Westman, Eric

Abstract Background and objectives. Sex is an important contributing factor to neuroimaging phenotypes in brain disorders. However, little is known about the contribution of sex differences to the neurodegeneration in dementia with Lewy bodies (DLB). We investigated sex differences in probable DLB patients by using both visual rating scales of lobar atrophy and automated estimations of regional atrophy. Methods. We included 442 probable DLB patients from the European-DLB consortium and the Mayo Clinic who have magnetic resonance imaging (MRI) data available. We assessed sex differences and the sex-by-age interaction in two largely independent samples through visual rating scales of lobar atrophy (n = 333; mean age 73 ± 8 years, 62% males) and automated regional estimations of gray matter (GM) volume and mean cortical thickness (CTh) (n = 165; mean age 69 ± 9 years, 72% males). We used binary logistic regression and ANOVA for statistical analysis. Results. We found a statistically significantly higher likelihood of frontal atrophy measured by the global cortical atrophy-frontal subscale (GCA-F) in males (40% of males had an abnormal GCA-F score versus 29% of females, P-value = 0.006). Using automated estimations, we found smaller GM volumes in 6 cortical regions in males compared with females, as well as smaller GM volume in the entorhinal cortex and thinner olfactory cortices in females, compared with males. The sex-by-age interaction showed statistically significant results in 6 cortical volumes and 7 mean CTh estimations (P-value ≤ 0.05), accentuated in the right middle frontal gyrus (FDR-adjusted P-value = 0.047). These cross-sectional interactions indicated that while females have statistically significantly less atrophy than males at younger ages, differences become non-significant at older ages, with females showing the same level of atrophy than males around the age of 75. Conclusions. This study demonstrates sex differences on brain atrophy in probable DLB. While male DLB patients have a more widespread pattern of cortical atrophy at younger ages, these sex differences tend to disappear with increasing age. Longitudinal studies will help establish these cross-sectional findings and inform on sex and age considerations to the use of MRI in clinical routine, as the field moves towards precision medicine.

Abstract Background Donepezil is an approved therapy for the treatment of Alzheimer’s disease (AD). Results across clinical trials have been inconsistent, which may be explained by design-methodological issues, the pathophysiological heterogeneity of AD, and diversity of included study participants. We investigated whether response to Donepezil differs in mild cognitive impaired (MCI) individuals demonstrating different magnetic resonance imaging (MRI) subtypes. Methods From the Hippocampus Study double-blind, randomized clinical trial, we included 173 MCI individuals (donepezil = 83; placebo = 90) with structural MRI data, at baseline and at clinical follow-up assessments (6-12-month). Efficacy outcomes were the annualized percentage change (APC) in hippocampal, ventricular, and total grey matter volumes, as well as in the AD cortical thickness signature. Participants were classified into MRI subtypes as typical-AD, limbic-predominant, hippocampal-sparing, or minimal atrophy at baseline. We compared two subtyping approaches: the conventional categorical approach and an approach based on continuous dimensions. Results Donepezil treated MCI individuals showed slower atrophy rates compared to the placebo group, but only if they belonged to the minimal atrophy or hippocampal sparing subtypes. Importantly, only the continuous subtyping approach, but not the conventional categorical approach, captured this differential response. Conclusions Our data suggest that individuals with MCI, with hippocampal sparing or minimal atrophy subtype, may have improved benefit from donepezil, as compared with MCI individuals with typical or limbic predominant patterns of atrophy. The newly proposed continuous subtyping approach may have advantages compared to the conventional categorical approach. Future research is warranted to demonstrate the potential of subtype stratification for disease prognosis and response to treatment. Trial registration: Clinical Trial.gov Number: NCT00403520, Submission Date: November 21, 2006.

AbstractBackgroundBiological heterogeneity in Alzheimer’s disease (AD) has been observed and described as subtypes in measures of neurodegeneration (e.g., hypometabolism and atrophy). However, the relationship between these AD subtypes have not been studied. Thus, we aimed to compare and identify pathways associated with hypometabolism‐based and atrophy‐based subtypes.MethodCross‐sectional FDG‐PET and MRI scans from 173 amyloid‐positive AD individuals and 120 amyloid‐negative cognitively normal control individuals from the ADNI were included. Subtypes were identified in each neuroimaging modality by random forest hierarchical clustering using FDG‐PET uptake (measuring hypometabolism) and MRI volumes (measuring atrophy) in cortical and subcortical regions. We performed cross‐modal comparisons of atrophy patterns in hypometabolism‐based subtypes and hypometabolism patterns in atrophy‐based subtypes. To identify neurodegenerative pathways corresponding to each subtype, we used event‐based modelling to predict sequential progression of abnormality in hypometabolism and atrophy across brain regions (hippocampus, AD signature, frontal, posterior areas).ResultClustering revealed four hypometabolism‐based (two relatively limbic‐predominant: 25.7%, 19.8% and two relatively cortical‐predominant: 25.7%, 28.6%) and three atrophy‐based (diffuse: 18.7%, relatively limbic‐predominant: 28.6%, minimal: 52.6%) subtypes of AD with distinct spatial patterns and demographic and clinical characteristics. Cross‐modally, we found comparable AD‐typical atrophy patterns (involving the hippocampus and temporal regions) across the four hypometabolism‐based subtypes and comparable AD‐typical hypometabolism patterns (involving the retrosplenial cortex) across the three atrophy‐based subtypes. Event‐based modelling showed that each hypometabolism‐based subtype was associated with a unique sequential progression of regional hypometabolism, but not regional atrophy (sequence always initiated with frontal atrophy across all subtypes). Similarly, each atrophy‐based subtype was associated with a unique sequential progression of regional atrophy, but not regional hypometabolism (sequence always initiated with hypometabolism in AD signature areas across all subtypes).ConclusionOur findings suggest that hypometabolism‐based and atrophy‐based AD subtypes are not interchangeable. We identified unique metabolic and atrophy pathways specific to each subtype, which supports the notion that neurodegeneration manifests and progresses differentially across subtypes of AD. Despite being measures of neurodegeneration, hypometabolism and atrophy may not share the same extent of heterogeneity, bearing a complex multimodal relationship. Disentangling such relationships and combining complementary biomarkers to investigate heterogeneity could aid personalized treatment of AD.

AbstractBackgroundSubjective cognitive decline (SCD) implies self‐reported cognitive complaints in absence of objective cognitive impairment. SCD has been postulated as an early marker of Alzheimer’s Disease (AD). However, longitudinal studies have linked SCD to future vascular dementia. Thus, we conducted a systematic review and meta‐analysis aiming to synthesise and analyse the available data on the association between SCD and the presence of underlying cerebrovascular pathology measured by MRI.MethodOur study was performed following the PRISMA statement. The search strategy included terms for “subjective cognitive decline” and “white matter signal abnormalities”. It was conducted in 3 databases (PubMed, Scopus and Web of Science) from origin by December 8th, 2021. Two authors screened the studies in a 2‐stepwise approach. Primary studies including cognitively unimpaired adults with subjective cognitive complaints meeting the SCD‐I criteria for SCD that evaluated cerebrovascular pathology based on white matter signal abnormalities (WMSA) on MR images were selected. Study quality was assessed using the FLC 3.0 tool. Meta‐analysis comparing case‐control mean difference of WMSA was performed.ResultOf 240 articles identified, 16 research articles were selected. Of those, 8 case‐control studies were selected for the meta‐analysis. The sample size of the SCD group across the studies ranged from 8 to 906 participants, with age ranged from 40 to 84 years. All eight studies comprised a total of 2.637 SCD individuals. Study quality was deemed moderate (n=6) to high (n=10). The meta‐analysis showed a significant overall effect‐size between the mean WMSA burden of SCD and the controls, that was not significantly heterogeneous (Q(gl=7)=14.20; p=0,04; I2=42,5%). SCD was significantly associated with higher CVP burden based on neuroimaging measures.ConclusionThis is the first study to synthesise and analyse the current evidence on the association between SCD and WMSA. Our findings show the usefulness of SCD as a marker of underlying cerebrovascular pathology. Thus, the potential role of SCD as a preclinical stage of vascular cognitive impairment needs further investigation. Changes in lifestyle (e.g. exercise, diet, smoking cessation), cognitive stimulation or pharmacotherapy may be key to avoid an evolution towards cognitive deterioration in SCD.

AbstractBackgroundSubjective cognitive decline (SCD) in cognitively normal individuals is a relevant predictor of future cognitive decline, dementia, and neurodegeneration. Previous studies showed that the cognitive decline cannot be captured by objective neuropsychological testing in SCD. However, whether sophisticated multivariate approaches such as graph theory can potentially capture subtle cognitive abnormalities in SCD individuals is unknown. This study aimed to assess the cognitive connectome in a relatively large cohort of SCD individuals, in comparison with healthy controls (HC), and assess whether such a connectome differs in SCD across age groups.MethodWe included a total of 390 individuals, of which 211 fulfilled the core SCD criteria proposed by the international SCD Initiative (SCD‐I), and 179 individuals were classified as healthy controls. Participants were stratified into early middle‐age (37–50 years, n = 125), late‐middle‐age (51–64 years, n = 119), and elderly (65–78 years, n = 146) groups. We built cognitive networks from 47 cognitive variables separately for each age and study group using graph theory and compared the groups using global measures of average strength, average global efficiency, average local efficiency, and transitivity.ResultSCD individuals had more segregated networks in all age groups, but more prominently in the late‐middle‐age group. We observed lower within‐module connectivity in SCD individuals, in verbal memory and executive—premotor functions compared with HC. The late middle‐age SCD group showed a pattern of connectivity similar to the elderly HC group. The late‐middle‐age SCD group also showed reduced transitivity compared with the HC. We did not observe significant differences in the rest of the graph measures and in the other groups.ConclusionUsing a sophisticated multivariate approach, we demonstrate that a segregated pattern of cognitive connectivity seems to underlie SCD, particularly in individuals in the age range 51 to 64 years. After the age of 65 years, this pattern tends to be less segregated, contrary to an efficient dedifferentiation process in aging. This, together with subtle signs of brain pathology and other risk factors identified in SCD may increase the likelihood of future cognitive impairment and dementia.

Abstract Background. Dementia with Lewy bodies (DLB) is a neurodegenerative disorder with a wide heterogeneity of symptoms, which suggests the existence of different subtypes. Objectives. We used data-driven analysis of MRI data to investigate DLB subtypes. Methods. We included 165 probable DLB from the Mayo Clinic and 3 centers from the European DLB consortium and performed a hierarchical cluster analysis to identify subtypes based on gray matter (GM) volumes. To characterize the subtypes, we used demographic and clinical data, as well as β-amyloid and cerebrovascular biomarkers at baseline, and cognitive decline over three years. Results. We identified 3 subtypes: an older subtype with reduced cortical GM volumes, worse cognition, and faster cognitive decline (n=49, 30%); a subtype with low GM volumes in fronto-occipital regions (n=76, 46%); and a subtype of younger patients with the highest cortical GM volumes, proportionally lower GM volumes in basal ganglia and the highest frequency of cognitive fluctuations (n=40, 24%). Conclusions. This study shows the existence of MRI subtypes in DLB, which may have implications for clinical workout, research, and therapeutic decisions.

AbstractBackgroundThe field of biological subtypes of Alzheimer’s disease (AD) has recently gained attention as a strong driver of precision medicine and future clinical trials. Neuropathology and neuroimaging studies have consistently identified four subtypes: hippocampal sparing AD, typical AD, limbic predominant AD, and minimal atrophy or minimal tau NFT AD. An important and still unresolved question is whether a truly hippocampal sparing subtype of AD can really exist, since it would challenge the widely accepted model of NFT spread. To address this question, we conducted a systematic review of the literature and performed original analyses on tau PET data.MethodOur systematic review included a search on EMBASE, PubMed, and Web of Science databases up to October 2020. Original analyses included implementation of several methods for AD subtyping on tau PET, and utilization of five complementary cut points to identify hippocampal sparing AD cases both in published studies and in data from the Alzheimer's Disease Neuroimaging Initiative (ADNI).ResultIn the three reviewed neuropathologic studies, we did not find any individual case with tau NFT in the association cortex while completely sparing the hippocampus (i.e., truly hippocampal sparing cases). In the in vivo tau PET studies, more lenient cut points consistently identified AD patients with tau NFT in the association cortex while completely sparing the hippocampus.ConclusionOur current data suggests that the hippocampal sparing subtype of AD does exist ante‐mortem, at earlier stages of the disease, but more research is needed to understand its pathogenesis and progression during life. Based on the findings from both in vivo tau PET and neuropathologic studies, we suggest that there are two possible independent pathways of tau spread: (1) a canonical pathway with early involvement of entorhinal cortex with subsequent involvement of limbic regions before eventually affecting multimodal association cortices, and (2) a less common pathway that affects multimodal association cortices with limbic involvement observed at end stages of the disease. As emphasized in the Murray 2011 study, hippocampal sparing relative to greater cortical involvement defines the phenotype.