Whitwell, Jennifer L.

Background Frontotemporal dementia is an umbrella term that encompasses several clinical syndromes with impaired behavioral, language, and motor functions. These syndromes show considerable overlap in clinical features and imaging patterns. Therefore, there is a need to investigate the syndromic heterogeneity in FTD using unbiased data-driven approaches. Methods We used data-driven clustering analysis of structural magnetic resonance imaging (MRI) data on 400 patients with clinical FTD diagnoses [behavioral variant of frontotemporal dementia (bvFTD), semantic variant of primary progressive aphasia (svPPA), right temporal variant of frontotemporal dementia (rtvFTD), apraxia of speech with agrammatic aphasia (AOS-PAA), primary progressive apraxia of speech (PPAOS), progressive supranuclear palsy (PSP), corticobasal syndrome (CBS) and primary progressive aphasia who did not fit into the other diagnostic categories (PPA-other)]. MR images were w-scored relative to cognitively unimpaired individuals, and principal component analysis was performed. A clustering ensemble approach, including hierarchical algorithms, was applied to the MR-based principal components, and imaging and clinical characteristics of the clusters were investigated. Various numbers of clusters ( K = 2, 3, or 4) were evaluated. Results The K = 3 solution offered the most clinically meaningful separation of FTD syndromes. The first cluster captured mostly frontal MRI abnormalities related to the speech, language and behavioral clinical dimensions, including patients with AOS-PAA, PPAOS, PPA-other, and bvFTD. The second cluster captured mostly temporal abnormalities and included mainly patients with svPPA and rtvFTD, but also bvFTD, AOS-PAA, and PPA-other. The third cluster captured cortical and subcortical atrophy, particularly in the midbrain, and included atypical Parkinsonian syndromes, with all PSP and CBS patients captured in this cluster, as well as most PPAOS patients. Considerable overlap of clinical syndromes was noted across these clusters, whereby patients with AOS-PAA, svPPA, PPA-other, and bvFTD were captured in more than one cluster. Discussion Our findings highlight heterogeneity in FTD, which mainly exists along three axes: speech, language and behavioral deficits reflecting frontal atrophy, language deficits reflecting temporal atrophy, and motor and motor speech deficits reflecting mostly midbrain and subcortical atrophy, with cortical involvement.

Objective Immunohistochemically (IHC) measured transactive response DNA‐binding protein 43 (TDP‐43) inclusions are observed in Alzheimer's disease (AD) and are associated with medial temporal lobe atrophy. Accumulation of cryptic exons occurs in AD in response to TDP‐43 pathology. We aimed to assess relationships between IHC and biochemically measured insoluble TDP‐43 and cryptic exons and assess associations with hippocampal and amygdala volume loss and atrophy rates on magnetic resonance imaging (MRI). Methods Eighty‐one neuropathologically diagnosed AD cases were analyzed. For biochemistry, insoluble TDP‐43 was quantified using a Meso‐scale discovery (MSD) immunoassay. IHC‐TDP burden was quantified with digital histopathology. Cryptic RNAs were assessed via quantitative real‐time polymerase chain reaction (qRT‐PCR). Thirty‐eight cases had serial brain MRI. Hippocampal and amygdala volumes were calculated using FreeSurfer. Regression models were used to investigate associations among IHC‐TDP‐43 status/burden, MSD‐TDP status/levels, cryptic RNAs, and hippocampal and amygdala volumes and atrophy rates. Results IHC‐TDP(+) cases exhibited elevated levels of MSD‐TDP and cryptic RNAs ( KCNQ2 , STMN2 , and UNC13A ) and increased MSD‐TDP levels were associated with increased cryptic RNA levels, in the hippocampus and amygdala. IHC‐TDP(+) cases had smaller hippocampal and amygdala volumes compared to IHC‐TDP(−) cases. MSD‐TDP(+) cases had smaller hippocampal volumes and faster amygdala rates of atrophy compared with MSD‐TDP(−) cases. Higher KCNQ2 and UNC13A levels were associated with smaller amygdala volumes. Interpretation MSD‐TDP level is a reliable surrogate for IHC‐based TDP‐43 status. Both TDP‐43 and cryptic RNA levels are associated with reduced medial temporal volumes, suggesting cryptic exons may be playing a role in brain volume loss in AD. ANN NEUROL 2026;100:193–205

Transactive response DNA-binding protein of 43 kDa (TDP-43) type-A is associated with frontotemporal lobar degeneration (FTLD). In primary age-related tauopathy (PART), TDP-type-α displays similar features to FTLD-TDP type-A. We compared antemortem MRI volumes of amygdala nuclei and hippocampal subfields between 16 PART-TDP-α and 12 FTLD-TDP-A autopsy-confirmed cases. Hippocampal tail and CA1 body volumes were smaller in PART-TDP-α group, which also had smaller lateral and central amygdala nuclei compared to FTLD-TDP-A group, but differences were non-significant after FDR correction. There is no evidence suggesting that TDP-43 type-A in FTLD affects hippocampal and amygdala volume loss differently than TDP-43 type-α in PART.

Background TAR DNA-binding protein 43 (TDP-43) proteinopathy contributes to Alzheimer's disease progression, but diagnosis remains autopsy-dependent. Objective This study aimed to develop a predictive model using FDG-PET imaging to identify brain regions associated with TDP-43 pathology in vivo. Methods Penalized logistic regression analyzed data from 294 participants and a subset of 159 with Braak and Thal ≥4. Features included FDG standard uptake value ratios (SUVRs) from 123 brain regions and age. Participants were split into training (90%) and testing (10%) datasets, with significant predictors identified by non-zero coefficients at optimal lambda. Results The model achieved 68% accuracy (AUC = 0.70) in 294 participants, highlighting the middle temporal gyrus, parahippocampal gyrus, and hippocampus. In the subset (n = 159), accuracy was 65% (AUC = 0.71), with the medial amygdala and precentral gyrus as key predictors of TDP-43 pathology. Conclusions This study suggests a moderate predictive accuracy of FDG-PET to identify brain regions associated with Alzheimer's disease-related TDP-43 proteinopathy.

Abstract INTRODUCTION Hippocampal subfields are vulnerable to the transactive response DNA‐binding protein of 43 kDa (TDP‐43) and tau in primary age‐related tauopathy (PART). Geometry‐based morphometric analysis can improve the detection of structural changes in the hippocampus. METHODS Forty‐seven cases of autopsy‐confirmed PART without TDP‐43 and 19 cases of PART with TDP‐43 underwent antemortem magnetic resonance imaging (MRI) hippocampal segmentation and shape analysis. A separate cohort of 16 younger healthy individuals (YHIs) was included as a reference group. Hippocampal shape was analyzed in Python with non‐parametric cluster permutation testing. RESULTS PART(TDP+) group exhibited thinner left subiculum and CA1, with curvature deformations in left CA1 and CA2/3, relative to PART(TDP–). Both PART groups showed right‐sided predominance of thinning in presubiculum and subiculum, as well as curvature deformations in right presubiculum, subiculum, and CA1 when compared to YHIs. DISCUSSION Geometry‐based analysis showed different patterns of hippocampal thinning and curvature associated with PART(TDP+) compared to PART(TDP–).

Abstract Background Dysphagia can lead to fatal aspiration pneumonia in progressive supranuclear palsy (PSP). Little is known about the longitudinal progression of dysphagia or whether it differs across PSP clinical variants. Objectives To characterize longitudinal changes in dysphagia across PSP variants and determine relationships with disease severity and rate of atrophy in PSP‐related regions. Methods Sixty‐one PSP patients were recruited and underwent at least two serial evaluations, comprising neurological and videofluorographic exams, and MRI. Variables‐of‐interest were the oral and pharyngeal total sum scores (OTSS/PTSS) from the Modified Barium Swallow Impairment Profile, the Penetration Aspiration Scale (PAS), Functional Oral Intake Scale (FOIS), and lingual pressure assessments. Rates of change were compared across PSP variants and related to baseline scores, PSP Rating Scale and regional brain atrophy rates. Results Dysphagia progressed longitudinally, particularly with worsening in OTSS and anterior and posterior lingual pressures. Rate of change in OTSS was fastest in PSP with predominant speech‐language disorder. Negative correlations were observed between rates of change and baseline scores for OTSS, PTSS and PAS. Rates of change in lingual pressure measures correlated with rates of change in the PSP Rating Scale. Rate of change in the FOIS correlated with rates of change in OTSS and lingual pressure. Rates of brain atrophy were associated with baseline OTSS, PTSS, and PAS. Conclusions Dysphagia and lingual pressure worsen over time in PSP, with variability in rates of change in the OTSS across PSP variants and evidence that dysphagia is related to rates of atrophy.

Abstract INTRODUCTION Globular glial tauopathy (GGT) is a rare type of frontotemporal lobar degeneration (FTLD) characterized by deposition of 4‐repeat tau. Detecting GGT with tau positron emission tomography (tau‐PET) is challenging. We aim to determine the associations between tau‐PET, autoradiography, and neuropathology methods in GGT. METHODS We identified three patients with GGT who had completed antemortem tau‐PET. Healthy control and two patients with Alzheimer's disease (AD) were also included for comparison. We analyzed gray matter (GM) and white matter (WM) from the superior/middle frontal gyrus (S/M‐FG) and the superior/middle temporal gyrus (S/M‐TG). Immunohistochemical staining was performed with antibodies against phospho‐tau (AT8, PHF‐1, RD4), glial fibrillary acidic protein (GFAP), and resting microglia (ionized calcium‐binding adaptor molecule 1; Iba1). Immunofluorescence with a fluorescent tau‐PET analog (T726) was performed. Regional tau‐PET standardized uptake value ratios (SUVRs) were calculated for comparative GM and WM regions. Autoradiographic studies with 18F‐AV1451 were also conducted. RESULTS Tau‐PET showed increased uptake in the WM regions of the S/M‐FG and S/M‐TG in GGT, and the GM regions in AD. Co‐localization was observed between T726 and PHF‐1, RD4, and GFAP in the WM in the patients with GGT, whereas co‐localization was observed with PHF‐1 predominantly in the GM in AD. Little co‐localization was observed with Iba1. In vitro 18F‐AV1451 autoradiography studies demonstrated minimal binding in GGT. Tau‐PET differentiated underlying GGT from AD based on the relative involvement of the WM and GM. CONCLUSION Histopathologic findings suggest that some flortaucipir uptake in GGT may represent underlying 4R tau, whereas autoradiographic analysis suggests that uptake is likely due to off‐target binding. Further studies with larger cohorts are needed to determine the pathological basis of flortaucipir uptake in GGT.

Abstract Distinguishing atypical parkinsonian disorders (APS) from Parkinson’s disease (PD) remains challenging due to overlapping clinical features, yet accurate differentiation is critical for prognosis and treatment. Here, we employed multi-model diffusion MRI (dMRI) analysis to characterize microstructural alterations across corticobasal syndrome (CBS), progressive supranuclear palsy-Richardson syndrome (PSP-RS) and PD, with the aim of identifying which dMRI model provides optimum differentiation. We analyzed 25 CBS, 42 PSP-RS, and 21 PD participants compared to 35 age and sex-matched controls. Using a clinically feasible 3-shell high angular resolution diffusion imaging (HARDI) protocol, we applied 11 metrics from five complementary dMRI models—diffusion tensor imaging (DTI), free-water-eliminated model of DTI (FWE), neurite orientation dispersion and density imaging (NODDI), tissue-weighted NODDI, and Fixel Density (FD) in fixel-based analysis (FBA) —to comprehensively assess regional white and gray matter integrity. Group differentiation was assessed using Cohen’s d effect sizes and spearman correlations were assessed between dMRI metrics and clinical scales. Distinct microstructural signatures were observed across disorders and the sensitivity of the dMRI models differed. In group contrasts, DTI and NODDI-derived metrics consistently captured the strongest effects in midbrain and peduncular pathways for PSP-RS, whereas precentral and corticospinal alterations in CBS were most prominent using NODDI and FBA measures. Free-water-corrected metrics showed attenuated group differences. Across clinical-diffusion analyses, NODDI metrics exhibited the most robust associations with disease severity, while DTI and FWE measures detected more limited, regionally constrained effects. Together, these findings highlight complementary yet distinct sensitivities of tensor, free-water, multi-compartment, and fixel-based models to APS-related neurodegeneration.

Abstract Background The cerebellar dentate is a known site of iron accumulation and tau deposition in progressive supranuclear palsy (PSP); however, detailed iron distribution and localized volume and shape changes remain unclear across PSP clinical variants. Objective The study aimed to clarify details about regional susceptibility distribution, volume, and shape deformation in the cerebellar dentate across PSP clinical variants. Methods Sixty‐seven PSP patients, including 31 PSP‐Richardson syndrome, 12 PSP‐parkinsonism, 10 PSP‐progressive gait freezing, and 14 PSP‐cortical variants (PSP‐frontal, PSP‐speech/language, and PSP‐corticobasal syndrome), and 31 healthy controls underwent 3 Tesla magnetic resonance imaging to reconstruct quantitative susceptibility maps. Manual dentate segmentation was performed to extract magnetic susceptibility and volume adjusted for total intracranial volume. Shape deformation was assessed using Deformetrica atlas construction. Group comparisons were evaluated with Kruskal–Wallis tests and receiver operating characteristic analysis. Results Patients with PSP‐Richardson syndrome, PSP‐parkinsonism, and PSP‐cortical variants showed significantly increased dentate susceptibility compared with controls ( P < 0.05). Patients with PSP‐progressive gait freezing showed no significant susceptibility differences. Volume loss was most prominent in PSP‐cortical variants, bilaterally, and PSP‐Richardson syndrome, left hemisphere only ( P < 0.05). Shape analysis revealed subregion‐specific deformation patterns, especially in the anterior and posterior deformation in PSP‐progressive gait freezing and the ventroanterior deformation in PSP‐cortical variants. Conclusions The PSP clinical variants had different patterns of susceptibility, volume, and shape metrics, reflecting distinct neurodegenerative patterns of the cerebellar dentate. These findings contribute to our understanding of the neurobiology of PSP and may help to improve phenotypic differentiation of PSP clinical variants. © 2026 International Parkinson and Movement Disorder Society.