Corriveau‐Lecavalier, Nick

Abstract Limbic predominant age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC) is highly prevalent in late life and a common co‐pathology with Alzheimer's disease neuropathologic change (ADNC). LATE‐NC is a slowly progressive, amnestic clinical syndrome. Alternatively, when present with ADNC, LATE‐NC is associated with a more rapid course. With the emergence of anti‐amyloid therapeutics, discrimination of LATE‐NC from ADNC is critical and will lead to greater clinical recognition of amnestic patients without ADNC. Furthermore, co‐pathology with LATE‐NC may influence outcomes of these therapeutics. Thus there is a need to identify patients during life with likely LATE‐NC. We propose criteria for clinical diagnosis of LATE as an initial framework for further validation. In the context of progressive memory loss and substantial hippocampal atrophy, criteria are laid out for probable (amyloid negative) or possible LATE (amyloid biomarkers are unavailable or when amyloid is present, but hippocampal neurodegeneration is out of proportion to expected pure ADNC). Highlights Limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) is a highly prevalent driver of neuropathologic memory loss in late life. LATE neuropathologic change (LATE‐NC) is a common co‐pathology with Alzheimer's disease neuropathologic change (ADNC) and may influence outcomes with emerging disease‐modifying medicines. We provide initial clinical criteria for diagnosing LATE during life either when LATE‐NC is the likely primary driver of symptoms or when observed in conjunction with AD. Definitions of possible and probable LATE are provided.

AbstractBackgroundLimbic‐predominant age‐related TDP‐43 encephalopathy (LATE) is a neuropathologically‐defined disease, and it is frequently comorbid with Alzheimer’s disease neuropathological change (ADNC). However, the neurological syndrome associated with LATE neuropathological change (LATE‐NC) is not defined. We propose a set of clinical criteria for a limbic‐predominant amnestic neurodegenerative syndrome (LANS) that is highly associated with LATE‐NC. These criteria assess degree of certainty (highest, high, moderate, low) based on features that are measurable in vivo, including older age at evaluation, a mild clinical syndrome, impaired semantic knowledge, disproportionate hippocampal atrophy, limbic hypometabolism, absence of neocortical degeneration patterns and low likelihood of neocortical tau. We operationalized these criteria using two large datasets with clinical and pathologic outcomes.MethodWe screened autopsied patients from Mayo Clinic and ADNI cohorts and applied the LANS criteria to those with an antemortem predominant amnestic syndrome (Mayo, n = 165; ADNI, n = 53). We compared frequencies of neuropathological diagnoses across LANS likelihoods, compared longitudinal CDR‐SB trajectories across LANS likelihoods, and stratified ADNC/LATE‐NC patients according to their LANS likelihood and compared their longitudinal CDR‐SB trajectories to those with ADNC or LATE‐NC.ResultADNC, ADNC/LATE‐NC and LATE‐NC accounted for 35%, 37% and 4% of cases in the Mayo cohort, respectively, and 30%, 22%, and 9% of cases in the ADNI cohort, respectively (Fig. 1). ADNC cases had the lowest LANS likelihoods, LATE‐NC patients had the highest likelihoods, and ADNC/LATE‐NC patients had intermediate likelihoods. Patients with high LANS likelihoods had a milder and slower clinical course and more severe temporo‐limbic degeneration compared to those with low likelihoods (Fig. 2). ADNC/LATE‐NC patients with higher likelihoods had more temporo‐limbic degeneration and a slower rate of cognitive decline, and those with lower likelihoods had more lateral temporo‐parietal degeneration and a faster rate of cognitive decline (Fig. 3).ConclusionThe implementation of LANS criteria has implications for disambiguating the different driving etiologies of progressive amnestic presentations in older age to guide prognosis, treatment, and clinical trial design and enrollment. The development of in vivo biomarkers specific to TDP‐43 pathology are needed to further refine molecular associations between LANS and LATE‐NC and precise antemortem diagnoses of LATE.

AbstractObjectivePrion disease classically presents with rapidly progressive dementia, leading to death within months of diagnosis. Advances in diagnostic testing have improved recognition of patients with atypical presentations and protracted disease courses, raising key questions surrounding the relationship between patterns of neurodegeneration and survival. We assessed the contribution of fluorodeoxyglucose (FDG‐PET) imaging for this purpose.MethodsFDG‐PET were performed in 40 clinic patients with prion disease. FDG‐PET images were projected onto latent factors generated in an external dataset to yield patient‐specific eigenvalues. Eigenvalues were input into a clustering algorithm to generate data‐driven clusters, which were compared by survival time.ResultsMedian age at FDG‐PET was 65.3 years (range 23–85). Median time from FDG‐PET to death was 3.7 months (range 0.3–19.0). Four data‐driven clusters were generated, termed “Neocortical” (n = 7), “Transitional” (n = 12), “Temporo‐parietal” (n = 13), and “Deep nuclei” (n = 6). Deep nuclei and transitional clusters had a shorter survival time than the neocortical cluster. Subsequent analyses suggested that this difference was driven by greater hypometabolism of deep nuclei relative to neocortical areas. FDG‐PET‐patterns were not associated with demographic (age and sex) or clinical (CSF total‐tau, 14‐3‐3) variables.InterpretationGreater hypometabolism within deep nuclei relative to neocortical areas associated with more rapid decline in patients with prion disease and vice versa. FDG‐PET informs large‐scale network physiology and may inform the relationship between spreading pathology and survival in patients with prion disease. Future studies should consider whether FDG‐PET may enrich multimodal prion disease prognostication models.

Abstract Neuronal dysfunction in specific brain regions or across distributed brain networks is a known feature of Alzheimer’s disease. An often reported finding in the early stage of the disease is the presence of increased functional MRI (fMRI) blood oxygenation level-dependent signal under task conditions relative to cognitively normal controls, a phenomenon known as ‘hyperactivation’. However, research in the past decades yielded complex, sometimes conflicting results. The magnitude and topology of fMRI hyperactivation patterns have been found to vary across the preclinical and clinical spectrum of Alzheimer’s disease, including concomitant ‘hypoactivation’ in some cases. These incongruences are likely due to a range of factors, including the disease stage at which the cohort is examined, the brain areas or networks studied and the fMRI paradigm utilized to evoke these functional abnormalities. Additionally, a perennial question pertains to the nature of hyperactivation in the context of Alzheimer’s disease. Some propose it reflects compensatory mechanisms to sustain cognitive performance, while others suggest it is linked to the pathological disruption of a highly regulated homeostatic cycle that contributes to, or even drives, disease progression. Providing a coherent narrative for these empirical and conceptual discrepancies is paramount to develop disease models, understand the synergy between hyperactivation and the Alzheimer’s disease pathological cascade and tailor effective interventions. We first provide a comprehensive overview of functional brain changes spanning the course from normal ageing to the clinical spectrum of Alzheimer’s disease. We then highlight evidence supporting a close relationship between fMRI hyperactivation and in vivo markers of Alzheimer’s pathology. We primarily focus on task-based fMRI studies in humans, but also consider studies using different functional imaging techniques and animal models. We then discuss the potential mechanisms underlying hyperactivation in the context of Alzheimer’s disease and provide a testable framework bridging hyperactivation, ageing, cognition and the Alzheimer’s disease pathological cascade. We conclude with a discussion of future challenges and opportunities to advance our understanding of the fundamental disease mechanisms of Alzheimer’s disease, and the promising development of therapeutic interventions incorporating or aimed at hyperactivation and large-scale functional systems.

Abstract Predominant limbic degeneration has been associated with various underlying aetiologies and an older age, predominant impairment of episodic memory and slow clinical progression. However, the neurological syndrome associated with predominant limbic degeneration is not defined. This endeavour is critical to distinguish such a syndrome from those originating from neocortical degeneration, which may differ in underlying aetiology, disease course and therapeutic needs. We propose a set of clinical criteria for a limbic-predominant amnestic neurodegenerative syndrome that is highly associated with limbic-predominant age-related TDP-43 encephalopathy but also other pathologic entities. The criteria incorporate core, standard and advanced features, including older age at evaluation, mild clinical syndrome, disproportionate hippocampal atrophy, impaired semantic memory, limbic hypometabolism, absence of neocortical degeneration and low likelihood of neocortical tau, with degrees of certainty (highest, high, moderate and low). We operationalized this set of criteria using clinical, imaging and biomarker data to validate its associations with clinical and pathologic outcomes. We screened autopsied patients from Mayo Clinic and Alzheimer’s Disease Neuroimaging Initiative cohorts and applied the criteria to those with an antemortem predominant amnestic syndrome (Mayo, n = 165; Alzheimer’s Disease Neuroimaging Initiative, n = 53) and who had Alzheimer’s disease neuropathological change, limbic-predominant age-related TDP-43 encephalopathy or both pathologies at autopsy. These neuropathology-defined groups accounted for 35, 37 and 4% of cases in the Mayo cohort, respectively, and 30, 22 and 9% of cases in the Alzheimer’s Disease Neuroimaging Initiative cohort, respectively. The criteria effectively categorized these cases, with Alzheimer’s disease having the lowest likelihoods, limbic-predominant age-related TDP-43 encephalopathy patients having the highest likelihoods and patients with both pathologies having intermediate likelihoods. A logistic regression using the criteria features as predictors of TDP-43 achieved a balanced accuracy of 74.6% in the Mayo cohort, and out-of-sample predictions in an external cohort achieved a balanced accuracy of 73.3%. Patients with high likelihoods had a milder and slower clinical course and more severe temporo-limbic degeneration compared to those with low likelihoods. Stratifying patients with both Alzheimer’s disease neuropathological change and limbic-predominant age-related TDP-43 encephalopathy from the Mayo cohort according to their likelihoods revealed that those with higher likelihoods had more temporo-limbic degeneration and a slower rate of decline and those with lower likelihoods had more lateral temporo-parietal degeneration and a faster rate of decline. The implementation of criteria for a limbic-predominant amnestic neurodegenerative syndrome has implications to disambiguate the different aetiologies of progressive amnestic presentations in older age and guide diagnosis, prognosis, treatment and clinical trials.

Importance Factors associated with clinical heterogeneity in Alzheimer disease (AD) lay along a continuum hypothesized to associate with tangle distribution and are relevant for understanding glial activation considerations in therapeutic advancement. Objectives To examine clinicopathologic and neuroimaging characteristics of disease heterogeneity in AD along a quantitative continuum using the corticolimbic index (CLix) to account for individuality of spatially distributed tangles found at autopsy. Design, Setting, and Participants This cross-sectional study was a retrospective medical record review performed on the Florida Autopsied Multiethnic (FLAME) cohort accessioned from 1991 to 2020. Data were analyzed from December 2022 to December 2023. Structural magnetic resonance imaging (MRI) and tau positron emission tomography (PET) were evaluated in an independent neuroimaging group. The FLAME cohort includes 2809 autopsied individuals; included in this study were neuropathologically diagnosed AD cases (FLAME-AD). A digital pathology subgroup of FLAME-AD cases was derived for glial activation analyses. Main Outcomes and Measures Clinicopathologic factors of heterogeneity that inform patient history and neuropathologic evaluation of AD; CLix score (lower, relative cortical predominance/hippocampal sparing vs higher, relative cortical sparing/limbic predominant cases); neuroimaging measures (ie, structural MRI and tau-PET). Results Of the 2809 autopsied individuals in the FLAME cohort, 1361 neuropathologically diagnosed AD cases were evaluated. A digital pathology subgroup included 60 FLAME-AD cases. The independent neuroimaging group included 93 cases. Among the 1361 FLAME-AD cases, 633 were male (47%; median [range] age at death, 81 [54-96] years) and 728 were female (53%; median [range] age at death, 81 [53-102] years). A younger symptomatic onset (Spearman ρ = 0.39, P < .001) and faster decline on the Mini-Mental State Examination (Spearman ρ = 0.27; P < .001) correlated with a lower CLix score in FLAME-AD series. Cases with a nonamnestic syndrome had lower CLix scores (median [IQR], 13 [9-18]) vs not (median [IQR], 21 [15-27]; P < .001). Hippocampal MRI volume (Spearman ρ = −0.45; P < .001) and flortaucipir tau-PET uptake in posterior cingulate and precuneus cortex (Spearman ρ = −0.74; P < .001) inversely correlated with CLix score. Although AD cases with a CLix score less than 10 had higher cortical tangle count, we found lower percentage of CD68-activated microglia/macrophage burden (median [IQR], 0.46% [0.32%-0.75%]) compared with cases with a CLix score of 10 to 30 (median [IQR], 0.75% [0.51%-0.98%]) and on par with a CLix score of 30 or greater (median [IQR], 0.40% [0.32%-0.57%]; P = .02). Conclusions and Relevance Findings show that AD heterogeneity exists along a continuum of corticolimbic tangle distribution. Reduced CD68 burden may signify an underappreciated association between tau accumulation and microglia/macrophages activation that should be considered in personalized therapy for immune dysregulation.

Abstract Disruption of the default mode network is a hallmark of Alzheimer’s disease, which has not been extensively examined in atypical phenotypes. We investigated cross-sectional and 1-year longitudinal changes in default mode network sub-systems in the visual and language variants of Alzheimer’s disease, in relation to age and tau. Sixty-one amyloid-positive Alzheimer’s disease participants diagnosed with posterior cortical atrophy (n = 33) or logopenic progressive aphasia (n = 28) underwent structural MRI, resting-state functional MRI and [18F]flortaucipir PET. One-hundred and twenty-two amyloid-negative cognitively unimpaired individuals and 60 amyloid-positive individuals diagnosed with amnestic Alzheimer’s disease were included as controls and as a comparison group, respectively, and had structural and resting-state functional MRI. Forty-one atypical Alzheimer’s disease participants, 26 amnestic Alzheimer’s disease participants and 40 cognitively unimpaired individuals had one follow-up functional MRI ∼1–2 years after the baseline scan. Default mode network connectivity was calculated using the dual regression method for posterior, ventral, anterior ventral and anterior dorsal sub-systems derived from independent component analysis. A global measure of default mode network connectivity, the network failure quotient, was also calculated. Linear mixed-effects models and voxel-based analyses were computed for each connectivity measure. Both atypical and amnestic Alzheimer’s disease participants had lower cross-sectional posterior and ventral and higher anterior dorsal connectivity and network failure quotient relative to cognitively unimpaired individuals. Age had opposite effects on connectivity in Alzheimer’s disease participants and cognitively unimpaired individuals. While connectivity declined with age in cognitively unimpaired individuals, younger Alzheimer’s disease participants had lower connectivity than the older ones, particularly in the ventral default mode network. Greater baseline tau-PET uptake was associated with lower ventral and anterior ventral default mode network connectivity in atypical Alzheimer’s disease. Connectivity in the ventral default mode network declined over time in atypical Alzheimer’s disease, particularly in older participants, with lower tau burden. Voxel-based analyses validated the findings of higher anterior dorsal default mode network connectivity, lower posterior and ventral default mode network connectivity and decline in ventral default mode network connectivity over time in atypical Alzheimer’s disease. Visuospatial symptoms were associated with default mode network connectivity disruption. In summary, default mode connectivity disruption was similar between atypical and amnestic Alzheimer’s disease variants, and discriminated Alzheimer’s disease from cognitively unimpaired individuals, with decreased posterior and increased anterior connectivity and with disruption more pronounced in younger participants. The ventral default mode network declined over time in atypical Alzheimer’s disease, suggesting a shift in default mode network connectivity likely related to tau pathology.