Citations

AbstractBackgroundDementia with Lewy bodies (DLB) is a neurodegenerative disorder that presents with a variety of clinical symptoms. Part of the clinical heterogeneity within DLB has been related to the atrophy/sparing of the hippocampus. We extended that previous research by investigating whether different atrophy patterns exist in DLB, beyond and above the atrophy/sparing of the hippocampus, and whether those patterns contribute to the clinical heterogeneity in DLB. We aimed to identify DLB atrophy subtypes using a hypothesis‐free data‐driven clustering approach based on regional gray matter (GM) volumes and characterize the resulting subtypes across key measures.MethodWe included data from three centers of the European DLB consortium. A high‐resolution 3D T1‐weigthed magnetization prepared rapid gradient echo (MPRAGE) sequence was acquired for 97 DLB patients. Eighty‐four cortical regions and 12 subcortical regions from Mayo Clinic Adult Lifespan Template (https://www.nitrc.org/projects/mcalt/) atlases were obtained. Clusters of DLB patients were then determined using the random forest method. Between‐group differences in key demographic, clinical, MRI volumes and cerebrospinal fluid biomarkers (CSF) (amyloid‐beta, phosphorylated‐tau) were performed for clusters characterization.ResultWe identified three subtypes of DLB patients, with distinct patterns of GM volumes and differences in several clinical and demographic measures. Cluster 1 (C1) included 32 DLB patients (33%), cluster 2 (C2) included 29 DLB patients (30%), and cluster 3 (C3) included 36 DLB patients (37%). The clusters differed in age, with C1 being significantly older (72±8.6) than C3 (66±9.5) (F=3.93, p=0.02). C1 was characterized by lower volumes in fronto‐temporal regions and had a higher frequency of visual hallucinations (68%, vs. C2 35%). C2 showed lower volumes in occipital regions. C3 had higher GM volumes overall compared with the other two clusters and presented with a higher frequency of cognitive fluctuations (91%, vs. C1 67%). There were no differences between groups in CSF biomarkers. These results were independent of cluster differences in age and global GM volume.ConclusionThere are distinct patterns of brain atrophy in patients with DLB. These patterns seem to differentially contribute to the frequencies of visual hallucinations and cognitive fluctuations, independently of differences in age and global GM volume across subtypes.

AbstractIntroductionHarboring two copies of the apolipoprotein E (APOE) ε2 allele strongly protects against Alzheimer's disease (AD). However, the effect of this genotype on gray matter (GM) volume in cognitively unimpaired individuals has not yet been described.MethodsMulticenter brain magnetic resonance images (MRIs) from cognitively unimpaired ε2 homozygotes were matched (1:1) against all other APOE genotypes for relevant confounders (n = 223). GM volumes of ε2 genotypic groups were compared to each other and to the reference group (APOE ε3/ε3).ResultsCarrying at least one ε2 allele was associated with larger GM volumes in brain areas typically affected by AD and also in areas associated with cognitive resilience. APOE ε2 homozygotes, but not APOE ε2 heterozygotes, showed larger GM volumes in areas related to successful aging.DiscussionIn addition to the known resistance against amyloid‐β deposition, the larger GM volumes in key brain regions may confer APOE ε2 homozygotes additional protection against AD‐related cognitive decline.

AbstractBackgroundAlzheimer’s disease (AD) is a heterogeneous disease. Recent neuropathology and neuroimaging studies have sought to formalize this heterogeneity by defining AD subtypes based on the distribution of tau neurofibrillary tangle pathology and regional brain atrophy. These studies consistently revealed the existence of four subtypes: typical, limbic‐predominant, hippocampal‐sparing, and minimal atrophy AD. We will give an overview on the current state‐of‐the‐art, leveraging on the first systematic review and meta‐analysis on subtype studies based on neuropathological and neuroimaging data, recently published by our group (Ferreira et al. 2020 Neurology). We will also present a conceptual framework to guide subtype studies in the future. Our ultimate goal was to advance our current understanding of mechanisms driving heterogeneity in AD dementia and its pre‐dementia stages.MethodThe EMBASE, PubMed and Web of Science databases were consulted for AD subtype studies based on neuropathological or neuroimaging data. We calculated meta‐analytical estimates on key demographic, clinical, and CSF biomarker measures. Prevalence values for the subtypes were also calculated. We summarized and integrated all the data on a hypothetical conceptual framework.ResultOur meta‐analytical analysis shows that typical AD displays tau neurofibrillary tangle pathology and atrophy both in hippocampus and association cortex, and has a pooled frequency of 55%. Limbic‐predominant, hippocampal‐sparing, and minimal atrophy AD had a pooled frequency of 21%, 17%, and 15%, respectively. Between‐subtype differences were found in age at onset, age at assessment, sex distribution, years of education, global cognitive status, disease duration, APOE ε4 genotype, and CSF biomarker levels.ConclusionWe identified two core dimensions of heterogeneity: “typicality” and “severity”. We propose that these two dimensions determine individuals’ belonging to one of the AD subtypes based on the combination of protective factors, risk factors, and comorbid non‐AD brain pathologies. This model is envisioned to aid with framing hypotheses, study design, results interpretation, and understanding mechanisms in future subtype studies. Unraveling the heterogeneity within AD is critical for implementing precision medicine approaches and for ultimately developing successful disease‐modifying drugs for AD.