Capgras syndrome is a delusional misidentification syndrome characterized by the recurrent belief that someone, usually a family member, has been replaced by an impostor. Although described over a century ago, its aetiology, clinical features and neuroimaging characteristics remain poorly understood due to its rarity. This study aimed to clarify these aspects through the analysis of a large cohort and to explore its clinical implications and underlying mechanisms. We conducted a retrospective cohort study by reviewing medical records of patients diagnosed with Capgras syndrome at the Mayo Clinic (Rochester, MN) over a 28-year period (January 1995 to December 2022). Clinical, neuropathological and neuroimaging data were analysed. A total of 204 patients were included (median age at onset: 73 years; 44% female). Twelve patients underwent neuropathological examination, all of whom exhibited α-synuclein pathology, including one patient with a clinical diagnosis of Alzheimer's disease (AD). Regarding clinical diagnoses, neurodegenerative diseases were the most common (69%, n = 140), with dementia with Lewy bodies (DLB) being predominant (58%, n = 118), followed by mixed aetiologies ('two-hits') (18%, n = 36) and AD (10%, n = 21). Psychotic disorders accounted for 9% (n = 18) of cases. No case was attributed to a single stroke, although 9% (n = 19) involved coexisting cerebrovascular disease in the context of AD or DLB. In DLB, the timing of Capgras syndrome onset varied: it occurred later than cognitive decline and core clinical features (e.g. visual hallucinations, fluctuating cognition, parkinsonism) in both DLB and mild cognitive impairment-onset prodromal DLB, but earlier in psychiatric-onset prodromal DLB. In both DLB and AD, Capgras syndrome typically targeted a single spouse, whereas in psychotic disorders, it often involved multiple, non-spousal targets. Depression or anxiety was present in 55% (n = 112). Capgras syndrome worsened in the evening or at night (87%, n = 45/52), suggesting a link to negative affective states. Among 82 patients with DLB and AD treated with cholinesterase inhibitors, 15% (n = 12) showed symptomatic improvement. Neuroimaging with MRI and 18F-fluorodeoxyglucose-PET revealed widespread bilateral cortical involvement and prominent right frontal dysfunction in DLB and AD. Capgras syndrome is associated with DLB and could serve as a potential early diagnostic clue. Recognizing its phenomenological features-the number and type of targeted individuals-can help differentiate between neurodegenerative and psychiatric aetiologies. In neurodegenerative diseases, Capgras syndrome may reflect a multifactorial, dynamic process, driven by widespread bilateral cortical dysfunction (particularly involving the right frontal lobe) and psychological factors. Thus, a combined approach involving pharmacological and non-pharmacological interventions may offer effective management strategies.

The length of the tectal plate, which sits above the midbrain, is reduced in both the Richardson’s syndrome (RS) and parkinsonism (P) variants of progressive supranuclear palsy (PSP). However, it is unclear whether tectal measurements could be useful biomarkers in other PSP variants or predict PSP pathology. The Neurodegenerative Research Group, Mayo Clinic, enrolled 115 PSP (including seven variants), 19 corticobasal syndrome (CBS), 21 Parkinson’s disease (PD), and 50 controls. Forty-seven PSP patients had PSP at autopsy, and 15 had a non-PSP pathology. Tectal plate length and area and area of the superior/inferior colliculi were measured. Measurements were compared across clinical and pathological groups, and associations were assessed with clinical severity. Effect sizes were evaluated using the area under the receiver operator characteristic curves (AUROCs). All PSP variants showed reduced tectal plate length compared to controls, with good differentiation (AUROC > 0.80). Excellent differentiation was observed for PSP-RS and PSP-P from controls (AUROC = 0.93/0.86), and PD (AUROC = 0.92/0.83), and PSP-RS showed good differentiation from CBS (AUROC = 0.80). Tectal plate and superior colliculus areas were reduced in all PSP variants, except PSP-Speech-language (SL), compared to controls. PSP-RS and PSP-P showed reduced area measurements compared to PSP-SL. No differences were observed between PSP and non-PSP pathology. Reduced tectal plate length was associated with worse clinical severity in PSP. Tectal plate length may have utility as a disease biomarker across PSP variants, although tectal plate measurements could not predict pathology within patients clinically diagnosed with PSP.

BackgroundStudies suggest that plasma Alzheimer's disease (AD) biomarkers may aid in the overall diagnosis of AD, but their utility among patients with atypical clinical presentations of AD are unknown.ObjectiveThe main objective of this study was to determine the relationship between amyloid-β (Aβ) and tau plasma biomarkers and PET measures of both Aβ and tau in atypical AD. The secondary objective was to determine if plasma biomarkers could differentiate patients with different atypical AD phenotypes and whether they were related to measures of disease severity.MethodsWe assessed whether plasma p-tau 181 and Aβ42/40 were associated with Aβ and tau PET uptake, clinical phenotype and severity in 77 patients with PET biomarker-confirmed atypical AD.ResultsPlasma Aβ42/40 ratio showed positive associations with tau PET uptake, with higher (more normal) Aβ42/40 ratio associated with higher tau uptake; the ratio was not associated with Aβ PET. No associations were noted with plasma p-tau 181. Plasma Aβ42/40 ratio and p-tau 181 concentrations were not associated with AD phenotype or cognitive severity.ConclusionPlasma Aβ42/40 ratio and p-tau 181 concentrations are not associated with amyloid or tau PET or with clinical severity among individuals presenting with atypical AD.

Individuals with primary progressive apraxia of speech (PPAOS) often develop parkinsonism and dysphagia. To evaluate the clinical correlates and impact of dysphagia in this population, we compared enrollment visit data between individuals with (n = 12) versus individuals without (n = 44) dysphagia symptoms. The group with dysphagia had more motor speech symptoms and parkinsonism. Longitudinal analysis revealed that almost everyone developed dysphagia before dying; the average time to death after developing dysphagia was 5.43 years and complications of dysphagia resulted in mortality for 35% of the individuals for whom data were available. These results emphasize the need for dysphagia management and provide useful prognostic estimates.

BACKGROUND:Primary progressive apraxia of speech is a neurodegenerative disorder characterized by early, isolated speech impairment due to impairment of motor speech planning and programming. Patients with PPAOS have varying disease durations from the estimated onset of the first symptom to death. Clinicopathological and neuroimaging features related to disease duration are unknown for PPAOS. We determine whether clinical, neuroimaging, or pathological features are associated with disease duration in primary progressive apraxia of speech (PPAOS). METHODS:We analyzed data from 41 PPAOS participants who were enrolled and longitudinally followed to death in NIH-funded studies over 15 years. Demographic, clinical, and genetic features were abstracted. Brain volumes of cortical, subcortical, and brainstem regions were calculated. Regional tau lesion count (burden) was assessed histologically. Spearman rank correlations were performed between disease duration and variables of interest, followed by multiple regression analyses. RESULTS:Disease duration did not correlate with any baseline demographic, clinical, or pathologic features. Shorter disease duration correlated with a faster rate of behavioral change and of apraxia of speech severity over time, smaller baseline volumes of the superior frontal lobe and supplementary motor cortex, and higher tau burden in the locus ceruleus (ρ = -0.5, p = 0.03). Multiple regression analysis identified rate of behavioral change and volume loss in the superior frontal lobe as key clinical and neuroimaging variables, respectively. CONCLUSION:In patients with PPAOS, we found shorter disease duration to be related to behavioral dyscontrol and involvement of the frontal lobe, as well as a higher burden of 4-repeat tau lesions in the locus ceruleus.

Alzheimer's disease (AD) is the leading cause of dementia in the elderly, marked by abnormal protein buildup (beta-amyloid and tau) resulting in neuronal loss, especially in the medial temporal lobe and other limbic regions. The presence of transactive response DNA binding protein 43 (TDP-43) immunoreactive inclusions in medial temporal lobe regions has also been associated with neuroimaging changes in limbic regions. It has been proposed that hypometabolism in limbic regions on [18F] fluorodeoxyglucose positron emission tomography (FDG-PET) in a patient with a slowly evolving amnestic syndrome may be a signature of the presence of TDP-43. In this context, we observed an 86-year-old Caucasian female with dementia characterized by a slowly evolving amnestic syndrome, along with focal medial temporal atrophy evident on MRI and hypometabolism in limbic regions on FDG-PET. The patient subsequently died and underwent an autopsy. We performed detailed neuroimaging and digital neuropathological analyses of the hippocampal subfields to better understand the relationship between clinico-imaging findings and histopathology. In addition to TDP-43, we identified three other pathological processes in the medial temporal lobe: sequestosome-1/p62, argyrophilic grain disease (AGD), and primary age-related tauopathy (PART). Hippocampal subfield volumes and rates of atrophy were no different from those of matched healthy controls, except for the atrophy rate in cornu ammonis 1 (CA1). Digital histopathology revealed the relative highest burden of pathology for p62, followed by TDP-43, AGD, and PART in CA1. Multiple pathological processes appear to have contributed to the hippocampal atrophy and hypometabolism in our patient with a slowly progressive amnestic syndrome.

Normal pressure hydrocephalus is typically defined by the triad of gait disturbance, cognitive impairment, and urinary incontinence, and is characterized on MRI by disproportionately enlarged subarachnoid-space. Gait disturbance is also a commonly reported symptom in Parkinsonian disorders, especially progressive supranuclear palsy, although the frequency, clinical significance and mechanisms of hydrocephalus in these disorders are unclear. We aimed to assess the prevalence of hydrocephalic MRI parameters in a large cohort of Parkinsonian disorders and evaluate associations with clinical features and abnormalities on MRI and PET. Two hundred and thirty-eight participants with a Parkinsonian disorder, including 181 progressive supranuclear palsy, 36 corticobasal syndrome and 21 Parkinson's disease, were enrolled from Mayo Clinic by the Neurodegenerative Research Group between September 2009 to October 2023. Automated detection of disproportionately enlarged subarachnoid-space hydrocephalus (D) was applied and using Evans' index (E) cut-off point >0.3, participants were classified based on both measures as imaging-suggestive of hydrocephalus (D+E+), enlarged subarachnoid-space only (D+E-), large Evans' index only (D-E+) and no imaging evidence of hydrocephalus (D-E-). Demographic, clinical and imaging features, including magnetic resonance parkinsonism index, cortical and subcortical volumes, white matter hyperintensities, diffusion tractography metrics, and metabolism on PET, were compared across groups. Among the 238 participants, 24 had borderline subarachnoid space scores and were excluded. The remaining 214 participants were classified as: D+E+ (n = 20, 9%); D+E- (n = 8, 4%); D-E+ (n = 71, 33%) and D-E- (n = 115, 54%). Among the progressive supranuclear palsy participants, 11% were D+E+, 4% D+E-, 34% D-E+ and 51% D-E-. Most cases (n = 18) in the imaging-suggestive of hydrocephalus D+E+ group had progressive supranuclear palsy. The D+E+ participants were older, had more disorientation, more downgaze palsy, greater midbrain and cortical atrophy, lower striatal metabolism, greater degeneration of long-range white matter tracts, larger cistern areas and more periventricular and deep white matter hyperintensities compared to the D-E- participants without imaging evidence of hydrocephalus. The D+E- participants had the highest metabolism in the paracentral lobule and superior parietal gyrus. The D-E+ participants showed worse disease severity and greater midbrain and cortical atrophy compared to the D-E- participants. These findings demonstrate that disproportionately enlarged subarachnoid-space hydrocephalus occurs in ∼15% of progressive supranuclear palsy participants, and is associated with worse clinical and imaging outcomes, as well as white matter hyperintensities. We hypothesize that disproportionately enlarged subarachnoid-space may be a mechanistic byproduct of degeneration and subsequent cerebrospinal fluid flow re-distribution in progressive supranuclear palsy.

Transactive response DNA-binding protein 43 kDa (TDP-43) deposition is linked to regional brain atrophy in Alzheimer's disease (AD), but diffusion changes associated with AD-related TDP-43 proteinopathy remain underexplored. This study evaluates the potential of diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) as in vivo markers for detecting TDP-43 proteinopathy in AD. We analyzed DTI and NODDI metrics in 49 cases with AD neuropathologic changes, categorized by postmortem TDP-43 status. Diffusion metrics from the temporal lobe gray and white matter regions and key white matter tracts were compared between TDP-43-positive and negative cases. Group differences were significant in the left hippocampus, amygdala, and uncinate fasciculus after adjusting for age, Braak neurofibrillary tangle (NFT) stage and APOE ε4 status. TDP-43-positive cases showed increased mean diffusivity (MD) and altered neurite density index (NDI) and orientation dispersion index (ODI). Area under the receiver operating characteristic curve (AUROC) analysis revealed high predictive accuracy for amygdala ODI (AUC = 0.809, sensitivity = 0.81, specificity = 0.76), hippocampal MD (AUC = 0.763, sensitivity = 0.81, specificity = 0.67), and uncinate fasciculus MD (AUC = 0.782, sensitivity = 0.88, specificity = 0.61). Combined, DTI/NODDI predictors demonstrated stronger discriminative ability (AUC = 0.856, sensitivity = 0.88, specificity = 0.76). These findings suggest that AD-related TDP-43 proteinopathy is associated with specific diffusion changes in the left temporal lobe. DTI and NODDI metrics, particularly MD, NDI, and ODI, may improve the antemortem detection of TDP-43 pathology in AD.

OBJECTIVES:The four-repeat (4R) tauopathies are a group of neurodegenerative diseases, including progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and globular glial tauopathy (GGT). This study aimed to characterize spatiotemporal atrophy progression using structural magnetic resonance imaging (MRI) and to examine its relationship with clinical course and neuropathology in a cohort of autopsy-confirmed 4R tauopathies. METHODS:The study included 85 autopsied patients (54 with PSP, 28 with CBD, and 3 with GGT) who underwent multiple 3T MRI scans, as well as neuropsychological, neurological, and speech/language examinations, and standardized postmortem neuropathological evaluations. An unsupervised machine-learning algorithm, Subtype and Stage Inference (SuStaIn), was applied to the cross-sectional brain volumes to estimate spatiotemporal atrophy patterns and data-driven subtypes and stages in each patient. The relationships among estimated subtypes, pathological diagnoses, and longitudinal changes in clinical testing were examined. RESULTS:The SuStaIn algorithm identified 2 distinct subtypes: (1) the subcortical subtype, in which atrophy progresses from the midbrain to the cortex, and (2) the cortical subtype, in which atrophy progresses from the frontal cortex to the subcortical regions. The subcortical subtype was more associated with typical PSP, whereas the cortical subtype was more associated with atypical PSP with a cortical distribution of pathology and CBD (p < 0.001). The cortical subtype had a faster rate of change on the PSP Rating Scale than the subcortical subtype (p < 0.05). INTERPRETATION:SuStaIn analysis revealed 2 MRI-driven subtypes with distinct spatiotemporal atrophy patterns, clinical courses, and neuropathology. Our findings contribute to a comprehensive and improved understanding of disease progression and its relationship to tau pathology in 4R tauopathies. ANN NEUROL 2025;98:492-507.

Introduction: Apraxia of speech (AOS) is a motor speech disorder characterized by sound distortions, substitutions, deletions, and additions; slow speech rate; abnormal prosody; and/or segmentation between words and syllables. AOS can result from neurodegeneration, in which case it can be accompanied by the primary agrammatic aphasia (PAA), which when presenting together are called AOS+PAA. AOS can also be the sole manifestation of neurodegeneration, termed primary progressive AOS (PPAOS). Together these form the agrammatic-apractic spectrum disorders. Recent work has shown that agrammatic-apractic spectrum patients show reduced quantity of written language production on a picture description task versus controls. However, no study to date has investigated if there are differences in quantity (amount of writing) and quality (grammaticality) in the written language production between PPAOS and AOS+PAA patients, which was the aim of this study. METHODS:Twenty-four AOS+PAA patients, 24 PPAOS patients, and 24 typical controls performed the Western Aphasia Battery (WAB) written picture description task. The total number of words and sentences, as well as the type-token frequency, mean length of utterance, proportion of nouns, and function words, and overall sentence grammaticality were compared among groups. RESULTS:The PPAOS group showed significantly reduced number of words (β = -44.2, p < 0.0001) and sentences (β = -4.04, p < 0.0001) compared to typical controls, and the AOS+PAA group showed significantly reduced number of words compared to both PPAOS patients (β = -17.0, p = 0.02) and controls (β = -61.20, p < 0.0001), as well as reduced number of sentences compared to controls (β = -4.33, p < 0.0001). AOS+PAA patients also showed grammatical deficits consistent with their concomitant aphasia diagnosis. CONCLUSIONS:This study provides novel quantitative data showing that agrammatic-apractic spectrum disorder patients show decreased written language output on a written picture description task compared to controls, even when there is no overt evidence of aphasia (i.e., PPAOS). Furthermore, these data show that controls, PPAOS patients, and AOS+PAA patients can all be distinguished based on the quantity of information and grammatical errors in a written picture description task. Future studies will explore sources beyond language, such as motoric impairment, that may result in reduced written quantity in agrammatic-apractic spectrum disorders. .

OBJECTIVE:To determine whether a machine learning model of voxel level [18f]fluorodeoxyglucose positron emission tomography (PET) data could predict progressive supranuclear palsy (PSP) pathology, as well as outperform currently available biomarkers. METHODS:One hundred and thirty-seven autopsied patients with PSP (n = 42) and other neurodegenerative diseases (n = 95) who underwent antemortem [18f]fluorodeoxyglucose PET and 3.0 Tesla magnetic resonance imaging (MRI) scans were analyzed. A linear support vector machine was applied to differentiate pathological groups with sensitivity analyses performed to assess the influence of voxel size and region removal. A radial basis function was also prepared to create a secondary model using the most important voxels. The models were optimized on the main dataset (n = 104), and their performance was compared with the magnetic resonance parkinsonism index measured on MRI in the independent test dataset (n = 33). RESULTS:The model had the highest accuracy (0.91) and F-score (0.86) when voxel size was 6mm. In this optimized model, important voxels for differentiating the groups were observed in the thalamus, midbrain, and cerebellar dentate. The secondary models found the combination of thalamus and dentate to have the highest accuracy (0.89) and F-score (0.81). The optimized secondary model showed the highest accuracy (0.91) and F-scores (0.86) in the test dataset and outperformed the magnetic resonance parkinsonism index (0.81 and 0.70, respectively). INTERPRETATION:The results suggest that glucose hypometabolism in the thalamus and cerebellar dentate have the highest potential for predicting PSP pathology. Our optimized machine learning model outperformed the best currently available biomarker to predict PSP pathology. ANN NEUROL 2025;98:410-420.

BACKGROUND AND OBJECTIVES:Hearing loss is relatively common in older individuals, and individuals with frontotemporal lobar degeneration (FTLD) are no exception; this can exacerbate communication difficulties stemming from speech-language impairments. The co-occurrence of these symptoms can contribute to increased frustration and isolation for patients and their communication partners. The objective of this study was to evaluate the feasibility of self-administered hearing testing. Ultimately, this could be administered remotely, which would increase access to assessment and inform management for this population. METHOD:Seventeen patients with underlying FTLD, clinically presenting with progressive apraxia of speech with and without agrammatic aphasia, independently completed the Home Hearing Test supervised while in office. RESULTS:Three patients self-reported hearing loss, but results for 100% recommended formal evaluation. Eleven patients demonstrated good test accuracy. Six patients had "poor" or not computable accuracy; among them, five had evidence of cognitive impairment and/or behavioral changes, and one had known severe hearing loss, although differences between those with good and poor test accuracy were not significant. Patients with poor test accuracy had more difficulty with limb praxis. CONCLUSIONS:Most participants independently completed the test, though some had reduced test accuracy that may have been associated with cognitive impairment and/or limb apraxia. This study supports the need for hearing screenings in all patients with progressive apraxia of speech and aphasia and highlights both the feasibility and caution required in implementing self-administered testing protocols. Further work should evaluate the feasibility of in-home hearing screenings in a broader range of FTLD phenotypes and directly compare sensitivity and specificity of hearing loss detection with in-clinic administration. SUPPLEMENTAL MATERIAL:https://doi.org/10.23641/asha.28306613.

There is a strong link between tau and progression of Alzheimer’s disease (AD), necessitating an understanding of tau spreading mechanisms. Prior research, predominantly in typical AD, suggested that tau propagates from epicenters (regions with earliest tau) to functionally connected regions. However, given the constrained spatial heterogeneity of tau in typical AD, validating this connectivity-based tau spreading model in AD variants with distinct tau deposition patterns is crucial. We included 269 amyloid-β-positive (PET/CSF) individuals with clinically diagnosed atypical AD (113 posterior cortical atrophy, PCA-AD; 83 logopenic variant primary progressive aphasia, lvPPA-AD; 33 behavioural variant AD, bvAD; 40 corticobasal syndrome, CBS-AD) and 68 with typical AD from 12 international cohorts, who underwent tau-PET (54% [ 18 F]AV1451/[ 18 F]flortaucipir/Tauvid, 27% [ 18 F]MK6240, 19% [ 18 F]PI2620). Using Gaussian mixture modeling including amyloid-β-negative controls, cross-sectional tau-PET standardized uptake value ratios within Schaefer-200 atlas regions were transformed to tau positivity probabilities. Tau epicenters were defined as the 5% regions with highest tau positivity probabilities. For each variant, the association between functional connectivity-based distance (using the 30% strongest positive region-to-region connections of a group-average connectivity matrix from ADNI elderly controls) and tau-PET covariance (group-average correlation per region pair) was assessed through linear regression, adjusting for age, sex, site, and Euclidean distance. Regions were categorized based on functional proximity to the epicenter (quartiles 1-4) and tau positivity probabilities were assessed accordingly. Tau positivity probabilities matched clinical variants, with a posterior pattern in PCA-AD, left-hemispheric dominant pattern in lvPPA-AD, widespread pattern in bvAD, sensorimotor cortex involvement in CBS-AD, and temporo-parietal predominance in typical AD (Figure 1). In line with this, tau epicenters were highly heterogeneous across variants (Figure 1). In all variants, greater tau-PET covariance was associated with shorter functional connectivity-based distance (Figure 2). We observed that regions in closer functional proximity to the epicenter exhibited higher tau positivity probabilities than regions functionally further away (p<0.05, Figure 3). This multi-center study shows that the brain’s functional architecture serves as a universal predictor of tau spreading in AD. Since tau is a key driver of neurodegeneration and cognitive decline in AD, this finding holds potential for personalized medicine and defining participant-specific endpoints in clinical trials.

BACKGROUND:Progressive apraxia of speech (PAOS) is a neurodegenerative disorder most commonly arising from a 4-repeat tauopathy that affects the programming or planning of speech, although many patients develop a Parkinson-plus syndrome. The role of neuroinflammation as a disease mechanism is unknown. We investigated the spatial pattern of neuroinflammation in PAOS using PET and evaluated whether it is associated with disease severity, presence of Parkinson-plus features, and tau PET uptake. PATIENTS AND METHODS:Twenty-five PAOS patients (13 with Parkinson-plus features) and 30 controls underwent inflammatory 11C-ER176 and tau 18F-flortaucipir PET scans as well as detailed clinical assessments. Multiple linear regression analyses compared the inflammatory standardized uptake value ratio (SUVR) between PAOS and controls and assessed the relationship with clinical test scores. Pearson correlation analysis examined the relationship between inflammatory and tau SUVRs. RESULTS:PAOS had greater neuroinflammatory SUVR than controls in the precentral, supplementary motor area, frontal gyri, putamen, pallidum, subthalamic nucleus, and red nucleus (adjusted P < 0.05). Greater neuroinflammation was associated with worse parkinsonism, and patients who had developed Parkinson-plus features showed a broader pattern of neuroinflammation, extending to prefrontal, temporal and parietal cortices. Neuroinflammation correlated with tau uptake in most (96%) PAOS patients (r > 0.3, P < 0.05). The higher correlation was associated with worse parkinsonism (r = 0.61, P < 0.05) and disease severity (r = 0.54, P < 0.05). CONCLUSIONS:11C-ER176 PET analysis demonstrates neuroinflammation in frontal and subcortical regions in PAOS which is particularly severe and widespread with the development of Parkinson-plus clinical features. The colocalization of neuroinflammation and tau may support a relationship between these disease mechanisms.

Dementia with Lewy bodies (DLB) and posterior cortical atrophy (PCA) are neurodegenerative disorders that can overlap clinically and in patterns of regional hypometabolism and show elevated white matter hyperintensity (WMH) burden. Little is known about the regional WMH burden in DLB patients without any interference of AD pathology and how these patterns compare to PCA patients. Twenty-two amyloid-negative DLB patients, 40 amyloid-positive PCA patients, and 49 amyloid-negative cognitively unimpaired (CU) healthy individuals were recruited at Mayo Clinic, Rochester, MN. They underwent a 3 T head MRI, a Pittsburgh Compound B (PiB) PET scan, and a fluid-attenuated inversion recovery scan (FLAIR). The relationship between regional WMH volume and diagnosis was evaluated while adjusting for age and sex. DLB showed greater periventricular WMH burden in the temporal, occipital, and frontal lobes and greater WMH burden in the posterior corpus callosum compared to CU. PCA showed greater subcortical WMH burden in temporal, parietal, and occipital lobes, and greater periventricular WMH burden in the temporal, occipital, and frontal lobes, compared to CU. On comparing both dementia groups, PCA showed greater subcortical WMH burden in the temporal and occipital lobes compared to DLB, while DLB showed greater WMH burden in the posterior corpus callosum compared to PCA. Hence, DLB and PCA are both associated with periventricular WMHs, with deep subcortical WMHs being more characteristic of PCA, and callosal WMHs more characteristic of Aβ-negative DLB patients, suggesting different pathophysiological mechanisms underlying the development of WMHs in these two neurodegenerative diseases.

The TAR DNA-binding protein of 43 kDa (TDP-43) is linked to hippocampal volume loss and faster rates of hippocampal atrophy in Alzheimer's disease and primary age-related tauopathy (PART). Hence, TDP-43 is becoming an important player in age-related neurodegeneration. To advance our understanding of TDP-43 effect on hippocampus, we conducted an imaging-pathological study to determine which specific hippocampal subfields are affected by TDP-43 in cases of PART. One-hundred fifteen autopsied cases from Mayo Clinic Alzheimer Disease Center, Study of Aging and Neurodegenerative Research Group were analyzed. All had completed antemortem brain MRIs, underwent neuropathological examination per NIA and Alzheimer’s Association (NIA-AA) criteria and had additional assessment for TDP-43 deposition. Only cases meeting criteria for PART (Thal phases 0-2 and Braak NFT stages I-IV) were included. Hippocampal subfield segmentation was performed using FreeSurfer-7. Brain volumes were normalized to total intracranial volume (TIV) when comparing TDP-43 groups. Statistical analyses including logistic regression analyses were utilized to explore associations between TDP-43 status and hippocampal subfield volumes. Forty-nine of the 115 cases (43%) with PART were female. Thirty-seven (32%) cases were TDP-positive. Mean age at last MRI was 84 years. There were no differences in pathological characteristics between both groups except for presence of hippocampal sclerosis which was more frequent in the TDP(+) group (P <0.001). Whole hippocampal volume was significantly smaller in the TDP(+) group (176 ±31 vs. 188 ±27, p=0.049). After stratification of hippocampus into head, body, and tail, TDP-positive cases had smaller volumes of hippocampal body (p=0.031) and tail (p=0.021) but did not reach significance for hippocampal head (p=0.129). When regions were subdivided into hippocampal subfields, TDP(+) cases showed smaller volumes of molecular layer of the hippocampal body (p=0.046), CA1 body (p=0.031), subiculum body (p=0.023), and presubiculum body (p=0.046) compared to TDP(-) cases. Logistic regression analysis adjusting for TIV confirmed these associations. This study underscores the association between TDP-43 and the hippocampus and provides further evidence that TDP-43 targets multiple regions and subfields of the hippocampus in patients with PART. Intriguingly, regions targeted are those where TDP-43 deposition is microscopically observed, suggesting a direct “hit” by TDP-43 deposition.

INTRODUCTION:Alzheimer's disease (AD) pathology causes corticobasal syndrome (CBS) in 21%-50% of patients. Studies have assessed hypometabolism in CBS according to β-amyloid (A) positron emission tomography (PET), but the understanding of the association of both AD-tau (T) and A with hypometabolism is incomplete. METHODS:Thirty-three CBS patients and 45 controls underwent fluorodeoxyglucose (FDG), flortaucipir, and Pittsburgh compound-B PET and were classified as A± and T±. FDG-PET uptake was extracted for 12 regions-of-interest in dominant (most affected) and non-dominant hemispheres and compared across A/T groups. RESULTS:A+T+ patients had greater hypometabolism in temporo-parieto-occipital cortices than A+T- and A-T- groups, with no differences observed between the A+T- and A-T- groups. FDG asymmetry was more accentuated in A+T+ patients. Medial temporal and basal ganglia metabolism were similar across AT groups. DISCUSSION:Amyloid and tau positivity contribute synergistically to hypometabolism and asymmetry in temporo-parieto-occipital cortices in CBS, with AD-like patterns of hypometabolism observed only in A+T+ patients. HIGHLIGHTS:Amyloid (A) and tau PET (T) status can be used to stratify CBS patients. A+T+ CBS patients show more hypometabolism in temporo-parieto-occipital cortices. Medial temporal metabolism (typical AD pattern) is similar across AT groups. Parieto-occipital cortices should be assessed when investigating AT pathology in CBS. Amyloid and tau positivity contribute synergistically to hypometabolism and asymmetry in CBS.