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Background and Objectives: Sporadic cerebral small vessel disease (CSVD) is a class of important pathologic processes known to affect the aging brain and to contribute to cognitive impairment. We aimed to identify clinical risk factors associated with postmortem CSVD in middle-aged to older adults., Methods: We developed and tested risk models for their predictive accuracy of a pathologic diagnosis of nonamyloid CSVD and cerebral amyloid angiopathy (CAA) in a retrospective sample of 160 autopsied cases from the Edinburgh Brain Bank. Individuals aged 40 years and older covering the spectrum of healthy aging and common forms of dementia (i.e., highly-prevalent etiologies such as Alzheimer disease (AD), vascular cognitive impairment (VCI), and mixed dementia) were included. We performed binomial logistic regression models using sample splitting and cross-validation methods. Demographics, lifestyle habits, traditional vascular risk factors, chronic medical conditions, APOE4 , and cognitive status were assessed as potential predictors., Results: Forty percent of our sample had a clinical diagnosis of dementia (AD = 33, VCI = 26 and mixed = 5) while others were cognitively healthy (n = 96). The mean age at death was 73.8 (SD 14.1) years, and 40% were female. The presence of none-to-mild vs moderate-to-severe nonamyloid CSVD was predicted by our model with good accuracy (area under the curve [AUC] = 0.84, sensitivity [SEN] = 72%, specificity [SPE] = 95%), with the most significant clinical predictors being age, history of cerebrovascular events, and cognitive impairment. The presence of CAA pathology was also predicted with high accuracy (AUC = 0.86, SEN = 93%, SPE = 79%). Significant predictors included alcohol intake, history of cerebrovascular events, and cognitive impairment. In a subset of atypical dementias (n = 24), our models provided poor predictive performance for both nonamyloid CSVD (AUC = 0.50) and CAA (AUC = 0.43)., Discussion: CSVD pathology can be predicted with high accuracy based on clinical factors in patients within the spectrum of AD, VCI, and normal aging. Whether this prediction can be enhanced by the addition of fluid and neuroimaging biomarkers warrants additional study. Improving our understanding of clinical determinants of vascular brain health may lead to novel strategies in the prevention and treatment of vascular etiologies contributing to cognitive decline., Classification of Evidence: This study provides Class II evidence that selected clinical factors accurately distinguish between middle-aged to older adults with and without cerebrovascular small vessel disease (amyloid and nonamyloid) pathology., Competing Interests: C. Dallaire-Théroux held a Frederick Banting and Charles Best Canada Graduate Scholarship Doctoral Award from the Canadian Institutes of Health Research (CIHR; #406235) at the time of study design, data collection and analysis. Her research journey in Edinburgh for data collection was sponsored by the Michael-Smith Foreign Study Supplements from the CIHR (#172804). C. Smith is the Director of The Edinburgh Brain Bank, which was funded by the UK Medical Research Council (MR/L016400/1) at the time of the study. All other authors report no disclosures relevant to the manuscript. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp., (© 2024 American Academy of Neurology.)

Objective: To investigate Tau pathology using multimodal biomarkers of neurodegeneration and neurocognition in participants with myotonic dystrophy type 1 (DM1)., Methods: We recruited twelve participants with DM1 and, for comparison, two participants with Alzheimer's Disease (AD). Participants underwent cognitive screening and social cognition testing using the Dépistage Cognitif de Québec (DCQ), among other tests. Biomarkers included Tau PET with [18F]-AV-1451, CSF (Aβ, Tau, phospho-Tau), and plasma (Aβ, Tau, Nf-L, GFAP) studies., Results: Of the twelve DM1 participants, seven completed the full protocol (Neurocognition 11/12; PET 7/12, CSF 9/12, plasma 12/12). Three DM1 participants were cognitively impaired (CI). On average, CI DM1 participants had lower scores on the DCQ compared to cognitively unimpaired (CU) DM1 participants (75.5/100 vs. 91.4/100) and were older (54 vs. 44 years old) but did not differ in years of education (11.3 vs. 11.1). The majority (6/7) of DM1 participants had no appreciable PET signal. Only one of the CI participants presented with elevated Tau PET SUVR in bilateral medial temporal lobes. This participant was the eldest and most cognitively impaired, and had the lowest CSF Aβ 1-42 and the highest CSF Tau levels, all suggestive of co-existing AD. CSF Tau and phospho-Tau levels were higher in the 3 CI compared to CU DM1 participants, but with a mean value lower than that typically observed in AD. Nf-L and GFAP were elevated in most DM1 participants (9/11 and 8/11, respectively). Finally, CSF phospho-Tau was significantly correlated with plasma Nf-L concentrations., Conclusions and Relevance: We observed heterogenous cognitive and biomarker profiles in individuals with DM1. While some participants presented with abnormal PET and/or CSF Tau, these patterns were highly variable and only present in a small subset. Although DM1 may indeed represent a non-AD Tauopathy, the Tau-PET tracer used in this study was unable to detect an in vivo Tau DM1 signature in this small cohort. Interestingly, most DM1 participants presented with elevated plasma Nf-L and GFAP levels, suggestive of other, possibly related, central brain alterations which motivate further research. This pioneering study provides novel insights towards the potential relationship between biomarkers and neurocognitive deficits commonly seen in DM1., (© 2022. The Author(s).)

Cerebrovascular disease (CVD) has been associated with cognitive impairment. Yet, our understanding of vascular contribution to cognitive decline has been limited by heterogeneity of definitions and assessment, as well as its occurrence in cognitively healthy aging. Therefore, we aimed to establish the natural progression of CVD associated with aging. We conducted a retrospective observational study of 63 cognitively healthy participants aged 19-84 years selected through the histological archives of the CHU de Québec. Assessment of CVD lesions was performed independently by 3 observers blinded to clinical data using the Vascular Cognitive Impairment Neuropathology Guidelines (VCING). We found moderate to almost perfect interobserver agreement for most regional CVD scores. Atherosclerosis (ρ = 0.758) and arteriolosclerosis (ρ = 0.708) showed the greatest significant association with age, followed by perivascular hemosiderin deposits (ρ = 0.432) and cerebral amyloid angiopathy (CAA; ρ = 0.392). Amyloid and tau pathologies were both associated with higher CVD load, but only CAA remained significantly associated with amyloid plaques after controlling for age. Altogether, these findings support the presence of multiple CVD lesions in the brains of cognitively healthy adults, the burden of which increases with age and can be quantified in a reproducible manner using standardized histological scales such as the VCING., (© 2021 American Association of Neuropathologists, Inc. All rights reserved.)

Importance: Optimal blood pressure (BP) targets for the prevention of cognitive impairment remain uncertain., Objective: To explore the association of intensive (ie, lower than usual) BP reduction vs standard BP management with the incidence of cognitive decline and dementia in adults with hypertension., Data Sources and Study Selection: A systematic review and meta-analysis of randomized clinical trials that evaluated the association of intensive systolic BP lowering on cognitive outcomes by searching MEDLINE, Embase, CENTRAL, Web of Science, CINAHL, PsycINFO, the International Clinical Trials Registry Platform, and ClinicalTrials.gov from database inception to October 27, 2020., Data Extraction and Synthesis: Data screening and extraction were performed independently by 2 reviewers based on Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. The risk of bias was assessed using the Cochrane risk of bias 2 tool. Random-effects models with the inverse variance method were used for pooled analyses. The presence of potential heterogeneity was evaluated with the I2 index., Main Outcomes and Measures: The primary outcome was cognitive decline. Secondary outcomes included the incidence of dementia, mild cognitive impairment (MCI), cerebrovascular events, serious adverse events, and all-cause mortality., Results: From 7755 citations, we identified 16 publications from 5 trials with 17 396 participants (mean age, 65.7 years [range, 63.0-80.5 years]; 10 562 [60.5%] men) and 2 additional ongoing trials. All 5 concluded trials included in quantitative analyses were considered at unclear to high risk of bias. The mean follow-up duration was 3.3 years (range, 2.0 to 4.7 years). Intensive BP reduction was not significantly associated with global cognitive performance (standardized mean difference, 0.01; 95% CI, -0.04 to 0.06; I2 = 0%; 4 trials; 5246 patients), incidence of dementia (risk ratio [RR], 1.09; 95% CI, 0.32 to 3.67; I2 = 27%; 2 trials; 9444 patients) or incidence of MCI (RR, 0.91; 95% CI, 0.73 to 1.14; I2 = 74%; 2 trials; 10 774 patients) when compared with standard treatment. However, a reduction of cerebrovascular events in the intensive group was found (RR, 0.79; 95% CI, 0.67 to 0.93; I2 = 0%; 5 trials; 17 396 patients) without an increased risk of serious adverse events or mortality., Conclusions and Relevance: In this study, there was no significant association between BP reduction and lower risk of cognitive decline, dementia, or MCI. The certainty of this evidence was rated low because of the limited sample size, the risk of bias of included trials, and the observed statistical heterogeneity. Therefore, current available evidence does not justify the use of lower BP targets for the prevention of cognitive decline and dementia.

The behavioural variant of frontotemporal dementia (bvFTD) is a frequent cause of early-onset dementia. The diagnosis of bvFTD remains challenging because of the limited accuracy of neuroimaging in the early disease stages and the absence of molecular biomarkers, and therefore relies predominantly on clinical assessment. BvFTD shows significant symptomatic overlap with non-degenerative primary psychiatric disorders including major depressive disorder, bipolar disorder, schizophrenia, obsessive-compulsive disorder, autism spectrum disorders and even personality disorders. To date, ∼50% of patients with bvFTD receive a prior psychiatric diagnosis, and average diagnostic delay is up to 5-6 years from symptom onset. It is also not uncommon for patients with primary psychiatric disorders to be wrongly diagnosed with bvFTD. The Neuropsychiatric International Consortium for Frontotemporal Dementia was recently established to determine the current best clinical practice and set up an international collaboration to share a common dataset for future research. The goal of the present paper was to review the existing literature on the diagnosis of bvFTD and its differential diagnosis with primary psychiatric disorders to provide consensus recommendations on the clinical assessment. A systematic literature search with a narrative review was performed to determine all bvFTD-related diagnostic evidence for the following topics: bvFTD history taking, psychiatric assessment, clinical scales, physical and neurological examination, bedside cognitive tests, neuropsychological assessment, social cognition, structural neuroimaging, functional neuroimaging, CSF and genetic testing. For each topic, responsible team members proposed a set of minimal requirements, optimal clinical recommendations, and tools requiring further research or those that should be developed. Recommendations were listed if they reached a ≥ 85% expert consensus based on an online survey among all consortium participants. New recommendations include performing at least one formal social cognition test in the standard neuropsychological battery for bvFTD. We emphasize the importance of 3D-T1 brain MRI with a standardized review protocol including validated visual atrophy rating scales, and to consider volumetric analyses if available. We clarify the role of 18F-fluorodeoxyglucose PET for the exclusion of bvFTD when normal, whereas non-specific regional metabolism abnormalities should not be over-interpreted in the case of a psychiatric differential diagnosis. We highlight the potential role of serum or CSF neurofilament light chain to differentiate bvFTD from primary psychiatric disorders. Finally, based on the increasing literature and clinical experience, the consortium determined that screening for C9orf72 mutation should be performed in all possible/probable bvFTD cases or suspected cases with strong psychiatric features., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Alzheimer's disease diagnosis requires postmortem visualization of amyloid and tau deposits. As brain atrophy can provide assessment of consequent neurodegeneration, our objective was to predict postmortem neurofibrillary tangles (NFT) from in vivo MRI measurements., Methods: All participants with neuroimaging and neuropathological data from the Alzheimer's Disease Neuroimaging Initiative, the National Alzheimer's Coordinating Center and the Rush Memory and Aging Project were selected (n = 186). Two hundred and thirty two variables were extracted from last MRI before death using FreeSurfer. Nonparametric correlation analysis and multivariable support vector machine classification were performed to provide a predictive model of Braak NFT staging., Results: We demonstrated that 59 of our MRI variables, mostly temporal lobe structures, were significantly associated with Braak NFT stages ( P  < .005). We obtained a 62.4% correct classification rate for discrimination between transentorhinal, limbic, and isocortical groups., Discussion: Structural neuroimaging may therefore be considered as a potential biomarker for early detection of Alzheimer's disease-associated neurofibrillary degeneration.

Molecular imaging techniques using 18 F-fluorodeoxyglucose, amyloid tracers, and, more recently, tau ligands have taken dementia research by storm and undoubtedly improved our understanding of neurodegenerative diseases. The ability to image in vivo the pathological substrates of degenerative diseases and visualize their downstream impact has led to improved models of pathogenesis, better differential diagnosis of atypical conditions, as well as focused subject selection and monitoring of treatment in clinical trials aimed at delaying or preventing the symptomatic phase of Alzheimer's disease. In this article, we present the main molecular imaging techniques used in research and practice. We further summarize the key findings brought about by each technique individually and more recently, as adjuncts to each other. Specific limitations of each imaging modality are discussed, as well as recommendations to overcome them. A nonvalidated clinical algorithm is proposed for earlier and more accurate identification of complex/atypical neurodegenerative diseases., (Copyright © 2018 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Sporadic Alzheimer's disease (AD), as opposed to its autosomal dominant form, is likely caused by a complex interaction of genetic, environmental, and health lifestyle factors. Twin studies indicate that sporadic AD heritability could be between 58% and 79%, around half of which is explained by the ε4 allele of the apolipoprotein E (APOE4). We hypothesized that genes associated with known risk factors for AD, namely hypertension, hypercholesterolemia, obesity, diabetes, and cardiovascular disease, would contribute significantly to the remaining heritability. We analyzed 22 AD-associated single-nucleotide polymorphisms (SNPs), associated with these risk factors, that were included in the sequencing data of the Alzheimer's Disease Neuroimaging Initiative 1 data set, which included 355 participants with mild cognitive impairment (MCI). We built survival models with the selected SNPs to predict progression of MCI to probable AD over the 10-year follow-up of the study. The rs391300 SNP, located on the serine racemase (SRR) gene and linked to increased susceptibility to type 2 diabetes, was associated with progression from MCI to probable AD., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: The standard method of ascertaining Alzheimer's disease (AD) remains postmortem assessment of amyloid plaques and neurofibrillary degeneration. Vascular pathology, Lewy bodies, TDP-43, and hippocampal sclerosis are frequent comorbidities. There is therefore a need for biomarkers that can assess these etiologies and provide a diagnosis in vivo., Objective: We conducted a systematic review of published radiological-pathological correlation studies to determine the relationship between antemortem magnetic resonance imaging (MRI) and neuropathological findings in AD., Methods: We explored PubMed in June-July 2015 using "Alzheimer's disease" and combinations of radiological and pathological terms. After exclusion following screening and full-text assessment of the 552 extracted manuscripts, three others were added from their reference list. In the end, we report results based on 27 articles., Results: Independently of normal age-related brain atrophy, AD pathology is associated with whole-brain and hippocampal atrophy and ventricular expansion as observed on T1-weighted images. Moreover, cerebral amyloid angiopathy and cortical microinfarcts are also related to brain volume loss in AD. Hippocampal sclerosis and TDP-43 are associated with hippocampal and medial temporal lobe atrophy, respectively. Brain volume loss correlates more strongly with tangles than with any other pathological finding. White matter hyperintensities observed on proton density, T2-weighted and FLAIR images are strongly related to vascular pathologies, but are also associated with other histological changes such as gliosis or demyelination., Conclusion: Cerebral atrophy and white matter changes in the living brain reflect underlying neuropathology and may be detectable using antemortem MRI. In vivo MRI may therefore be an avenue for AD pathological staging.