Machulda, Mary M.

AbstractINTRODUCTIONCorticobasal syndrome (CBS) can result from underlying Alzheimer's disease (AD) pathologies. Little is known about the utility of blood plasma metrics to predict positron emission tomography (PET) biomarker‐confirmed AD in CBS.METHODSA cohort of eighteen CBS patients (8 amyloid beta [Aβ]+; 10 Aβ−) and 8 cognitively unimpaired (CU) individuals underwent PET imaging and plasma analysis. Plasma concentrations were compared using a Kruskal–Wallis test. Spearman correlations assessed relationships between plasma concentrations and PET uptake.RESULTSCBS Aβ+ group showed a reduced Aβ42/40 ratio, with elevated phosphorylated tau (p‐tau)181, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) concentrations, while CBS Aβ− group only showed elevated NfL concentration compared to CU. Both p‐tau181 and GFAP were able to differentiate CBS Aβ− from CBS Aβ+ and showed positive associations with Aβ and tau PET uptake.DISCUSSIONThis study supports use of plasma p‐tau181 and GFAP to detect AD in CBS. NfL shows potential as a non‐specific disease biomarker of CBS regardless of underlying pathology.Highlights Plasma phosphorylated tau (p‐tau)181 and glial fibrillary acidic protein (GFAP) concentrations differentiate corticobasal syndrome (CBS) amyloid beta (Aβ)− from CBS Aβ+. Plasma neurofilament light concentrations are elevated in CBS Aβ− and Aβ+ compared to controls. Plasma p‐tau181 and GFAP concentrations were associated with Aβ and tau positron emission tomography (PET) uptake. Aβ42/40 ratio showed a negative correlation with Aβ PET uptake.

Purpose: We describe the communication challenges of four patients with a neurodegenerative disorder consistent with behavioral variant frontotemporal dementia (bvFTD), characterized by early behavioral and personality changes. By describing their clinical profiles, we identify common barriers to functional communication in this population and provide recommendations for how speech-language pathologists (SLPs) might contribute to minimizing them. Method: Four patients with bvFTD were selected from a cohort of patients with progressive communication impairments. Three of them returned for at least one follow-up visit. Case histories are presented along with the results of comprehensive speech and language, neuropsychological, and neurological testing. Results: At the time of initial evaluation, patients were between the ages of 54 and 66 years and had been experiencing symptoms for 1.5–6 years. Consistent with their bvFTD diagnoses, all patients had prominent behavioral and personality changes that impacted communication. Patients 1 and 2 also had mild aphasia at enrollment, primarily characterized by anomia and loss of word meaning. Patients 3 and 4 both had apraxia of speech and moderate-to-severe aphasia at enrollment with prominent anomia and agrammatism. All four patients had impaired executive functioning and relative sparing of visuospatial skills; episodic memory was also impaired for Patients 2 and 4. Even though functional communication was progressively limited for all patients, none of them received regular support from an SLP. Conclusions: This case series adds to a scant, but growing, literature demonstrating that patients with bvFTD have communication impairments. SLPs are uniquely positioned to identify barriers to functional communication and to provide tailored strategy training to the patients and their care partners over the course of their disease. Systematic evaluation of the efficacy of treatment in this population would be valuable. Supplemental Material: https://doi.org/10.23641/asha.25933762

AbstractProgressive apraxia of speech (PAOS) is a 4R tauopathy characterized by difficulties with motor speech planning. Neurodegeneration in PAOS targets the premotor cortex, particularly the supplementary motor area (SMA), with degeneration of white matter (WM) tracts connecting premotor and motor cortices and Broca's area observed on diffusion tensor imaging (DTI). We aimed to assess flortaucipir uptake across speech‐language‐related WM tracts identified using DTI tractography in PAOS. Twenty‐two patients with PAOS and 26 matched healthy controls were recruited by the Neurodegenerative Research Group (NRG) and underwent MRI and flortaucipir‐PET. The patient population included patients with primary progressive apraxia of speech (PPAOS) and non‐fluent variant/agrammatic primary progressive aphasia (agPPA). Flortaucipir PET scans and DTI were coregistered using rigid registration with a mutual information cost function in subject space. Alignments between DTI and flortaucipir PET were inspected in all cases. Whole‐brain tractography was calculated using deterministic algorithms by a tractography reconstruction tool (DSI‐studio) and specific tracts were identified using an automatic fiber tracking atlas‐based method. Fractional anisotropy (FA) and flortaucipir standardized uptake value ratios (SUVRs) were averaged across the frontal aslant tract, arcuate fasciculi, inferior frontal‐occipital fasciculus, inferior and middle longitudinal fasciculi, as well as the SMA commissural fibers. Reduced FA (p < .0001) and elevated flortaucipir SUVR (p = .0012) were observed in PAOS cases compared to controls across all combined WM tracts. For flortaucipir SUVR, the greatest differentiation of PAOS from controls was achieved with the SMA commissural fibers (area under the receiver operator characteristic curve [AUROC] = 0.83), followed by the left arcuate fasciculus (AUROC = 0.75) and left frontal aslant tract (AUROC = 0.71). Our findings demonstrate that flortaucipir uptake is increased across WM tracts related to speech/language difficulties in PAOS.

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.

Background: TAR DNA binding protein 43 (TDP-43) has been shown to be associated with whole hippocampal atrophy in primary age-related tauopathy (PART). It is currently unknown which subregions of the hippocampus are contributing to TDP-43 associated whole hippocampal atrophy in PART. Objective: To identify which specific hippocampal subfield regions are contributing to TDP-43-associated whole hippocampal atrophy in PART. Methods: A total of 115 autopsied cases from the Mayo Clinic Alzheimer Disease Research Center, Neurodegenerative Research Group, and the Mayo Clinic Study of Aging were analyzed. All cases underwent antemortem brain volumetric MRI, neuropathological assessment of the distribution of Aβ (Thal phase), and neurofibrillary tangle (Braak stage) to diagnose PART, as well as assessment of TDP-43 presence/absence in the amygdala, hippocampus and beyond. Hippocampal subfield segmentation was performed using FreeSurfer version 7.4.1. Statistical analyses using logistic regression were performed to assess for associations between TDP-43 and hippocampal subfield volumes, accounting for potential confounders. Results: TDP-43 positive patients ( n = 37, 32%), of which 15/15 were type-α, had significantly smaller whole hippocampal volumes, and smaller volumes of the body and tail of the hippocampus compared to TDP-43 negative patients. Subfield analyses revealed an association between TDP-43 and the molecular layer of hippocampal body and the body of cornu ammonis 1 (CA1), subiculum, and presubiculum regions. There was no association between TDP-43 stage and subfield volumes. Conclusions: Whole hippocampal volume loss linked to TDP-43 in PART is mainly due to volume loss occurring in the molecular layer, CA1, subiculum and presubiculum of the hippocampal body.

Abstract Introduction Meta-analytic studies support that insomnia is a risk factor for cognitive decline and dementia, but limited accounting of confounders reduces their validity. Further, it is unclear whether these associations are driven by specific insomnia phenotypes. In this study, we aimed to assess the relationship between insomnia and longitudinal global cognitive decline in community-dwelling older adults after considering self-reported sleep duration changes and other important characteristics. Methods From the Mayo Clinic Study of Aging (MCSA) cohort, we identified all (age&gt;=50yo) cognitively unimpaired participants at baseline without comorbid neurological disease with at least two previous comprehensive neuropsychological evaluations. Participants with at least two occurrences of insomnia ICD diagnosis (by EMR and Rochester Epidemiological Project data) at least 30 days apart were classified as having insomnia, and those without any instance of diagnosis were considered negative for insomnia. Changes in sleep duration were assessed using the question #16 of BDI-2 and categorized in reduced sleep (yes/no). We fit mixed-effect regression models to assess whether insomnia was associated with standardized global cognitive scores, after adjusting for age, sex, education, APOEe4, composite cardiovascular and metabolic conditions scores, anxiety/depression, reduced sleep, OSA (ICD diagnosis), alcoholism (CAGE≥2), and pain (NSAIDs use). Number of cognitive assessments and time from baseline were included as both fixed and random effects. Multiple interactions (e.g. insomnia*reduced sleep) were included. A backward stepwise procedure maintaining the hierarchical principal for interactions was utilized to reach the most parsimonious models. Results 3063 participants (50.24% males, aged 70±9.73 at baseline) were included. Insomnia alone was not associated with a decrease in global cognition, but when combined with subjective reduction in sleep duration at baseline it was associated with a -0.19 (95% CI: -0.32, -0.07; interaction p=0.01) reduction in global cognitive scores. This was equivalent to approximately 3 additional years of age or 6 cardiometabolic comorbidities at baseline. The effect size was greater than those associated with baseline cognition for having any APOE e4 allele (-0.12) and alcoholism (-0.15). Conclusion Insomnia with reduced sleep duration phenotype is a potentially modifiable risk factor for cognitive decline in older adults. Further studies with objective sleep measures are necessary for objective confirmation. Support (if any) NIA/NIH

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 &amp;lt; .001) and faster decline on the Mini-Mental State Examination (Spearman ρ = 0.27; P &amp;lt; .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 &amp;lt; .001). Hippocampal MRI volume (Spearman ρ = −0.45; P &amp;lt; .001) and flortaucipir tau-PET uptake in posterior cingulate and precuneus cortex (Spearman ρ = −0.74; P &amp;lt; .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.