Citations

Abstract Neuroimaging can assess different pathophysiological features of the brain in Alzheimer's disease (AD), including structure, function and protein deposition, and can be used to help identify patients for clinical treatment trials and monitor and assess potential treatment effects on disease progression. While large scale longitudinal studies are underway to validate potential neuroimaging biomarkers in amnestic AD, less efforts have focused on atypical clinical presentations, such as language, visual, dysexecutive, behavioral and motor presentations of AD. These patients would be ideal candidates for treatment trials given that they are relatively young, and the disease is less influenced by age‐associated co‐pathologies, providing a purer disease model of AD. Rates of brain atrophy provide excellent surrogate disease markers in amnestic AD and they will also likely have utility in atypical AD, although cortical, rather than medial temporal, measurements perform better. Optimum sample size estimates required to detect a 20% treatment effect in both the language and visual variants of AD were obtained with rates of inferior temporal atrophy in our sample (113 and 100 patients required per arm, respectively). However, heterogeneity in rates and patterns of atrophy are observed across phenotypes, and with age and disease stage, and these factors would need to be considered in clinical trials. Utilizing direct markers of tau deposition from PET would be optimal. Tau uptake increases over time in relatively consistent patterns across atypical AD phenotypes, although rates vary across patients and with age and baseline levels, with tau uptake plateauing at high levels potentially limiting utility as an outcome measure in patients with advanced disease. Metrics of connectivity also worsen over time in atypical AD patients, with evidence that declines in default mode network connectivity may be common across phenotypes and have some utility, although once again changes are highly variable and influenced by age and tau burden. In summary, we are gaining a better understanding of factors that influence rates of change in atypical AD that need to be considered in treatment trials, although more work is needed to identify optimum biomarkers to track disease progression across the AD clinical spectrum.

Abstract Background Neuropathologic evaluation is essential for diagnosing and treating dementia, but definitive diagnoses is only available after post‐mortem brain autopsy. Positron emission tomography (PET) offers a potential in vivo proxy for predicting neuropathology. This study proposes a semi‐supervised learning (SSL) model using a single FDG‐PET image to predict underlying neuropathology. Method The SSL model leverages a self‐organized graph structure based on a patient similarity network (PSN) created from 1,495 FDG‐PET images across the aging and neurodegenerative spectrum. Each patient is represented by a node, with edges indicating image similarity derived from principal component analysis features and cosine similarity weights. The PSN structure connects 20 nearest neighbors. Neuropathologic labels were available for 204 autopsied patients. The Poisson Learning Method was employed to propagate labels from these annotated nodes to unlabeled nodes, guided by the PSN structure. FDG‐PET images were collected from clinical and research participants at the Mayo Clinic and processed using an MRI‐free pipeline. Neuropathologic labels were assigned based on widely accepted diagnostic criteria. Leave‐one‐out cross‐validation (LOOCV) was used to assess model performance. Results The confusion matrix demonstrated high accuracy in predicting Alzheimer's disease, frontotemporal lobar degeneration with tau inclusions, and Lewy body disease pathology. A Sankey diagram and label distribution analysis revealed strong correlations between clinical and predicted neuropathologic labels. Conclusion This study highlights the potential of a graph‐based SSL pipeline to predict neuropathological changes using FDG‐PET imaging data, despite limited pathology labels. The findings underscore the value of SSL in bridging the gap between abundant neuroimaging data and scarce neuropathologic labels, contributing to improved dementia diagnosis and understanding.

Background: Posterior cortical atrophy (PCA) patients typically show progressive visual decline, although language impairment can be a prominent feature. Previous studies have explored language connectivity impairment in PCA; not much is known about the exact nature of language processing disruptions in PCA. Methods: Thirty-seven PCA patients were compared with 39 cognitively unimpaired (CU) individuals. Functional connectivity was evaluated for the language processing system, which consisted of language, perceptual, motor, and cognitive networks. Linear regression was performed to compare within- and between-network connectivity across networks and within the language network in PCA compared to CU individuals. Relationships between language network connectivity, clinical performance, and gray matter volumes were also evaluated. Results: PCA showed reduced connectivity within the language and perceptual networks, along with reduced between-network connectivity compared to CU individuals. Regional connectivity breakdown within the language network was also noted. Language processing system connectivity was not associated with clinical performance on language processing tests. However, a breakdown in Broca-Wernicke, Wernicke-middle frontal gyrus, and Wernicke-frontal orbital gyrus connectivity was related to worse performance on sentence repetition. Lastly, gray matter volume was not associated with language network connectivity. Discussion: Together, these results reiterate the breakdown of language network connectivity in PCA and highlight the disruption in connectivity at the regional level within the language network. Reduced connectivity within the perceptual network and associations between reduced language network connectivity and worse performance on sentence repetition imply a breakdown within the language processing systems in PCA.

Objective: Progressive apraxia of speech (PAOS) is a neurodegenerative syndrome characterized by impaired motor speech planning and programming, whereas behavioral variant frontotemporal dementia (bvFTD) is characterized by deviant behavioral (e.g., personality and social) features. Clinical and anatomic characteristics of bvFTD in the context of PAOS are understudied. Methods: We identified 12 participants with PAOS and features that were consistent with bvFTD at baseline or follow-up. Eleven completed a head MRI scan. We compared clinical features and anatomical patterns of atrophy in these 11 PAOS-bvFTD participants to 11 matched PAOS participants without bvFTD and 22 age- and sex-matched healthy controls. Statistical Parametric Mapping (SPM) was applied to visualize gray matter volume across both groups compared to controls and each other. Medians and 25th and 75th percentiles were assessed in patients and across groups; Fisher’s Exact Test and Mann–Whitney U tests were applied using BlueSky software, version 10.3.1-Pro. Results: As expected, PAOS-bvFTD participants performed worse on the Frontal Behavioral Inventory (median: 33/72 vs. 10/72), 20-item behavioral assessment scale (4.5/20 vs. 1.0/20), and the Neuropsychiatry inventory (4/36 vs. 1.5/36) compared to the PAOS group (p < 0.01 for all), with no differences in other demographic, neurological, or language tests. Seven of the eleven PAOS-bvFTD participants had bvFTD features develop within three years of symptom onset. The PAOS-bvFTD and PAOS groups showed volume loss in frontal lobe regions compared to controls, with PAOS-bvFTD participants having more prefrontal volume loss than PAOS participants. Conclusions: Behavioral features consistent with bvFTD can co-occur in patients with PAOS and are related to greater atrophy of the prefrontal cortex.

Abstract 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.

ABSTRACTBackgroundPrimary 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).MethodsWe 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.ResultsDisease 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.ConclusionIn 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.

Abstract Background Quantitative susceptibility mapping ( QSM ) is a promising neuroimaging biomarker for detecting abnormal iron deposition in progressive supranuclear palsy ( PSP ); however, the QSM profile and its accuracy in autopsy‐confirmed PSP remain unexplored. Objective The aim of the study was to elucidate and validate the QSM profiles in autopsy‐confirmed PSP. Methods Eight patients with a clinically diagnosed PSP syndrome ( PSPS ) underwent antemortem 3 T magnetic resonance imaging ( MRI) scanning and subsequent pathological diagnosis, confirming 6 PSP pathology and 2 multiple system atrophy ( MSA ) pathology cases. QSM analysis and Prussian blue staining were performed across subcortical regions. Results PSP cases showed higher susceptibility than age‐matched controls in the pallidum, subthalamic nucleus, substantia nigra, and cerebellar dentate (false discovery rate [ FDR] ‐corrected P < 0.05). PSP had higher susceptibility in the subthalamic nucleus and lower susceptibility in the putamen than the clinically atypical MSA ( P = 0.08). Subcortical susceptibilities correlated with Prussian blue–stained areas ( r = 0.63, P < 0.001). Conclusions QSM could be a reliable measure to evaluate abnormal iron accumulation patterns in PSP.

Abstract Background Progressive Supranuclear Palsy (PSP) is a rare and severe neurodegenerative tauopathy characterized by diverse clinical phenotypes, including Richardson's syndrome (PSP‐RS), PSP‐parkinsonism (PSP‐P), PSP‐progressive gait freezing (PSP‐PGF), and PSP‐corticobasal syndrome (PSP‐CBS). Significant geographic variation exists in prevalence, clinical presentations, and prognosis. Objectives This global review aims to systematically evaluate the epidemiological variation, clinical phenotypes, diagnostic practices, and management strategies for PSP, focusing on regional disparities and identifying influencing genetic and environmental factors. Methodology A comprehensive literature search following PRISMA guidelines was conducted, analyzing studies reporting PSP epidemiology, phenotypes, diagnostic criteria, risk factors, treatments, and prognoses. Data were categorized into epidemiology, risk factors, clinical presentations, diagnosis, treatment accessibility, and outcomes, considering geographic variation. Results Global PSP prevalence ranges between 5–6.4 per 100,000, influenced by diagnostic criteria and healthcare infrastructure. Clinical manifestations commonly include supranuclear gaze palsy, frequent falls, cognitive impairment, and motor dysfunction. Prognosis significantly varies with subtype; PSP‐RS shows rapid progression and shorter survival (5–7 years), whereas PSP‐P has a milder clinical course (8–12 years). Regional variations highlight differences in genetic predispositions, notably the MAPT H1 haplotype, environmental risk factors such as dietary neurotoxins and industrial pollutants, and accessibility to comprehensive healthcare services. Diagnostic accuracy has improved with the adoption of MDS‐PSP criteria, facilitating recognition of diverse phenotypes. Conclusions Regional disparities in PSP prevalence, phenotypic presentation, and healthcare accessibility underscore the importance of standardized diagnostic criteria, targeted genetic and environmental studies, and equitable healthcare strategies. Enhanced global collaboration is essential for improving PSP diagnosis, management, and patient outcomes worldwide.