Motor speech disorders in the nonfluent, semantic and logopenic variants of primary progressive aphasia. Supplementary data: Motor speech characterization per participant

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Exploring Links Between Psychosis and Frontotemporal Dementia Using Multimodal Machine Learning Dementia Praecox Revisited

ImportanceThe behavioral and cognitive symptoms of severe psychotic disorders overlap with those seen in dementia. However, shared brain alterations remain disputed, and their relevance for patients in at-risk disease stages has not been explored so far.ObjectiveTo use machine learning to compare the expression of structural magnetic resonance imaging (MRI) patterns of behavioral-variant frontotemporal dementia (bvFTD), Alzheimer disease (AD), and schizophrenia; estimate predictability in patients with bvFTD and schizophrenia based on sociodemographic, clinical, and biological data; and examine prognostic value, genetic underpinnings, and progression in patients with clinical high-risk (CHR) states for psychosis or recent-onset depression (ROD).Design, Setting, and ParticipantsThis study included 1870 individuals from 5 cohorts, including (1) patients with bvFTD (n = 108), established AD (n = 44), mild cognitive impairment or early-stage AD (n = 96), schizophrenia (n = 157), or major depression (n = 102) to derive and compare diagnostic patterns and (2) patients with CHR (n = 160) or ROD (n = 161) to test patterns’ prognostic relevance and progression. Healthy individuals (n = 1042) were used for age-related and cohort-related data calibration. Data were collected from January 1996 to July 2019 and analyzed between April 2020 and April 2022.Main Outcomes and MeasuresCase assignments based on diagnostic patterns; sociodemographic, clinical, and biological data; 2-year functional outcomes and genetic separability of patients with CHR and ROD with high vs low pattern expression; and pattern progression from baseline to follow-up MRI scans in patients with nonrecovery vs preserved recovery.ResultsOf 1870 included patients, 902 (48.2%) were female, and the mean (SD) age was 38.0 (19.3) years. The bvFTD pattern comprising prefrontal, insular, and limbic volume reductions was more expressed in patients with schizophrenia (65 of 157 [41.2%]) and major depression (22 of 102 [21.6%]) than the temporo-limbic AD patterns (28 of 157 [17.8%] and 3 of 102 [2.9%], respectively). bvFTD expression was predicted by high body mass index, psychomotor slowing, affective disinhibition, and paranoid ideation (R2 = 0.11). The schizophrenia pattern was expressed in 92 of 108 patients (85.5%) with bvFTD and was linked to the C9orf72 variant, oligoclonal banding in the cerebrospinal fluid, cognitive impairment, and younger age (R2 = 0.29). bvFTD and schizophrenia pattern expressions forecasted 2-year psychosocial impairments in patients with CHR and were predicted by polygenic risk scores for frontotemporal dementia, AD, and schizophrenia. Findings were not associated with AD or accelerated brain aging. Finally, 1-year bvFTD/schizophrenia pattern progression distinguished patients with nonrecovery from those with preserved recovery.Conclusions and RelevanceNeurobiological links may exist between bvFTD and psychosis focusing on prefrontal and salience system alterations. Further transdiagnostic investigations are needed to identify shared pathophysiological processes underlying the neuroanatomical interface between the 2 disease spectra.</p

Resting-state alterations in behavioral variant frontotemporal dementia are related to the distribution of monoamine and GABA neurotransmitter systems

Introduction: Aside to changes in personality and behavior, behavioral variant frontotemporal dementia (bvFTD) is characterized by progressive structural and functional alterations in frontal and temporal regions. Only little is known about the underlying mechanisms leading to the anatomical constraints of the pathophysiology. Here, we evaluated if these alterations are linked to the distribution of specific neurotransmitter systems.Methods: Maps of fractional amplitude of low frequency fluctuations (fALFF) were derived as a measure of local activity from resting state functional magnetic resonance imaging for 52 bvFTD patients and 22 healthy controls (HC). We tested if alterations in the fALFF signal of bvFTD patients co-localize with the known non-pathological distribution of specific neurotransmitter systems and their coding mRNA gene expression. Furthermore, we evaluated if the strength of this co-localization is associated with respective symptom severity.Results: Compared to HC, patients displayed significantly reduced fractional amplitude of low frequency fluctuations in fronto-temporal and fronto-parietal regions. These alterations significantly co-localized with the distribution of serotonin (5-HT1b, 5-HT2a), dopamine (D2), and gamma-aminobutyric acid type A receptors, the noradrenaline transporter, and their encoding mRNA gene expression. The strength of the co-localization with D2 and noradrenaline transporter was associated with cognitive symptoms of bvFTD. Conclusion: Local brain functional activity reductions in bvFTD follow the distribution of specific neurotransmitter systems supporting the notion of the preferential vulnerability of specific neurotransmitter systems. These findings provide novel insight into neuropathophysiological mechanisms underlying functional alterations in bvFTD