cases of FTLD according to histological subtype. Methods The distribution and extent of microglial cell activation was assessed semi-quantitatively in cortical grey and subcortical white matter of CD68 immunostained sections of frontal and temporal cortex from 78 pathologically confirmed cases of FTLD, 13 of Alzheimer's disease ( AD) and 13 controls. Results Significantly higher levels of microglial cell activation than controls occurred in all four regions in FTLD, and in three of the four regions in AD. Microglial activation was greater in frontal subcortical white matter in FTLD than AD, whereas it was higher in temporal cortical grey matter in AD than FTLD. Microglial cell activation was significantly higher in temporal subcortical white matter in FTLD- MAPT than in other genetic ( GRN, C9ORF 72) or non-genetic forms of FTLD. Conclusions The present study suggests that high levels of microglial cell involvement in temporal lobe (subcortical white matter) might serve as a marker of inherited FTLD associated with intronic mutations in MAPT, with a relatively intense signal in this region in PET studies using [11 C]( R)- PK11195 as microglial cell marker could indicate the presence of MAPT mutation in vivo. [ABSTRACT FROM AUTHOR]

The use of post-mortem human tissue is indispensable in studies investigating alterations in metabolite levels in neurodegenerative conditions such as Alzheimer's disease (AD). However, variability between samples may have unknown effects on metabolite concentrations. The aim of this study was to characterize the impact of such variables. Cingulate gyrus was obtained from AD cases and controls, from three brain banks. Gas chromatography-mass spectrometry (GC-MS) was used to measure and compare the levels of 66 identifiable metabolites in these tissues to determine effects of tissue-collection variables. The effect of PMD was further investigated by analysis of rat brain cortex and cerebellum collected following post-mortem delays (PMDs) of zero to 72 h. Metabolite levels between cases and controls were not replicable across cohorts with variable age- and gender-matching, PMD, and control Braak staging. Analysis of rat tissues found significant effects of PMD on 31 of 63 identified metabolites over periods up to 72 h. PMD must be kept under 24 h for metabolomics analyses on brain tissues to yield replicable results. Tissues should also be well age- and gender-matched, and Braak stage in controls should be kept to a minimum in order to minimize the impact of these variables in influencing metabolite variability. [ABSTRACT FROM AUTHOR]

The cytokine interleukin 6 (IL-6) has been linked to the pathogenesis of Alzheimer's disease (AD). This is the first study to investigate the genetic and epigenetic interactions in the control of IL-6 in human brain and its relation to AD neuropathology in prefrontal cortex tissues from AD and controls genotyped for the SNP −174 C/G rs1800795, a polymorphic CpG in which the G allele creates a CpG site. Within CC homozygotes there were significantly higher brain levels of IL-6 protein compared to G allele carriers. The C allele that resulted in an absence of methylation at a CpG was also associated with significant changes in methylation at neighboring CpGs. Furthermore, there were significant differences in methylation between CC and CG/GG at CpG sites in the AD and control groups. That DNA methylation was altered in the brains by the presence of rs1800795, which further correlated with protein levels suggests the presence of a polymorphic CpG and genetic-epigenetic interactions in the regulation of IL-6 in the prefrontal cortex within AD brains. • The IL-6 polymorphism rs1800795 linked to Alzheimer''s disease changes a CpG site. • CC homozygotes show higher brain levels of IL-6 protein compared to G carriers. • C allele altered methylation at a polymorphic CpG and neighbouring CpGs. • Methylation differed in the brains by the presence of CC and CG/GG genotypes. • Results imply genetic-epigenetic interactions in regulation of IL-6 in AD brains. [ABSTRACT FROM AUTHOR]

Chronic low-grade inflammation during aging (inflammaging) is associated with cognitive decline and neurodegeneration; however, the mechanisms underlying inflammaging are unclear. We studied a population ( n = 361) of healthy young and old adults from the MyoAge cohort. Peripheral levels of C-X-C motif chemokine ligand 10 (CXCL10) was found to be higher in older adults, compared with young, and negatively associated with working memory performance. This coincided with an age-related reduction in blood DNA methylation at specific CpGs within the CXCL10 gene promoter. In vitro analysis supported the role of DNA methylation in regulating CXCL10 transcription. A polymorphism (rs56061981) that altered methylation at one of these CpG sites further associated with working memory performance in 2 independent aging cohorts. Studying prefrontal cortex samples, we found higher CXCL10 protein levels in those with Alzheimer's disease, compared with aged controls. These findings support the association of peripheral inflammation, as demonstrated by CXCL10, in aging and cognitive decline. We reveal age-related epigenetic and genetic factors which contribute to the dysregulation of CXCL10 . [ABSTRACT FROM AUTHOR]

Abstract: Frontotemporal lobar degeneration (FTLD) is a highly familial neurodegenerative disease. It has recently been shown that the most common genetic cause of FTLD and amyotrophic lateral sclerosis (ALS) is a hexanucleotide repeat expansion in C9ORF72. To investigate whether this expansion was specific to the FTLD/ALS disease spectrum, we genotyped the hexanucleotide repeat region of C9ORF72 in a large cohort of patients with Alzheimer''s disease (AD). A normal range of repeats was found in all cases. We conclude that the hexanucleotide repeat expansion is specific to the FTLD/ALS disease spectrum. [Copyright &y& Elsevier]