Citations

AbstractObjectivePrimary progressive apraxia of speech (PPAOS) is associated with imaging abnormalities in the lateral premotor cortex (LPC) and supplementary motor area (SMA). It is not known whether greater involvement of these regions in either hemisphere is associated with demographics, presenting, and/or longitudinal features.MethodsIn 51 prospectively recruited PPAOS patients who completed [18F]‐fluorodeoxyglucose (FDG) positron emission tomography (PET), we classified patients as left‐dominant, right‐dominant, or symmetric, based on visual assessment of the LPC and SMA on FDG‐PET. SPM and statistical analyses of regional metabolic values were performed. Diagnosis of PPAOS was made if apraxia of speech was present and aphasia absent. Thirteen patients completed ioflupane‐123I (dopamine transporter [DAT]) scans. We compared cross‐sectional and longitudinal clinicopathological, genetic, and neuroimaging characteristics across the three groups, with area under the receiver‐operating curve (AUROC) determined as a measure of effect size.ResultsIn all, 49% of the PPAOS patients were classified as left‐dominant, 31% as right‐dominant, and 20% as symmetric, which was supported by results from the SPM and regional analyses. There were no differences in baseline characteristics. Longitudinally, right‐dominant PPAOS showed faster rates of progression of ideomotor apraxia (AUROC 0.79), behavioral disturbances (AUROC 0.84), including disinhibition symptoms (AUROC 0.82) and negative behaviors (AUROC 0.82), and parkinsonism (AUROC 0.75) compared to left‐dominant PPAOS. Symmetric PPAOS showed faster rates of dysarthria progression compared to left‐dominant (AUROC 0.89) and right‐dominant PPAOS (AUROC 0.79). Five patients showed abnormal DAT uptake. Braak neurofibrillary tangle stage differed across groups (p = 0.01).ConclusionsPatients with PPAOS and a right‐dominant pattern of hypometabolism on FDG‐PET have the fastest rates of decline of behavioral and motor features.

Background: Phosphorylated cytoplasmic tau inclusions correlate with and precede cognitive deficits in Alzheimer’s disease (AD). However, pathological tau accumulation and relationships to synaptic changes remain unclear. Objective: To address this, we examined postmortem brain from 50 individuals with the full spectrum of AD (clinically and neuropathologically). Total tau, pTau231, and AMPA GluR1 were compared across two brain regions (entorhinal and middle frontal cortices), as well as clinically stratified groups (control, amnestic mild cognitive impairment, AD dementia), NIA-AA Alzheimer’s Disease Neuropathologic Change designations (Not, Low, Intermediate, High), and Braak tangle stages (1–6). Significant co-existing pathology was excluded to isolate changes attributed to pathologic AD. Methods: Synaptosomal fractionation and staining were performed to measure changes in total Tau, pTau231, and AMPA GluR1. Total Tau and pTau231 were quantified in synaptosomal fractions using Quanterix Simoa HD-X. Results: Increasing pTau231 in frontal postsynaptic fractions correlated positively with increasing clinical and neuropathological AD severity. Frontal cortex is representative of early AD, as it does not become involved by tau tangles until late in AD. Entorhinal total tau was significantly higher in the amnestic mild cognitive impairment group when compared to AD, but only after accounting for AD associated synaptic changes. Alterations in AMPA GluR1 observed in the entorhinal cortex, but not middle frontal cortex, suggest that pTau231 mislocalization and aggregation in postsynaptic structures may impair glutamatergic signaling by promoting AMPA receptor dephosphorylation and internalization. Conclusion: Results highlight the potential effectiveness of early pharmacological interventions targeting pTau231 accumulation at the postsynaptic density.

Abstract Background: As part of the CurePSP brain donation program, a questionnaire was developed to capture basic information from the next-of-kin or someone familiar with the brain donor with respect to symptoms and clinical course. The usefulness of information from the questionnaire has not been assessed. Objective: To assess the value of information from the brain donation questionnaire as it relates to differential diagnosis of parkinsonian disorders. Methods: We reviewed 150 questionnaires, including 50 patients, each with a neuropathologic diagnosis of Lewy body disease (LBD), multiple system atrophy (MSA), or progressive supranuclear palsy (PSP). The frequency of clinical features recorded in the questionnaires was compared for the three disorders, and machine learning algorithm, XGBoost, was applied to tabulated information from the questionnaires to identify features that had predictive value with respect to neuropathologic diagnosis. Results: The information from the questionnaires correlated with core clinical features for each disorder - hallucinations for LBD, autonomic dysfunction for MSA, and early falls for PSP. Age at onset and early falls were identified as the key variables that contributed most to prediction of neuropathology. Conclusion: While less optimal than prospectively collected information, a questionnaire can provide useful clinical information for clinicopathological correlative studies.

Abstract Neuropathological assessment at autopsy is the gold standard for diagnosing neurodegenerative disorders. We aimed to develop a pipeline for diagnosing Alzheimer's disease and other tauopathies, including corticobasal degeneration, globular glial tauopathy, Pick’s disease, and progressive supranuclear palsy. We used deep learning (DL)-based approach called clustering-constrained-attention multiple instance learning (CLAM) on whole slide images (WSIs) of tau immunohistochemistry in three brain regions from 120 patients. We also augmented gradient-weighted class activation mapping (Grad-CAM) to the model for visualizing cellular-level evidence in the model’s decisions. The model using the sections of cingulate and superior frontal gyri achieved the highest area under the curve (0.970±0.037) and diagnostic accuracy (0.873±0.087). Grad-CAM showed the highest attention in known pathognomonic tau lesions for each disease (e.g., Pick bodies for Pick’s disease). Our findings supported the feasibility of the DL-based approach for the classification task on WSIs, which encouraged further investigation, especially focusing on clinicopathological correlation studies.

Abstract Neuropathological assessment at autopsy is the gold standard for diagnosing neurodegenerative disorders. We aimed to develop a pipeline for diagnosing Alzheimer's disease and other tauopathies, including corticobasal degeneration, globular glial tauopathy, Pick’s disease, and progressive supranuclear palsy. We used deep learning (DL)-based approach called clustering-constrained-attention multiple instance learning (CLAM) on whole slide images (WSIs) of tau immunohistochemistry in three brain regions from 120 patients. We also augmented gradient-weighted class activation mapping (Grad-CAM) to the model for visualizing cellular-level evidence in the model’s decisions. The model using the sections of cingulate and superior frontal gyri achieved the highest area under the curve (0.970±0.037) and diagnostic accuracy (0.873±0.087). Grad-CAM showed the highest attention in known pathognomonic tau lesions for each disease (e.g., Pick bodies for Pick’s disease). Our findings supported the feasibility of the DL-based approach for the classification task on WSIs, which encouraged further investigation, especially focusing on clinicopathological correlation studies.

AbstractBackgroundMultiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by various combinations of autonomic failure, parkinsonism, and cerebellar syndromes. Although consensus criteria have been widely used to diagnose MSA, accurate clinical diagnosis remains challenging. Other neurodegenerative disorders, such as Lewy body disease, can mimic MSA.ObjectivesWe described clinical and neuropathologic findings of two patients with Creutzfeldt–Jakob disease (CJD) who had antemortem clinical diagnoses of MSA.MethodsThe brain bank for neurodegenerative disorders was queried for cases with a clinical diagnosis of MSA, but neuropathologic findings of CJD.ResultsCase 1 was a 55‐year‐old man with a 6‐month history of orthostatic hypotension, parkinsonism, cerebellar ataxia, bradyphrenia, and memory impairment. Case 2 was a 65‐year‐old man who had a 5‐year history of cerebellar ataxia, parkinsonism, and cognitive impairment, as well as a 7‐year history of dream enactment behavior. Neither case had characteristic α‐synuclein immunoreactive neuronal or glial inclusions typical of MSA. Instead, they had spongiform encephalopathy with neuronal loss and gliosis with prion protein‐immunoreactive kuru‐like plaques. Genetic analyses in case 1 had wild‐type PRNP, whereas case 2 revealed a 4‐octapeptide repeat insertion in PRNP.ConclusionsEven when clinical features suggest MSA, CJD should also be considered if the progression is rapid or the disease course is atypical, such as the absence of autonomic dysfunction for an extended period.

ABSTRACTBackgroundAdult‐onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare neurodegenerative disorder with characteristic clinicopathological features. Identification of pathogenic mutations in CSF1R, AARS1, and AARS2 genes led to increased recognition and diagnosis of the ALSP.ObjectivesThis paper presents the first family with typical clinical, radiological, and pathological features of ALSP, yet negative for CSF1R, AARS1, and AARS2 mutations.MethodsThe index case was a 30‐year‐old male who presented with gait difficulty, followed by cognitive decline and incontinence.ResultsNeurological examination evidenced progressive dementia, dysarthria, spasticity, parkinsonism, and severe gait disturbances. Brain MRI showed confluent white matter abnormalities with scattered foci of restricted diffusion, and atrophy of the corpus callosum. He was suspected of ALSP; however, the extensive genetic work‐up did not find pathogenic mutation. He died at 33 years, and brain autopsy was performed. He had myelin staining pallor and axonal swellings, spheroids, and pigmented glia in affected white matter. His father developed similar symptoms in his early 40s and died at 46 years. Neuropathological examination also confirmed ALSP diagnosis. We found two similar cases in the literature with typical ALSP features but negative for CSF1R mutation; however, none were tested for AARS1 and AARS2 mutations.ConclusionsWe draw attention to a new entity within the ALSP disease spectrum that needs further investigation. As the disease‐modifying therapy is already available for ALSP‐CSF1R, there is a strong need to identify the genetic cause of patients such as these in the ALSP spectrum, enabling research toward implementing effective treatment.

ObjectiveRecent evidence supports a link between increased TDP‐43 burden and the presence of an APOE4 gene allele in Alzheimer's disease (AD); however, it is difficult to conclude the direct effect of APOE on TDP‐43 pathology due to the presence of mixed AD pathologies. The goal of this study is to address how APOE isoforms impact TDP‐43 pathology and related neurodegeneration in the absence of typical AD pathologies.MethodsWe overexpressed human TDP‐43 via viral transduction in humanized APOE2, APOE3, APOE4 mice, and murine Apoe‐knockout (Apoe‐KO) mice. Behavior tests were performed across ages. Animals were harvested at 11 months of age and TDP‐43 overexpression‐related neurodegeneration and gliosis were assessed. To further address the human relevance, we analyzed the association of APOE with TDP‐43 pathology in 160 postmortem brains from autopsy‐confirmed amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with motor neuron disease (FTLD‐MND) in the Mayo Clinic Brain Bank.ResultsWe found that TDP‐43 overexpression induced motor function deficits, neuronal loss, and gliosis in the motor cortex, especially in APOE2 mice, with much milder or absent effects in APOE3, APOE4, or Apoe‐KO mice. In the motor cortex of the ALS and FTLD‐MND postmortem human brains, we found that the APOE2 allele was associated with more severe TDP‐43‐positive dystrophic neurites.InterpretationOur data suggest a genotype‐specific effect of APOE on TDP‐43 proteinopathy and neurodegeneration in the absence of AD pathology, with the strongest association seen with APOE2. ANN NEUROL 2023;93:830–843

AbstractBackgroundOther than the typical (memory‐dominant) variant, Alzheimer’s disease (AD) can present as posterior cortical atrophy (PCA) and behavioral/dysexecutive AD. Tangle distribution differs amongst clinical variants. Neuroinflammation is important in AD pathogenesis and may contribute to Aβ and p‐tau distribution. The relationship between pathological hallmarks, neuroinflammation and, APOE genotype in (a)typical AD is still largely unknown.MethodI will discuss our most recent studies on neuroinflammation in (a)typical AD from cohorts derived from the Netherlands Brain Bank and the Mayo Clinic. Atypicality is investigated from both a neuropathological perspective(N=19) and a clinical perspective (N=30, unpublished data). Additionally, the association ofAPOE ε4 with specific Aβ deposits (i.e., the ‘coarse‐grained plaque’ and the classic cored plaque) and their underlying neuroinflammatory response is investigated (N=60, unpublished data).ResultIn neuropathologically‐defined atypical AD, microglia, and complement show an atypical distribution across regions, resembling that of p‐tau. Clinical atypical AD variants show in addition to a distinct distribution for p‐tau and Aβ, a distinct distribution for activated microglia (CD68, MHC‐II), complement (C4b), and astrocytes (GFAP) (p<.05) (Fig. 1). Furthermore, when investigating Aβ in detail, we observed an atypical plaque, defined as the ‘coarse‐grained plaque’. This APOE ε4+ plaque is associated with increased neuroinflammation and p‐tau burden (ρ(58)=0.5 and 0.6;p<.05) in contrast to the classic cored plaque.ConclusionOur data supports that not all types of Aβ deposits are associated to p‐tau damage. Neuroinflammation, a process that is differently activated within AD variants, may be the link between Aβ aggregation and subsequent neurodegeneration and contribute to clinical variability.