Citations

AbstractIntroductionAlzheimer's disease (AD) patients ≥70 years show smaller medial temporal volumes despite less 18F‐flortaucipir‐positron emission tomography (PET) uptake than younger counterparts. We investigated whether TAR DNA‐binding protein 43 (TDP‐43) was contributing to this volume‐uptake mismatch.MethodsSeventy‐seven participants with flortaucipir‐PET and volumetric magnetic resonance imaging underwent postmortem AD and TDP‐43 pathology assessments. Bivariate‐response linear regression estimated the effect of age and TDP‐43 pathology on volume and/or flortaucipir standardized uptake volume ratios of the hippocampus, amygdala, entorhinal, inferior temporal, and midfrontal cortices.ResultsOlder participants had lower hippocampal volumes and overall flortaucipir uptake. TDP‐43‐immunoreactivity correlated with reduced medial temporal volumes but was unrelated to flortaucipir uptake. TDP‐43 effect size was consistent across the age spectrum. However, at older ages, the cohort mean volumes moved toward those of TDP‐43‐positives, reflecting the increasing TDP‐43 pathology frequency with age.DiscussionTDP‐43 pathology is a relevant contributor driving the volume‐uptake mismatch in older AD participants.Highlights TDP‐43 pathology affects medial temporal volume loss but not tau radiotracer uptake. Greater TDP‐43 pathology effect is seen in old age due to its increasing frequency. TDP‐43 pathology is a relevant driver of the volume‐uptake mismatch in old AD patients.

AbstractBackgroundGlobular glial tauopathy (GGT) has been associated with frontotemporal dementia syndromes; little is known about the clinical and imaging characteristics of GGT and how they differ from other non‐globular glial 4‐repeat tauopathies (N4GT) such as progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD).MethodsFor this case–control study the Mayo Clinic brain banks were queried for all cases with an autopsy‐confirmed diagnosis of GGT between 1 January 2011 and 31 October 2021. Fifty patients with N4GT (30 PSP, 20 CBD) were prospectively recruited and followed by the Neurodegenerative Research Group at Mayo Clinic, Minnesota. Magnetic resonance imaging was used to characterize patterns of gray/white matter atrophy, MR‐parkinsonism index, midbrain volume, and white matter hyperintensities.18F‐Fluorodeoxyglucose‐, 11C Pittsburg compound‐, and 18F‐flortaucipir‐positron emission tomography scans were reviewed.ResultsTwelve patients with GGT were identified: 83% were women compared to 42% in NG4T (p = 0.02) with median age at death 76.5 years (range: 55–87). The most frequent clinical features were eye movement abnormalities, parkinsonism, behavioral changes followed by pyramidal tract signs and motor speech abnormalities. Lower motor neuron involvement was present in 17% and distinguished GGT from NG4T (p = 0.035). Primary progressive apraxia of speech was the most frequent initial diagnosis (25%); 50% had a Parkinson‐plus syndrome before death. Most GGT patients had asymmetric frontotemporal atrophy with matching hypometabolism. GGT patients had more gray matter atrophy in temporal lobes, normal MR‐parkinsonism index, and larger midbrain volumes.ConclusionsFemale sex, lower motor neuron involvement in the context of a frontotemporal dementia syndrome, and asymmetric brain atrophy with preserved midbrain might be suggestive of underlying GGT.

Background: Dementia, vascular disease, and cancer increase with age, enabling complex comorbid interactions. Understanding vascular and cancer contributions to dementia risk and neuropathology in oldest-old may improve risk modification and outcomes. Objective: Investigate the contributions of vascular factors and cancer to dementia and neuropathology. Methods: Longitudinal clinicopathologic study of prospectively followed Mayo Clinic participants dying≥95 years-old who underwent autopsy. Participants were stratified by dementia status and compared according to demographics, vascular risk factors, cancer, and neuropathology. Results: Participants (n = 161; 83% female; 99% non-Hispanic whites)≥95 years (95–106 years-old) with/without dementia did not differ based on demographics. APOE ɛ2 frequency was higher in no dementia (20/72 [28%]) versus dementia (11/88 [12%]; p = 0.03), but APOE ɛ4 frequency did not differ. Coronary artery disease was more frequent in no dementia (31/72 [43%]) versus dementia (23/89 [26%]; p = 0.03) associated with 56% lower dementia odds (odds ratio [OR] = 0.44 [confidence interval (CI) = 0.19–0.98]; p = 0.04) and fewer neuritic/diffuse plaques. Diabetes had an 8-fold increase in dementia odds (OR = 8.42 [CI = 1.39–163]; p = 0.02). Diabetes associated with higher cerebrovascular disease (Dickson score; p = 0.05). Cancer associated with 63% lower dementia odds (OR = 0.37 [CI = 0.17–0.78]; p < 0.01) and lower Braak stage (p = 0.01). Conclusion: Cancer exposure in the oldest-old was associated with lower odds of dementia and tangle pathology, whereas history of coronary artery disease was associated with lower odds of dementia and amyloid-β plaque pathology. History of diabetes mellitus was associated with increased odds of dementia and cerebrovascular disease pathology. Cancer-related mechanisms and vascular risk factor reduction strategies may alter dementia risk and neuropathology in oldest-old.

Introduction: In the context of Alzheimer’s disease phenotypes, patients may present with symptoms and signs that do not exclusively fit into one of the existing phenotypic categories, which often delays timely diagnosis and initiation of services to optimize patient awareness and coping. Case Report: A 74-year-old woman presented with the complaint of progressive word-finding difficulty, raising our suspicion for primary progressive aphasia. Clinical evaluations, however, also revealed emerging cortical visual deficits consistent with posterior cortical atrophy. During evaluation 1 year later, Gerstmann syndrome was evident. Her in vivo neuroimaging was positive for beta-amyloid and tau biomarkers of Alzheimer’s disease pathology. Conclusion: In addition to contributing to the literature on the heterogeneity of the clinical manifestations of Alzheimer’s disease, this report highlights that a breakdown in the visual-lexical interface can account for anomia in posterior cortical atrophy at least in some cases. Other relevant clinical insights pertinent to this case are discussed.

ObjectiveThis study was undertaken to assess cross‐sectional and longitudinal [18F]‐flortaucipir positron emission tomography (PET) uptake in pathologically confirmed frontotemporal lobar degeneration (FTLD) and to compare FTLD to cases with high and low levels of Alzheimer disease (AD) neuropathologic changes (ADNC).MethodsOne hundred forty‐three participants who had completed at least one flortaucipir PET and had autopsy‐confirmed FTLD (n = 52) or high (n = 58) or low ADNC (n = 33) based on Braak neurofibrillary tangle stages 0–IV versus V–VI were included. Flortaucipir standard uptake value ratios (SUVRs) were calculated for 9 regions of interest (ROIs): an FTLD meta‐ROI, midbrain, globus pallidum, an AD meta‐ROI, entorhinal, inferior temporal, orbitofrontal, precentral, and medial parietal. Linear mixed effects models were used to compare mean baseline SUVRs and annual rate of change in SUVR by group. Sensitivity and specificity to distinguish FTLD from high and low ADNC were calculated.ResultsBaseline uptake in the FTLD meta‐ROI, midbrain, and globus pallidus was greater in FTLD than high and low ADNC. No region showed a greater rate of flortaucipir accumulation in FTLD. Baseline uptake in the AD‐related regions and orbitofrontal and precentral cortices was greater in high ADNC, and all showed greater rates of accumulation compared to FTLD. Baseline differences were superior to longitudinal rates in differentiating FTLD from high and low ADNC. A simple baseline metric of midbrain/inferior temporal ratio of flortaucipir uptake provided good to excellent differentiation between FTLD and high and low ADNC (sensitivities/specificities = 94%/95% and 71%/70%).InterpretationThere are cross‐sectional and longitudinal differences in flortaucipir uptake between FTLD and high and low ADNC. However, optimum differentiation between FTLD and ADNC was achieved with baseline uptake rather than longitudinal rates. ANN NEUROL 2022;92:1016–1029

Background: The hippocampus and temporal lobe are atrophic in typical amnestic Alzheimer’s disease (tAD) and are used as imaging biomarkers in treatment trials. However, a better understanding of how temporal structures differ across atypical AD phenotypes and relate to cognition is needed. Objective: Our goal was to compare temporal lobe regions between tAD and two atypical AD phenotypes (logopenic progressive aphasia (LPA) and posterior cortical atrophy (PCA)), and assess cognitive associations. Methods: We age and gender-matched 77 tAD participants to 50 LPA and 27 PCA participants, all of which were amyloid-positive. We used linear mixed-effects models to compare FreeSurfer-derived hippocampal volumes and cortical thickness of entorhinal, inferior and middle temporal, and fusiform gyri, and to assess relationships between imaging and memory, naming, and visuospatial function across and within AD phenotype. Results: Hippocampal volume and entorhinal thickness were smaller bilaterally in tAD than LPA and PCA. PCA showed greater right inferior temporal and bilateral fusiform thinning and LPA showed greater left middle and inferior temporal and left fusiform thinning. Atypical AD phenotypes differed with greater right hemisphere thinning in PCA and greater left hemisphere thinning in LPA. Verbal and visual memory related most strongly to hippocampal volume; naming related to left temporal thickness; and visuospatial related to bilateral fusiform thickness. Fewer associations remained when examined within AD group. Conclusion: Atypical AD phenotypes are associated with greater thinning of lateral temporal structures, with relative sparing of medial temporal lobe, compared to tAD. These findings may have implications for future clinical trials in AD.

AbstractA 57‐year‐old man presented with dynamic aphasia with evolving agrammatism and anomia. Additionally, he exhibited emerging atypical parkinsonism and features of behavioral variant frontotemporal dementia. Insights pertinent to this complex clinical presentation are discussed.

AbstractThis study aimed to assess and compare the burden of transactive response DNA‐binding protein of 43 kDa (TDP‐43) pathology and clinical features of amyotrophic lateral sclerosis (ALS) in three age groups. All cases were from the Mayo Clinic brain bank for neurodegenerative disorders and most were followed longitudinally in the ALS Clinic. Cases with moderate‐to‐severe Alzheimer's disease neuropathological change were excluded. The 55 cases included in the study were divided into three groups by age at death: 75 years or older (old‐ALS, n = 8), 64–74 years (middle‐ALS, n = 23), and 63 years or younger (young‐ALS, n = 24). Clinical features, including disease duration, initial symptoms, and ALS Cognitive Behavior Score (ALS‐CBS), were summarized. Sections of paraffin‐embedded tissue from the motor cortex, basal forebrain, medial temporal lobe, and middle frontal gyrus were processed for phospho‐TDP‐43 immunohistochemistry. The burden of TDP‐43 pathology was analyzed using digital image analysis. The TDP‐43 burden in the limbic system (i.e., amygdala, dentate gyrus and CA1 sector of the hippocampus, subiculum, and entorhinal cortex) was greater in old‐ALS than in young‐ALS and middle‐ALS. TDP‐43 burden in the middle frontal gyrus was sparse and did not differ between the three groups. The average of ALS‐CBS was not different between the three groups. The present study shows that the amygdala and hippocampus are vulnerable to TDP‐43 pathology in older patients with ALS. We discuss the evidence for and against this pathology being related to concurrent limbic‐predominant, age‐related TDP‐43 encephalopathy neuropathologic change.

AbstractIntroductionApolipoprotein E (APOE) ε4 is an important genetic risk factor for typical Alzheimer's disease (AD), influencing brain volume and tau burden. Little is known about its influence in atypical presentations of AD.MethodsAn atypical AD cohort of 140 patients diagnosed with either posterior cortical atrophy or logopenic progressive aphasia underwent magnetic resonance imaging and positron emission tomography. Linear mixed effects models were fit to assess the influence of APOE ε4 on cross‐sectional and longitudinal regional metrics.ResultsAt baseline, APOE ε4 carriers had smaller hippocampal and amygdala volumes and greater tau standardized uptake volume ratio in the hippocampus and entorhinal cortex compared to non‐carriers while longitudinally, APOE ε4 non‐carriers showed faster rates of atrophy and tau accumulation in the entorhinal cortex, with faster tau accumulation in the hippocampus.DiscussionAPOE ε4 influences patterns of neurodegeneration and tau deposition and was associated with more medial temporal involvement, although there is evidence that non‐carriers may be catching up over time.