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Objective: Frontotemporal dementia (FTD) is a progressive neurodegenerative disorder that affects the frontal and temporal lobes of the brain, leading to cognitive decline and personality changes. The objective of this cross-sectional study was to characterize angioarchitectural changes in the retina and choroid of individuals with FTD compared to cognitively normal controls using optical coherence tomography (OCT) and OCT angiography (OCTA)., Methods: Cross-sectional comparison of patients with FTD and controls with normal cognition. All participants underwent Mini-Mental State Examination (MMSE) at the time of imaging. Outcome measures included OCT parameters: retinal nerve fiber layer (RNFL) thickness, ganglion cell layer-inner plexiform layer (GC-IPL) thickness, central subfield thickness (CST), subfoveal choroidal thickness (SFCT), choroidal vascularity index (CVI); and OCTA superficial capillary plexus parameters: foveal avascular zone (FAZ) area, 3x3mm and 6x6mm macular perfusion density (PD) and vessel density (VD), 4.5x4.5mm peripapillary capillary perfusion density (CPD) and capillary flux index (CFI). Generalized estimating equation analysis was used to account for the inclusion of 2 eyes from the same participant., Results: 29 eyes of 19 patients with FTD and 85 eyes of 48 controls were analyzed. In FTD, 3x3mm macular PD (p = 0.02) and VD (p = 0.02) and CFI (p = 0.01) were reduced compared to controls. There was no difference in average 4.5x4.5mm CPD, RNFL thickness, GC-IPL thickness, CST, SFCT, CVI, FAZ, or 6x6mm VD or PD between FTD and controls (all p > 0.05); however, there was a trend toward lower macular 6x6mm PD and VD in patients with FTD., Conclusion: Decline of peripapillary and macular OCT and OCTA parameters merit further investigation as potential biomarkers for FTD detection. Noninvasive retinal and choroidal imaging may hold promise for earlier detection, and future longitudinal studies will clarify their role in monitoring of FTD., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Allen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background and Purpose: Brain atrophy occurs in the late stage of dementia, yet structural MRI is widely used in the work-up. Atrophy patterns can suggest a diagnosis of Alzheimer disease (AD) or frontotemporal dementia (FTD) but are difficult to assess visually. We hypothesized that the availability of a quantitative volumetric brain MRI report would increase neuroradiologists' accuracy in diagnosing AD, FTD, or healthy controls compared with visual assessment., Materials and Methods: Twenty-two patients with AD, 17 with FTD, and 21 cognitively healthy patients were identified from the electronic health systems record and a behavioral neurology clinic. Four neuroradiologists evaluated T1-weighted anatomic MRI studies with and without a volumetric report. Outcome measures were the proportion of correct diagnoses of neurodegenerative disease versus normal aging ("rough accuracy") and AD versus FTD ("exact accuracy"). Generalized linear mixed models were fit to assess whether the use of a volumetric report was associated with higher accuracy, accounting for random effects of within-rater and within-subject variability. Post hoc within-group analysis was performed with multiple comparisons correction. Residualized volumes were tested for an association with the diagnosis using ANOVA., Results: There was no statistically significant effect of the report on overall correct diagnoses. The proportion of "exact" correct diagnoses was higher with the report versus without the report for AD (0.52 versus 0.38) and FTD (0.49 versus 0.32) and lower for cognitively healthy (0.75 versus 0.89). The proportion of "rough" correct diagnoses of neurodegenerative disease was higher with the report than without the report within the AD group (0.59 versus 0.41), and it was similar within the FTD group (0.66 versus 0.63). Post hoc within-group analysis suggested that the report increased the accuracy in AD (OR = 2.77) and decreased the accuracy in cognitively healthy (OR = 0.25). Residualized hippocampal volumes were smaller in AD (mean difference -1.8; multiple comparisons correction, -2.8 to -0.8; P < .001) and FTD (mean difference -1.2; multiple comparisons correction, -2.2 to -0.1; P = .02) compared with cognitively healthy., Conclusions: The availability of a brain volumetric report did not improve neuroradiologists' accuracy over visual assessment in diagnosing AD or FTD in this limited sample. Post hoc analysis suggested that the report may have biased readers incorrectly toward a diagnosis of neurodegeneration in cognitively healthy adults., (© 2024 by American Journal of Neuroradiology.)

Purpose: The loss of olfactory function is known to occur in patients suffering from (behavioral variant) frontotemporal dementia ((bv)FTD) and Alzheimer's disease (AD), although different pathophysiological mechanisms underpin this clinical symptom in both disorders. This study assessed whether brain metabolism of the olfactory circuit as assessed by positron emission tomography (PET) imaging with 2-[fluorine-18]fluoro-2-deoxy-d-glucose ([ 18 F]-FDG) can distinguish these entities in different subsets of patients., Methods: Patients presenting with cognitive decline were included from a prospectively kept database: (1) bvFTD patients, (2) AD patients and (3) patients with logopenic primary progressive aphasia (PPA). Metabolic rates were calculated for different regions of the olfactory circuit for each subgroup and compared with a cohort of subjects with normal brain metabolism. Additionally, in patients with a logopenic PPA pattern on PET-imaging, statistical parametric mapping (SPM) analysis was performed., Results: The metabolism of subdivisions of the olfactory circuit as assessed by [ 18 F]-FDG PET brain imaging to bvFTD and AD from control subjects resulted in sensitivity/specificity rates of 95/87.5% and 80/83.3%, respectively. A sensitivity/specificity rate of 100/87.5% was achieved when used to differentiate AD from bvFTD. In patients with the PPA pattern on imaging, the underlying cause (either FTD or AD) could be determined with a sensitivity/specificity rate of 88/82%. SPM analysis concurred that different regions of the olfactory circuit were affected in patients suffering from AD PPA or bvFTD PPA., Conclusion: Metabolic dysfunction in the olfactory circuit is different in various neurodegenerative disorders. Further investigation of the correlations between the cerebral metabolism and the mechanisms which drive olfactory dysfunction is needed., (© 2024. The Author(s).)

Behavioral variant frontotemporal dementia (bvFTD) is characterized by profound and early deficits in social cognition (SC) and executive functions (EF). To date it remains unclear whether deficits of the respective cognitive domains are based on the degeneration of distinct brain regions. In 103 patients with a diagnosis of bvFTD (possible/probable/definite: N = 40/58/5) from the frontotemporal lobar degeneration (FTLD) consortium Germany cohort (age 62.5±9.4 years, gender 38 female/65 male) we applied multimodal structural imaging, i.e. voxel-based morphometry, cortical thickness (CTH) and networks of structural covariance via source based morphometry. We cross-sectionally investigated associations with performance in a modified Reading the Mind in the Eyes Test (RMET; reflective of theory of mind - ToM) and five different tests reflective of EF (i.e. Hamasch-Five-Point Test, semantic and phonemic Fluency, Trail Making Test, Stroop interference). Finally, we investigated the conjunction of RMET correlates with functional networks commonly associated with SC respectively ToM and EF as extracted meta-analytically within the Neurosynth database. RMET performance was mainly associated with gray matter volume (GMV) and CTH within temporal and insular cortical regions and less within the prefrontal cortex (PFC), whereas EF performance was mainly associated with prefrontal regions (GMV and CTH). Overlap of RMET and EF associations was primarily located within the insula, adjacent subcortical structures (i.e. putamen) and the dorsolateral PFC (dlPFC). These patterns were more pronounced after adjustment for the respective other cognitive domain. Corroborative results were obtained in analyses of structural covariance networks. Overlap of RMET with meta-analytically extracted functional networks commonly associated with SC, ToM and EF was again primarily located within the temporal and insular region and the dlPFC. In addition, on a meta-analytical level, strong associations were found for temporal cortical RMET correlates with SC and ToM in particular. These data indicate a temporo-frontal dissociation of bvFTD related disturbances of ToM and EF, with atrophy of the anterior temporal lobe being critically involved in ToM deficits. The consistent overlap within the insular cortex may be attributable to the multimodal and integrative role of this region in socioemotional and cognitive processing., (© 2024. The Author(s).)

Background and Objectives: Behavioral and neuropsychiatric symptoms are frequent in patients with genetic frontotemporal dementia (FTD). We aimed to describe behavioral and neuropsychiatric phenotypes in genetic FTD, quantify their temporal association, and investigate their regional association with brain atrophy., Methods: We analyzed data of pathogenic variant carriers in the chromosome 9 open reading frame 72 ( c9orf72 ), progranulin ( GRN ), or microtubule-associated protein tau ( MAPT ) gene from the Genetic Frontotemporal dementia Initiative cohort study that enrolls both symptomatic pathogenic variant carriers and first-degree relatives of known carriers. Principal component analysis was performed to identify behavioral and neuropsychiatric clusters that were compared with respect to frequency and severity between groups. Associations between neuropsychiatric clusters and MRI-assessed atrophy were determined using voxel-based morphometry. We applied linear mixed effects and generalized linear mixed effects models to assess the longitudinal course of symptoms., Results: A total of 522 participants were included: 221 c9orf72 (138 presymptomatic), 213 GRN (157 presymptomatic), and 88 MAPT (62 presymptomatic) pathogenic variant carriers. Principal component analysis revealed 5 phenotypic clusters (67.6% of variance), labeled diverse behavioral, affective, psychotic, euphoric/hypersexual, and tactile hallucinations phenotype. In participants presenting behavioral or neuropsychiatric symptoms, affective symptoms were most frequent across groups (83.6%-88.1%), followed by diverse behavioral symptoms (68.4%-77.9%). In c9orf72 and GRN pathogenic variant carriers, psychotic symptoms (32.0% and 19.4%, respectively) were more frequent than euphoric/hypersexual symptoms (28.7% and 14.2%, respectively), which was the other way around in MAPT pathogenic variant carriers (28.6% and 23.8%). Although diverse behavioral symptoms were associated with gray and white matter frontotemporal atrophy, only a small atrophy cluster in the right thalamus was associated with psychotic symptoms. Euphoric/hypersexual symptoms were associated with atrophy in mesial temporal lobes, basal forebrain structures, and the striatum ( p < 0.05). Estimated time to symptom onset, genetic group, education, and sex influenced behavioral and neuropsychiatric symptoms ( p < 0.05). Particularly, in c9orf72 pathogenic variant carriers, psychotic symptoms may be starting decades before recognition of onset of illness., Discussion: We identified multiple clusters of behavioral and neuropsychiatric symptoms in participants with genetic FTD that relate to distinct cerebral atrophy patterns. Their severity depends on time, affected gene, sex, and education. These clinical-genetic associations can guide diagnostic evaluations and the design of clinical trials for new disease-modifying and preventive treatments.

Studies exploring the brain correlates of behavioral symptoms in the frontotemporal dementia spectrum (FTD) have mainly searched for linear correlations with single modality neuroimaging data, either structural magnetic resonance imaging (MRI) or fluoro-deoxy-D-glucose positron emission tomography (FDG-PET). We aimed at studying the two imaging modalities in combination to identify nonlinear co-occurring patterns of atrophy and hypometabolism related to behavioral symptoms. We analyzed data from 93 FTD patients who underwent T1-weighted MRI, FDG-PET imaging, and neuropsychological assessment including the Neuropsychiatric Inventory, Frontal Systems Behavior Scale, and Neurobehavioral Rating Scale. We used a data-driven approach to identify the principal components underlying behavioral variability, then related the identified components to brain variability using a newly developed method fusing maps of grey matter volume and FDG metabolism. A component representing apathy, executive dysfunction, and emotional withdrawal was associated with atrophy in bilateral anterior insula and putamen, and with hypometabolism in the right prefrontal cortex. Another component representing the disinhibition versus depression/mutism continuum was associated with atrophy in the right striatum and ventromedial prefrontal cortex for disinhibition, and hypometabolism in the left fronto-opercular region and sensorimotor cortices for depression/mutism. A component representing psychosis was associated with hypometabolism in the prefrontal cortex and hypermetabolism in auditory and visual cortices. Behavioral symptoms in FTD are associated with atrophy and altered metabolism of specific brain regions, especially located in the frontal lobes, in a hierarchical way: apathy and disinhibition are mostly associated with grey matter atrophy, whereas psychotic symptoms are mostly associated with hyper-/hypo-metabolism., Competing Interests: Declarations. Ethics approval and patients consents statement: Written informed consent for the study, approved by the NINDS Institutional Review Board and in accordance with the Declaration of Helsinki, was obtained from a family member. Assent from the patient was always required in all circumstances. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Abstract: We reported imaging findings with a peculiar tau accumulation pattern in a 56 year-old woman with frontotemporal dementia caused by Q351R mutation in the microtubule-associated protein tau ( MAPT ) gene. She had a 10-year history of gradually worsening memory loss. 18 F-FDG PET demonstrated hypometabolism in medial temporal lobes, but 18 F-florbetapir PET manifested no abnormal amyloid beta deposition, which ruled out Alzheimer disease. 18 F-florzolotau PET showed tau proteins accumulated in medial temporal lobes, basal ganglia brainstem, and cerebellum. The pattern is different from other known MAPT gene mutation. Multitracer imaging can help differentiate between Alzheimer disease and frontotemporal dementia caused by MAPT mutation., Competing Interests: Conflicts of interest and sources of funding: This work was financially supported by a grant (2022-PUMCH-B-070) from the National High Level Hospital Clinical Research Funding. We express our gratitude to APRINOIA Therapeutics (Suzhou, China) for supplying the tosylate precursor of 18 F-florzolotau. We are also grateful to Tzu-Chen Yen, an employee and shareholder of APRINOIA Therapeutics, for her valuable professional advice. The authors declare that they have no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Brain MRI with volumetric quantification, MRI volumetry, can improve diagnostic delineation of patients with neurocognitive disorders by identifying brain atrophy that may not be evident on visual assessments., Objective: To investigate diagnostic utility of MRI volumetry in traumatic brain injury (TBI), early-onset Alzheimer disease (EOAD), late-onset Alzheimer disease, and behavioral variant frontotemporal dementia (bvFTD)., Method: We utilized 137 participants of TBI (n = 40), EOAD (n = 45), LOAD (n = 32), and bvFTD (n = 20). Participants had 3D T1 brain MRI imaging amendable to MRI volumetry. Scan volumes were analyzed with Neuroreader. One-way ANOVA compared brain volumes across diagnostic groups. Discriminant analysis was done with leave-one-out cross validation on Neuroreader metrics to determine diagnostic delineation across groups., Result: LOAD was the oldest compared to other groups (F = 27.5, p < .001). There were no statistically significant differences in sex (p = .58) with women comprising 54.7% of the entire cohort. EOAD and LOAD had the lowest Mini-Mental State Exam (MMSE) scores compared to TBI (p = .04 for EOAD and p = .01 for LOAD). LOAD had lowest hippocampal volumes (Left Hippocampus F = 13.1, Right Hippocampus F = 7.3, p < .001), low white matter volume in TBI (F = 5.9, p < .001), lower left parietal lobe volume in EOAD (F = 9.4, p < .001), and lower total gray matter volume in bvFTD (F = 32.8, p < .001) and caudate atrophy (F = 1737.5, p < .001). Areas under the curve ranged from 92.3 to 100%, sensitivity between 82.2 and 100%, specificity of 78.1-100%. TBI was the most accurately delineated diagnosis. Predictive features included caudate, frontal, parietal, temporal lobar and total white matter volumes., Conclusion: We identified the diagnostic utility of regional volumetric differences across multiple neurocognitive disorders. Brain MRI volumetry is widely available and can be applied in distinguishing these disorders., (© 2024. The Author(s).)

Frontotemporal dementia (FTD) is a disease of high heterogeneity, apathy and disinhibition present in all subtypes of FTD and imposes a significant burden on families/society. Traditional neuroimaging analysis has limitations in elucidating the network localization due to individual clinical and neuroanatomical variability. The study aims to identify the atrophy network map associated with different FTD clinical subtypes and determine the specific localization of the network for apathy and disinhibition. Eighty FTD patients [45 behavioural variant FTD (bvFTD) and 35 semantic variant progressive primary aphasia (svPPA)] and 58 healthy controls at Xuanwu Hospital were enrolled as Dataset 1; 112 FTD patients including 50 bvFTD, 32 svPPA and 30 non-fluent variant PPA (nfvPPA) cases, and 110 healthy controls from the Frontotemporal Lobar Degeneration Neuroimaging Initiative (FTLDNI) dataset were included as Dataset 2. Initially, single-subject atrophy maps were defined by comparing cortical thickness in each FTD patient versus healthy controls. Next, the network of brain regions functionally connected to each FTD patient's location of atrophy was determined using seed-based functional connectivity in a large (n = 1000) normative connectome. Finally, we used atrophy network mapping to define clinical subtype-specific network (45 bvFTD, 35 svPPA and 58 healthy controls in Dataset 1; 50 bvFTD, 32 svPPA, 30 nfvPPA and 110 healthy controls in Dataset 2) and symptom-specific networks [combined Datasets 1 and 2, apathy without depression versus non-apathy without depression (80:26), disinhibition versus non-disinhibition (88:68)]. We compare the result with matched symptom networks derived from patients with focal brain lesions or conjunction analysis. Through the analysis of two datasets, we identified heterogeneity in atrophy patterns among FTD patients. However, these atrophy patterns are connected to a common brain network. The primary regions affected by atrophy in FTD included the frontal and temporal lobes, particularly the anterior temporal lobe. bvFTD connects to frontal and temporal cortical areas, svPPA mainly impacts the anterior temporal region and nfvPPA targets the inferior frontal gyrus and precentral cortex regions. The apathy-specific network was localized in the orbital frontal cortex and ventral striatum, while the disinhibition-specific network was localized in the bilateral orbital frontal gyrus and right temporal lobe. Apathy and disinhibition atrophy networks resemble known motivational and criminal lesion networks, respectively. A significant correlation was found between the apathy/disinhibition scores and functional connectivity between atrophy maps and the peak of the networks. This study localizes the common network of clinical subtypes and main symptoms in FTD, guiding future FTD neuromodulation interventions., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Focal atrophy of the left anterior temporal lobe has been associated with the semantic type of primary progressive aphasia evolving to semantic dementia. In contrast, focal atrophy of the right temporal lobe has more recently been described as a controverse entity reported as the right temporal variant of FTD. We describe two cases of FTD dementia syndromes: in Case 1, atrophy of the right temporal lobe led to significant behavioural impairment and difficulties in recognizing known people. In Case 2, atrophy of the left temporal lobe was associated with severe aggressive, ritualistic behaviour and aphasia., (© 2024 The British Psychological Society.)

Introduction: Frontotemporal dementia (FTD) can be phenotypically divided into behavioral variant FTD (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), and semantic variant PPA (svPPA). However, the neural underpinnings of this phenotypic heterogeneity remain elusive., Methods: Cortical morphology, white matter hyperintensities (WMH), diffusion tensor image analysis along the perivascular space (DTI-ALPS), and their interrelationships were assessed in subtypes of FTD. Neuroimaging-transcriptional analyses on the regional cortical morphological deviances among subtypes were also performed., Results: Changes in cortical thickness, surface area, gyrification, WMH, and DTI-ALPS were subtype-specific in FTD. The three morphologic indices are related to whole-brain WMH volume and cognitive performance, while cortical thickness is related to DTI-ALPS. Neuroimaging-transcriptional analyses identified key biological pathways linked to the formation and/or spread of TDP-43/tau pathologies., Discussion: We found subtype-specific changes in cortical morphology, WMH, and glymphatic function in FTD. Our findings have the potential to contribute to the development of personalized predictions and treatment strategies for this disorder., Highlights: Cortical morphologic changes, white matter hyperintensities (WMH), and glymphatic dysfunction are subtype-specific. Cortical morphologic changes, WMH, and glymphatic dysfunction are inter-correlated. Cortical morphologic changes and WMH burden contribute to cognitive impairments., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background and Purpose: Frontotemporal dementia (FTD) is a clinically and pathologically heterogeneous neurodegenerative condition with a prevalence comparable to Alzheimer's disease for patients under 65 years of age. Limited studies have examined the association between cognition and neuroimaging in FTD using different imaging modalities., Methods: We examined the association of cognition using Montreal Cognitive Assessment (MoCA) with both gray matter (GM) volume and glucose metabolism using magnetic resonance imaging and fluorodeoxyglucose (FDG)-PET in 21 patients diagnosed with FTD. Standardized uptake value ratio (SUVR) using the brainstem as a reference region was the primary outcome measure for FDG-PET. Partial volume correction was applied to PET data to account for disease-related atrophy., Results: Significant positive associations were found between whole-cortex GM volume and MoCA scores (r = 0.46, p = .04). The association between whole-cortex FDG SUVR and MoCA scores was not significant (r = 0.37, p = .09). GM volumes of the frontal cortex (r = 0.54, p = .01), caudate (r = 0.62, p<.01), and insula (r = 0.57, p<.01) were also significantly correlated with MoCA, as were SUVR values of the insula (r = 0.51, p = .02), thalamus (r = 0.48, p = .03), and posterior cingulate cortex (PCC) (r = 0.47, p = .03)., Conclusions: Whole-cortex atrophy is associated with cognitive dysfunction, and this association is larger than for whole-cortex hypometabolism as measured with FDG-PET. At the regional level, focal atrophy and/or hypometabolism in the frontal cortex, insula, PCC, thalamus, and caudate seem to be important for the decline of cognitive function in FTD. Furthermore, these results highlight how functional and structural changes may not overlap and might contribute to cognitive dysfunction in FTD in different ways., (© 2024 American Society of Neuroimaging.)

Objective: Socioemotional changes, rather than cognitive impairments, are the feature that defines behavioral variant frontotemporal dementia (bvFTD). Investigators have attributed the socioemotional changes in bvFTD and other dementias to frontal lobe dysfunction; however, recent work implies a further contribution from right anterior temporal disease. The authors evaluated relationships between regional brain atrophy and socioemotional changes in both bvFTD and early-onset Alzheimer's disease (EOAD)., Methods: This study explored the neuroanatomical correlations of performance on the Socioemotional Dysfunction Scale (SDS), an instrument previously shown to document socioemotional changes in bvFTD, among 13 patients with bvFTD not preselected for anterior temporal involvement and 16 age-matched patients with early-onset Alzheimer's disease (EOAD). SDS scores were correlated with volumes of regions of interest assessed with tensor-based morphometric analysis of MRI images., Results: As expected, the bvFTD group had significantly higher SDS scores overall and smaller frontal regions compared with the EOAD group, which in turn had smaller volumes in temporoparietal regions. SDS scores significantly correlated with lateral anterior temporal lobe (ATL) atrophy, and a regression analysis that controlled for diagnosis indicated that SDS scores predicted lateral ATL volume. Within the bvFTD group, higher SDS scores were associated with smaller lateral and right ATL regions, as well as a smaller orbitofrontal cortex. Within the EOAD group, higher SDS scores were associated with a smaller right parietal cortex., Conclusions: This study confirms that, in addition to orbitofrontal disease, there is a prominent right and lateral ATL origin of socioemotional changes in bvFTD and further suggests that right parietal involvement contributes to socioemotional changes in EOAD., Competing Interests: The authors report no financial relationships with commercial interests.

Background and Objectives: Pathogenic variants in the GRN gene cause frontotemporal dementia (FTD- GRN ) with marked brain asymmetry. This study aims to assess whether the disease progression of FTD- GRN depends on the initial side of the atrophy. We also investigated the potential use of brain asymmetry as a biomarker of the disease., Methods: Retrospective examination of data from the prospective Genetic Frontotemporal Initiative (GENFI) cohort study that recruits individuals who carry or were at risk of carrying a pathogenic variant causing FTD. GENFI participants underwent a standardized clinical and neuropsychological assessment, MRI, and a blood sample test yearly. We generated an asymmetry index for brain MRI to characterize brain asymmetry in participants with or at risk of FTD- GRN . Depending on the side of the asymmetry, we classified symptomatic GRN patients as right- GRN or left- GRN and compared their clinical features and disease progression. We generated generalized additive models to study how the asymmetry index evolves in carriers and noncarriers and compare its models with others created with volumetric values and plasma neurofilament light chain., Results: A total of 399 participants (mean age 49.7 years, 59% female) were included (63 symptomatic carriers, 177 presymptomatic carriers, and 159 noncarriers). Symptomatic carriers showed higher brain asymmetry (11.6) than noncarriers (1.0, p < 0.001) and presymptomatic carriers (1.0, p < 0.001), making it possible to classify most of them as right- GRN (n = 21) or left- GRN (n = 36). Patients with right- GRN showed more disease severity at baseline ( β = 6.9, 95% CI 2.4-11.0, p = 0.003) but a lower deterioration by year ( β = -1.5, 95% CI -2.7 to -0.31, p = 0.015) than patients with left- GRN . Brain asymmetry could be found in GRN carriers 10.4 years before the onset of the symptoms (standard difference 0.85, CI 0.01-1.68)., Discussion: FTD- GRN affects the brain hemispheres asymmetrically and causes 2 anatomical asymmetry patterns depending on the side of the disease onset. We demonstrated that these 2 anatomical asymmetry patterns present different symptoms, severity at the time of the first visit, and different disease courses. Our results also suggest brain asymmetry as a possible biomarker of conversion in GRN carriers.

Background and Objectives: Sleep dysfunction is common in patients with neurodegenerative disorders; however, its neural underpinnings remain poorly characterized in genetic frontotemporal dementia (FTD). Hypothalamic nuclei important for sleep regulation may be related to this dysfunction. Thus, we examined changes in hypothalamic structure across the lifespan in patients with genetic FTD and whether these changes related to sleep dysfunction., Methods: Data from the observational multisite Genetic Frontotemporal Dementia Initiative (GENFI) study were used. GENFI participants were adult members of a family with known pathogenic variants in the microtubule-associated protein tau (MAPT) or progranulin (GRN) genes or an expansion in the chromosome 9 open reading frame 72 (C9orf72) gene. Family members without a pathogenic variant served as controls. GENFI participants were followed annually, with up to 7 visits, and underwent clinical characterization, neuropsychological testing, biological sampling, and brain MRI. For our analyses, participants were included if they had at least 1 T1-weighted structural MRI scan available. Linear mixed-effect models were used to examine changes in sleep dysfunction, measured using the Cambridge Behavioural Inventory-Revised sleep subscale, volumetric changes in hypothalamic regions, and the associations between cortical and hypothalamic atrophy and sleep dysfunction., Results: Participants included 491 adults with pathogenic genetic variants of FTD (27.9% symptomatic; median age: 49.4 years, 56.4% F ) and 321 controls (median age: 44.2 years, 57.3% F ). Pathogenic variant carriers showed greater sleep dysfunction across the adult lifespan (β = [0.25-0.34], q < 0.005) with MAPT carriers alone showing presymptomatic sleep changes (β = 0.34, q = 0.005). Cortical thinning in frontal and parietal regions was associated with greater sleep disturbances in C9orf72 and GRN carriers (q < 0.05). MAPT carriers showed consistently significant volume loss over time across all sleep-relevant hypothalamic subunits (β = [-0.56 to -0.39], q < 0.005), and reduced volumes in these subunits were related to increased sleep dysfunction (β = [-0.20 to -0.16], q < 0.05)., Discussion: These findings suggest that sleep dysfunction in patients with genetic FTD may be attributable to atrophy in sleep-relevant hypothalamic subunits, with the most severe and consistent deficits observed in MAPT carriers. While biologically plausible, our statistical approach cannot confirm a causal link between atrophy and sleep disturbances.

Neuroimaging and fluid biomarkers are used to differentiate frontotemporal dementia (FTD) from Alzheimer's disease (AD). We implemented a machine learning algorithm that provides individual probabilistic scores based on magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) data. We investigated whether combining MRI and CSF levels could improve the diagnosis confidence. 215 AD patients, 103 FTD patients, and 173 healthy controls (CTR) were studied. With MRI data, we obtained an accuracy of 82 % for AD vs. FTD. A total of 74 % of FTD and 73 % of AD participants have a high probability of accurate diagnosis. Adding CSF-NfL and 14-3-3 levels improved the accuracy and the number of patients in the confidence group for differentiating FTD from AD. We obtain individual diagnostic probabilities with high precision to address the problem of confidence in the diagnosis. We suggest when MRI, CSF, or the combination are necessary to improve the FTD and AD diagnosis. This algorithm holds promise towards clinical applications as support to clinical findings or in settings with limited access to expert diagnoses., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Neurodegenerative diseases are incurable conditions that lead to gradual and progressive deterioration of brain function in patients. With the aging population, the prevalence of these diseases is expected to increase, posing a significant economic burden on society. Imaging techniques play a crucial role in the diagnosis and monitoring of neurodegenerative diseases. This study utilized a two-sample Mendelian randomization (MR) analysis to assess the causal relationship between different imaging-derived phenotypes (IDP) in the brain and neurodegenerative diseases. Multiple MR methods were employed to minimize bias and obtain reliable estimates of the potential causal relationship between the variable exposures of interest and the outcomes. The study found potential causal relationships between different IDPs and Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and frontotemporal dementia (FTD). Specifically, the study identified potential causal relationships between 2 different types of IDPs and AD, 8 different types of IDPs and PD, 11 different types of imaging-derived phenotypes and ALS, 1 type of IDP and MS, and 1 type of IDP and FTD. This study provides new insights for the prevention, diagnosis, and treatment of neurodegenerative diseases, offering important clues for understanding the pathogenesis of these diseases and developing relevant intervention strategies., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Semantic dementia is a kind of neurodegenerative disorder, characterized by prominent semantic impairments and anterior temporal lobe atrophy. Since 2010, more studies have devoted to this rare disorder, revealing that it is more complex than we think. Clinical advances include more specific findings of semantic impairments and other higher order cognitive deficits. Neuroimaging techniques can help revealing the different brain networks affected (both structurally and functionally) in this condition. Pathological and genetic studies have also found more complex situations of semantic dementia, which might explain the huge variance existing in semantic dementia. Moreover, the current diagnosis criteria mainly focus on semantic dementia's classical prototype. We further delineated the features of three subtypes of semantic dementia based on atrophy lateralization with three severity stages. In a broader background, as a part of the continuum of neurodegenerative disorders, semantic dementia is commonly compared with other resembling conditions. Therefore, we summarized the differential diagnosis between semantic dementia and them. Finally, we introduced the challenges and achievements of its diagnosis, treatment, care and cross cultural comparison. By providing a comprehensive picture of semantic dementia on different aspects of advances, we hope to deepen the understanding of semantic dementia and promote more inspirations on both clinical and theoretical studies about it., Competing Interests: Declaration of Competing Interest The authors declare no competing interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: We investigated the effect of perivascular spaces (PVS) volume on speeded executive function (sEF), as mediated by white matter hyperintensities (WMH) volume and plasma glial fibrillary acidic protein (GFAP) in neurodegenerative diseases., Methods: A mediation analysis was performed to assess the relationship between neuroimaging markers and plasma biomarkers on sEF in 333 participants clinically diagnosed with Alzheimer's disease/mild cognitive impairment, frontotemporal dementia, or cerebrovascular disease from the Ontario Neurodegenerative Disease Research Initiative., Results: PVS was significantly associated with sEF (c = -0.125 ± 0.054, 95% bootstrap confidence interval [CI] [-0.2309, -0.0189], p = 0.021). This effect was mediated by both GFAP and WMH., Discussion: In this unique clinical cohort of neurodegenerative diseases, we demonstrated that the effect of PVS on sEF was mediated by the presence of elevated plasma GFAP and white matter disease. These findings highlight the potential utility of imaging and plasma biomarkers in the current landscape of therapeutics targeting dementia., Highlights: Perivascular spaces (PVS) and white matter hyperintensities (WMH) are imaging markers of small vessel disease. Plasma glial fibrillary protein acidic protein (GFAP) is a biomarker of astroglial injury. PVS, WMH, and GFAP are relevant in executive dysfunction from neurodegeneration. PVS's effect on executive function was mediated by GFAP and white matter disease., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Objective : Behavioral variant frontotemporal dementia (bvFTD) is a neurodegenerative condition characterized by progressive changes in behavior, cognition, and day-to-day functioning. Progression of the disease usually leads to death 3-5 years after diagnosis. However, there are reports of individuals who are initially diagnosed with bvFTD but fail to progress. These individuals are thought to have what is becoming known as phenocopy bvFTD (phFTD). Methods : This manuscript reviews a single case study of a 68-year-old male Veteran who was diagnosed with bvFTD in 2010, which has not progressed over time. Results : Review of serial neuropsychological evaluations was broadly normal with mild evidence of executive dysfunction with minimal reliable change in his performances from 2015, 2017, and 2022 evaluations. He also has not developed neuroimaging evidence of FTD. Conclusions : This case illustrates the importance of monitoring individuals over time and incorporating neuroimaging data into the diagnosis. We believe this Veteran's presentation is most consistent with what has been described as phFTD.

Background: Alzheimer's disease (AD) and frontotemporal dementia (FTD) require different treatments. Since clinical presentation can be nuanced, imaging biomarkers aid in diagnosis. Automated software such as Neuroreader (NR) provides volumetric imaging data, and indices between anterior and posterior brain areas have proven useful in distinguishing dementia subtypes in research cohorts. Existing indices are complex and require further validation in clinical settings., Purpose: To provide initial validation for a simplified anterior-posterior index (API) from NR in distinguishing FTD and AD in a clinical cohort., Material and Methods: A retrospective chart review was completed. We derived a simplified API: API = (logV A /V P -μ)/σ where V A is weighted volume of frontal and temporal lobes and V P of parietal and occipital lobes. μ and σ are the mean and standard deviation of logV A /V P computed for AD participants. Receiver operating characteristic (ROC) curves and regression analyses assessed the efficacy of the API versus brain areas in predicting diagnosis of AD versus FTD., Results: A total of 39 participants with FTD and 78 participants with AD were included. The API had an excellent performance in distinguishing AD from FTD with an area under the ROC curve of 0.82 and a positive association with diagnostic classification on logistic regression analysis (B = 1.491, P  < 0.001)., Conclusion: The API successfully distinguished AD and FTD with excellent performance. The results provide preliminary validation of the API in a clinical setting., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Semantic behavioral variant frontotemporal dementia (sbvFTD) is a neurodegenerative condition presenting with specific behavioral and semantic derangements and predominant atrophy of the right anterior temporal lobe (ATL). The objective was to evaluate clinical, neuropsychological, neuroimaging, and genetic features of an Italian sbvFTD cohort, defined according to recently proposed guidelines, compared to semantic variant primary progressive aphasia (svPPA) and behavioral variant FTD (bvFTD) patients., Methods: Fifteen sbvFTD, sixty-three bvFTD, and twenty-five svPPA patients and forty controls were enrolled. Patients underwent clinical, cognitive evaluations, and brain MRI. Symptoms of bvFTD patients between onset and first visit were retrospectively recorded and classified as early and late. Grey matter atrophy was investigated using voxel-based morphometry., Results: sbvFTD experienced early criteria-specific symptoms: world, object and person-specific semantic loss (67%), complex compulsions and rigid thought (60%). Sequentially, more behavioral symptoms emerged (apathy/inertia, loss of empathy) along with non-criteria-specific symptoms (anxiety, suspiciousness). sbvFTD showed sparing of attentive/executive functions, especially compared to bvFTD and better language functions compared to svPPA. All sbvFTD patients failed at the famous face recognition test and more than 80% failed in understanding written metaphors and humor. At MRI, sbvFTD had predominant right ATL atrophy, almost specular to svPPA. Three sbvFTD patients presented pathogenic genetic variants., Conclusion: We replicated the application of sbvFTD diagnostic guidelines in an independent Italian cohort, demonstrating that the presence of person-specific semantic knowledge loss and mental rigidity, along with preserved executive functions and a predominant right ATL atrophy with sparing of frontal lobes, should prompt a diagnosis of sbvFTD., (© 2024. The Author(s).)

We present an in-depth clinical and neuroimaging analysis of a family carrying the MAPT K298E mutation associated with frontotemporal dementia (FTD). Initial identification of this mutation in a single clinical case led to a comprehensive investigation involving four affected siblings allowing to elucidate the mutation's phenotypic expression.A 60-year-old male presented with significant behavioral changes and progressed rapidly, exhibiting speech difficulties and cognitive decline. Neuroimaging via FDG-PET revealed asymmetrical frontotemporal hypometabolism. Three siblings subsequently showed varied but consistent clinical manifestations, including abnormal behavior, speech impairments, memory deficits, and motor symptoms correlating with asymmetric frontotemporal atrophy observed in MRI scans.Based on the genotype-phenotype correlation, we propose that the p.K298E mutation results in early-onset behavioral variant FTD, accompanied by a various constellation of speech and motor impairment.This detailed characterization expands the understanding of the p.K298E mutation's clinical and neuroimaging features, underlining its role in the pathogenesis of FTD. Further research is crucial to comprehensively delineate the clinical and epidemiological implications of the MAPT p.K298E mutation., (© 2024. The Author(s).)

Impaired social cognition is a core deficit in frontotemporal dementia (FTD). It is most commonly associated with the behavioural-variant of FTD, with atrophy of the orbitofrontal and ventromedial prefrontal cortex. Social cognitive changes are also common in semantic dementia, with atrophy centred on the anterior temporal lobes. The impairment of social behaviour in FTD has typically been attributed to damage to the orbitofrontal cortex and/or temporal poles and/or the uncinate fasciculus that connects them. However, the relative contributions of each region are unresolved. In this review, we present a unified neurocognitive model of controlled social behaviour that not only explains the observed impairment of social behaviours in FTD, but also assimilates both consistent and potentially contradictory findings from other patient groups, comparative neurology and normative cognitive neuroscience. We propose that impaired social behaviour results from damage to two cognitively- and anatomically-distinct components. The first component is social-semantic knowledge, a part of the general semantic-conceptual system supported by the anterior temporal lobes bilaterally. The second component is social control, supported by the orbitofrontal cortex, medial frontal cortex and ventrolateral frontal cortex, which interacts with social-semantic knowledge to guide and shape social behaviour., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background and Purpose: Thalamic alterations have been reported as a major feature in presymptomatic and symptomatic patients carrying the C9orf72 mutation across the frontotemporal dementia-amyotrophic lateral sclerosis (ALS) spectrum. Specifically, the pulvinar, a high-order thalamic nucleus and timekeeper for large-scale cortical networks, has been hypothesized to be involved in C9orf72-related neurodegenerative diseases. We investigated whether pulvinar volume can be useful for differential diagnosis in ALS C9orf72 mutation carriers and noncarriers and how underlying functional connectivity changes affect this region., Methods: We studied 19 ALS C9orf72 mutation carriers (ALSC9+) accurately matched with wild-type ALS (ALSC9-) and ALS mimic (ALSmimic) patients using structural and resting-state functional magnetic resonance imaging data. Pulvinar volume was computed using automatic segmentation. Seed-to-voxel functional connectivity analyses were performed using seeds from a pulvinar functional parcellation., Results: Pulvinar structural integrity had high discriminative values for ALSC9+ patients compared to ALSmimic (area under the curve [AUC] = 0.86) and ALSC9- (AUC = 0.77) patients, yielding a volume cutpoint of approximately 0.23%. Compared to ALSmimic, ALSC9- showed increased anterior, inferior, and lateral pulvinar connections with bilateral occipital-temporal-parietal regions, whereas ALSC9+ showed no differences. ALSC9+ patients when compared to ALSC9- patients showed reduced pulvinar-occipital connectivity for anterior and inferior pulvinar seeds., Conclusions: Pulvinar volume could be a differential biomarker closely related to the C9orf72 mutation. A pulvinar-cortical circuit dysfunction might play a critical role in disease progression and development, in both the genetic phenotype and ALS wild-type patients., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

We describe a male patient presenting with cerebellar ataxia and behavioural frontotemporal dementia in whom imaging showed cerebellar atrophy. He had significantly low N-acetyl aspartate to creatine (NAA/Cr) area ratio on MR spectroscopy of the cerebellum, primarily affecting the vermis. CT body scan showed extensive abnormal tissue within the mesentery, the retroperitoneum and perinephric areas. PET-CT showed increased tracer uptake within the wall of the aorta suggestive of an aortitis and within the perinephric tissue bilaterally. Biopsy of the perinephric tissue confirmed IgG4 disease. Treatment with steroids and mycophenolate improved his clinical state, but he developed symptoms attributed to pericardiac effusion that necessitated treatment initially with drainage and subsequently with pericardial window. After a course of rituximab, he had an episode of sepsis that did not respond to appropriate treatment and died as a result. Both the imaging findings and neurological presentation with cerebellar ataxia and behavioural frontotemporal dementia are novel in the context of IgG4 disease., (© 2023. The Author(s).)

Introduction/aims: VCP multisystem proteinopathy 1 (MSP1), encompassing inclusion body myopathy (IBM), Paget's disease of bone (PDB) and frontotemporal dementia (FTD) (IBMPFD), features progressive muscle weakness, fatty infiltration, and disorganized bone structure in Pagetic bones. The aim of this study is to utilize dual-energy x-ray absorptiometry (DXA) parameters to examine it as a biomarker of muscle and bone disease in MSP1., Methods: DXA scans were obtained in 28 patients to assess body composition parameters (bone mineral density [BMD], T-score, total fat, and lean mass) across different groups: total VCP disease (n = 19), including myopathy without Paget's ("myopathy"; n = 12) and myopathy with Paget's ("Paget"; n = 7), and unaffected first-degree relatives serving as controls (n = 6)., Results: In the VCP disease group, significant declines in left hip BMD and Z-scores were noted versus the control group (p ≤ .03). The VCP disease group showed decreased whole body lean mass % (p = .04), and increased total body fat % (p = .04) compared to controls. Subgroup comparisons indicated osteopenia in 33.3% and osteoporosis in 8.3% of the myopathy group, with 14.3% exhibiting osteopenia in the Paget group. Moreover, the Paget group displayed higher lumbar L1-L4 T-score values than the myopathy group., Discussion: In MSP1, DXA revealed reduced bone and lean mass, and increased fat mass. These DXA insights could aid in monitoring disease progression of muscle loss and secondary osteopenia/osteoporosis in MSP1, providing value both clinically and in clinical research., (© 2024 The Authors. Muscle & Nerve published by Wiley Periodicals LLC.)

Previous observational investigations suggest that structural and diffusion imaging-derived phenotypes (IDPs) are associated with major neurodegenerative diseases; however, whether these associations are causal remains largely uncertain. Herein we conducted bidirectional two-sample Mendelian randomization analyses to infer the causal relationships between structural and diffusion IDPs and major neurodegenerative diseases using common genetic variants-single nucleotide polymorphism (SNPs) as instrumental variables. Summary statistics of genome-wide association study (GWAS) for structural and diffusion IDPs were obtained from 33,224 individuals in the UK Biobank cohort. Summary statistics of GWAS for seven major neurodegenerative diseases were obtained from the largest GWAS for each disease to date. The forward MR analyses identified significant or suggestively statistical causal effects of genetically predicted three structural IDPs on Alzheimer's disease (AD), frontotemporal dementia (FTD), and multiple sclerosis. For example, the reduction in the surface area of the left superior temporal gyrus was associated with a higher risk of AD. The reverse MR analyses identified significantly or suggestively statistical causal effects of genetically predicted AD, Lewy body dementia (LBD), and FTD on nine structural and diffusion IDPs. For example, LBD was associated with increased mean diffusivity in the right superior longitudinal fasciculus and AD was associated with decreased gray matter volume in the right ventral striatum. Our findings might contribute to shedding light on the prediction and therapeutic intervention for the major neurodegenerative diseases at the neuroimaging level., (© 2024. The Author(s).)

Background: The use of amyloid-PET in dementia workup is upcoming. At the same time, amyloid-PET is costly and limitedly available. While the appropriate use criteria (AUC) aim for optimal use of amyloid-PET, their limited sensitivity hinders the translation to clinical practice. Therefore, there is a need for tools that guide selection of patients for whom amyloid-PET has the most clinical utility. We aimed to develop a computerized decision support approach to select patients for amyloid-PET., Methods: We included 286 subjects (135 controls, 108 Alzheimer's disease dementia, 33 frontotemporal lobe dementia, and 10 vascular dementia) from the Amsterdam Dementia Cohort, with available neuropsychology, APOE, MRI and [18F]florbetaben amyloid-PET. In our computerized decision support approach, using supervised machine learning based on the DSI classifier, we first classified the subjects using only neuropsychology, APOE, and quantified MRI. Then, for subjects with uncertain classification (probability of correct class (PCC) < 0.75) we enriched classification by adding (hypothetical) amyloid positive (AD-like) and negative (normal) PET visual read results and assessed whether the diagnosis became more certain in at least one scenario (PPC≥0.75). If this was the case, the actual visual read result was used in the final classification. We compared the proportion of PET scans and patients diagnosed with sufficient certainty in the computerized approach with three scenarios: 1) without amyloid-PET, 2) amyloid-PET according to the AUC, and 3) amyloid-PET for all patients., Results: The computerized approach advised PET in n = 60(21%) patients, leading to a diagnosis with sufficient certainty in n = 188(66%) patients. This approach was more efficient than the other three scenarios: 1) without amyloid-PET, diagnostic classification was obtained in n = 155(54%), 2) applying the AUC resulted in amyloid-PET in n = 113(40%) and diagnostic classification in n = 156(55%), and 3) performing amyloid-PET in all resulted in diagnostic classification in n = 154(54%)., Conclusion: Our computerized data-driven approach selected 21% of memory clinic patients for amyloid-PET, without compromising diagnostic performance. Our work contributes to a cost-effective implementation and could support clinicians in making a balanced decision in ordering additional amyloid PET during the dementia workup., Competing Interests: We have read the journal’s policy and the authors of this paper have the following competing interests: Hanneke F.M. Rhodius-Meester performs contract research for Combinostics; all funding is paid to her institution. Ingrid van Maurik received a consultancy fee (paid to the university) from Roche. Lyduine E. Collij has received consultancy fees from GE Healthcare; all funding is paid to her institution. Juha Koikkalainen and Jyrki Lötjönen report that Combinostics Oy owns the following IPR related to the paper: 1. J. Koikkalainen and J. Lotjonen, “A method for inferring the state of a system,” US7,840,510 B2, PCT/FI2007/050277. 2. J. Lotjonen, J. Koikkalainen and J. Mattila, “State Inference in a heterogeneous system,” PCT/FI2010/050545, FI20125177. Koikkalainen and Lötjönen are shareholders in Combinostics Oy. Yolande A.L. Pijnenburg has received funding from Dioraphte Foundation, Zabawas Foundation, JPND, ZonMW, NWO, Team Alzheimer and the Dutch Brain Foundation. Frederik Barkhof is member of the Steering committee or Data Safety Monitoring Board member for Biogen, Merck, ATRI/ACTC and Prothena. Barkhof is a consultant for Roche, Celltrion, Rewind Therapeutics, Merck, IXICO, Jansen, Combinostics. Barkhof has research agreements with Merck, Biogen, GE Healthcare, Roche. Co-founder and shareholder of Queen Square Analytics LTD. Elsmarieke van de Giessen has received research support from NWO, ZonMw, Hersenstichting and KWF. van de Giessen has performed contract research for Heuron Inc., Roche and 1st Biotherapeutics. van deGiessen has a consultancy agreement with IXICO for the reading of PET scans. Wiesje M van der Flier performs contract research for Biogen. Research programs of van der Flier have been funded by ZonMW, NWO, EU-FP7, EU-JPND, Alzheimer Nederland, CardioVascular Onderzoek Nederland, Health~Holland, Topsector Life Sciences & Health, stichting Dioraphte, Gieskes-Strijbis fonds, stichting Equilibrio, Pasman stichting, stichting Alzheimer & NeuroPsychiatry Foundation, Philips, Biogen MA Inc, Novartis-NL, Life-MI, AVID, Roche BV, Fujifilm, Combinostics. van der Flier has performed contract research for Biogen MA Inc, and Boehringer Ingelheim. van der Flier has been an invited speaker at Boehringer Ingelheim, Biogen MA Inc, Danone, Eisai, WebMD Neurology (Medscape), Springer Healthcare. van der Flier is consultant to Oxford Health Policy Forum CIC, Roche and Biogen MA Inc. van der Flier participated in advisory boards of Biogen MA Inc. and Roche. All funding is paid to her institution. van der Flier was associate editor of Alzheimer, Research & Therapy in 2020/2021. van der Flier is associate editor at Brain. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Rhodius-Meester et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The locus coeruleus (LC) and the nucleus basalis of Meynert (NBM) are altered in early stages of Alzheimer's disease (AD). Little is known about LC and NBM alteration in limbic-predominant age-related TDP-43 encephalopathy (LATE) and frontotemporal dementia (FTD). The aim of the present study is to investigate in vivo LC and NBM integrity in patients with suspected-LATE, early-amnestic AD and FTD in comparison with controls., Methods: Seventy-two participants (23 early amnestic-AD patients, 17 suspected-LATE, 17 FTD patients, defined by a clinical-biological diagnosis reinforced by amyloid and tau PET imaging, and 15 controls) underwent neuropsychological assessment and 3T brain MRI. We analyzed the locus coeruleus signal intensity (LC-I) and the NBM volume as well as their relation with cognition and with medial temporal/cortical atrophy., Results: We found significantly lower LC-I and NBM volume in amnestic-AD and suspected-LATE in comparison with controls. In FTD, we also observed lower NBM volume but a slightly less marked alteration of the LC-I, independently of the temporal or frontal phenotype. NBM volume was correlated with the global cognitive efficiency in AD patients. Strong correlations were found between NBM volume and that of medial temporal structures, particularly the amygdala in both AD and FTD patients., Conclusions: The alteration of LC and NBM in amnestic-AD, presumed-LATE and FTD suggests a common vulnerability of these structures to different proteinopathies. Targeting the noradrenergic and cholinergic systems could be effective therapeutic strategies in LATE and FTD., (© 2024. The Author(s).)

Background and Purpose: Frontotemporal dementia (FTD) is the second most common cause of presenile dementia. The clinical distinction between FTD, Alzheimer's disease (AD), and other dementias is a clinical challenge. Brain perfusion SPECT may contribute to the diagnosis of FTD, but its value is unclear., Methods: We performed a systematic review to investigate the diagnostic accuracy of the brain SPECT in (1) distinguishing FTD from AD and other dementias and (2) differentiating FTD variants., Results: Overall, 391 studies were retrieved on the initial search and 35 studies composed the final selection, comprising a total number of 3142 participants of which 1029 had FTD. The sensitivity and the specificity for the differential diagnosis of FTD versus AD ranged from 56% to 88% and from 51% to 93%, respectively. SPECT is not superior to the clinical method of diagnosis, but the combination of SPECT with clinical data seems to improve the diagnostic accuracy., Conclusion: Brain perfusion SPECT has a limited value in the diagnostic framework of FTD. SPECT can be performed when FDG-PET is not available. SPECT is recommended only for selected cases when the diagnosis is challenging using conventional methods., (© 2024 American Society of Neuroimaging.)

Amygdala atrophy has been found in frontotemporal dementia (FTD), yet the specific changes of its subregions across different FTD phenotypes remain unclear. The aim of this study was to investigate the volumetric alterations of the amygdala subregions in FTD phenotypes and how they evolve with disease progression. Patients clinically diagnosed with behavioral variant FTD (bvFTD) (n = 20), semantic dementia (SD) (n = 20), primary nonfluent aphasia (PNFA) (n = 20), Alzheimer's disease (AD) (n = 20), and 20 matched healthy controls underwent whole brain structural MRI. The patient groups were followed up annually for up to 3.5 years. Amygdala nuclei were segmented using FreeSurfer, corrected by total intracranial volumes, and grouped into the basolateral, superficial, and centromedial subregions. Linear mixed effects models were applied to identify changes in amygdala subregional volumes over time. At baseline, bvFTD, SD, and AD displayed global amygdala volume reduction, whereas amygdala volume appeared to be preserved in PNFA. Asymmetrical amygdala atrophy (left > right) was most pronounced in SD. Longitudinally, SD and PNFA showed greater rates of annual decline in the right basolateral and superficial subregions compared to bvFTD and AD. The findings provide comprehensive insights into the differential impact of FTD pathology on amygdala subregions, revealing distinct atrophy patterns that evolve over disease progression. The characterization of amygdala subregional involvement in FTD and their potential role as biomarkers carry substantial clinical implications., (© 2024. The Author(s).)

Introduction: Effective longitudinal biomarkers that track disease progression are needed to characterize the presymptomatic phase of genetic frontotemporal dementia (FTD). We investigate the utility of cerebral perfusion as one such biomarker in presymptomatic FTD mutation carriers., Methods: We investigated longitudinal profiles of cerebral perfusion using arterial spin labeling magnetic resonance imaging in 42 C9orf72, 70 GRN, and 31 MAPT presymptomatic carriers and 158 non-carrier controls. Linear mixed effects models assessed perfusion up to 5 years after baseline assessment., Results: Perfusion decline was evident in all three presymptomatic groups in global gray matter. Each group also featured its own regional pattern of hypoperfusion over time, with the left thalamus common to all groups. Frontal lobe regions featured lower perfusion in those who symptomatically converted versus asymptomatic carriers past their expected age of disease onset., Discussion: Cerebral perfusion is a potential biomarker for assessing genetic FTD and its genetic subgroups prior to symptom onset., Highlights: Gray matter perfusion declines in at-risk genetic frontotemporal dementia (FTD). Regional perfusion decline differs between at-risk genetic FTD subgroups . Hypoperfusion in the left thalamus is common across all presymptomatic groups. Converters exhibit greater right frontal hypoperfusion than non-converters past their expected conversion date. Cerebral hypoperfusion is a potential early biomarker of genetic FTD., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Objective: To evaluate automated digital speech measures, derived from spontaneous speech (picture descriptions), in assessing bulbar motor impairments in patients with ALS-FTD spectrum disorders (ALS-FTSD)., Methods: Automated vowel algorithms were employed to extract two vowel acoustic measures: vowel space area (VSA), and mean second formant slope (F2 slope). Vowel measures were compared between ALS with and without clinical bulbar symptoms (ALS + bulbar (n = 49, ALSFRS-r bulbar subscore: x¯ = 9.8 (SD = 1.7)) vs. ALS-nonbulbar (n = 23), behavioral variant frontotemporal dementia (bvFTD, n = 25) without a motor syndrome, and healthy controls (HC, n = 32). Correlations with bulbar motor clinical scales, perceived listener effort, and MRI cortical thickness of the orobuccal primary motor cortex (oral PMC) were examined. We compared vowel measures to speaking rate, a conventional metric for assessing bulbar dysfunction., Results: ALS + bulbar had significantly reduced VSA and F2 slope than ALS-nonbulbar (|d|=0.94 and |d|=1.04, respectively), bvFTD (|d|=0.89 and |d|=1.47), and HC (|d|=0.73 and |d|=0.99). These reductions correlated with worse bulbar clinical scores (VSA: R = 0.33, p  = 0.043; F2 slope: R = 0.38, p  = 0.011), greater listener effort (VSA: R=-0.43, p  = 0.041; F2 slope: p  > 0.05), and cortical thinning in oral PMC (F2 slope: β = 0.0026, p  = 0.017). Vowel measures demonstrated greater sensitivity and specificity for bulbar impairment than speaking rate, while showing independence from cognitive and respiratory impairments., Conclusion: Automatic vowel measures are easily derived from a brief spontaneous speech sample, are sensitive to mild-moderate stage of bulbar disease in ALS-FTSD, and may present better sensitivity to bulbar impairment compared to traditional assessments such as speaking rate.

Objectives: The aim of this review is to provide an overview on prevalence and clinical tools for the diagnosis of apathy, as well as on neurophysiological and neuroimaging findings obtained from studies in patients with apathy in different forms of dementia, including Alzheimer's disease (AD), vascular (VaD) and mixed dementia, frontotemporal dementia (FTD), and Parkinson's disease dementia (PDD)., Methods: Randomized controlled trials, non-randomized controlled trials, controlled before-after studies, and interrupted time series from four databases (WebOfScience, Scopus, Pubmed, and PsycINFO) addressing apathy in adults or older people aged over 65 years of age affected by dementia were included., Results: The prevalence of apathy was 26-82% for AD, 28.6-91.7 for VaD, 29-97.5% in PDD, and 54.8-88.0 in FTD. The assessment of apathy was not consistent in the reviewed studies. Methylphenidate was the most successful pharmacological treatment for apathy. Neurobiological studies highlighted the relationship between both structural and functional brain areas and the presence or severity of apathy., Conclusion: Apathy is a very common disorder in all types of dementia, although it is often underdiagnosed and undertreated. Further studies are needed to investigate its diagnosis and management. A consensus on the different evaluation scales should be achieved., (© 2023. The Author(s).)

Purpose: Individuals with behavioral-variant frontotemporal dementia (bvFTD) show changes in brain structure as assessed by MRI and brain function assessed by 18FDG-PET hypometabolism. However, current understanding of the spatial and temporal interplay between these measures remains limited., Methods: Here, we examined longitudinal atrophy and hypometabolism relationships in 15 bvFTD subjects with 2 to 4 follow-up MRI and PET scans (56 visits total). Subject-specific slopes of atrophy and hypometabolism over time were extracted across brain regions and correlated with baseline measures both locally, via Pearson correlations, and nonlocally, via sparse canonical correlation analyses (SCCA)., Results: Notably, we identified a robust link between initial hypometabolism and subsequent cortical atrophy rate changes in bvFTD subjects. Network-level exploration unveiled alignment between baseline hypometabolism and ensuing atrophy rates in the dorsal attention, language, and default mode networks. SCCA identified 2 significant and highly localized components depicting the connection between baseline hypometabolism and atrophy slope over time. The first centered around bilateral orbitofrontal, frontopolar, and medial prefrontal lobes, whereas the second concentrated in the left temporal lobe and precuneus., Conclusions: This study highlights 18FDG-PET as a dependable predictor of forthcoming atrophy in spatially adjacent brain regions for individuals with bvFTD., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Multisystem Proteinopathy 1 (MSP1) disease is a rare genetic disorder caused by mutations in the Valosin-Containing Protein (VCP) gene with clinical features of inclusion body myopathy (IBM), frontotemporal dementia (FTD), and Paget's disease of bone (PDB). We performed bone scan imaging in twelve patients (6 females, 6 males) with confirmed VCP gene mutation six (50%) of which has myopathy alone, four (33%) with both PDB and myopathy, and two (15%) were presymptomatic carriers. We aim to characterize the PDB in diagnosed individuals, and potentially identify PDB in the myopathy and presymptomatic groups. Interestingly, two patients with previously undiagnosed PDB had positive diagnostic findings on the bone scan and subsequent radiograph imaging. Among the individuals with PDB, increased radiotracer uptake of the affected bones were of typical distribution as seen in conventional PDB and those reported in other MSP1 cohorts which are the thoracic spine and ribs (75%), pelvis (75%), shoulder (75%) and calvarium (15%). Overall, we show that technetium-99m bone scans done at regular intervals are a sensitive screening tool in patients with MSP1 associated VCP variants at risk for PDB. However, diagnostic confirmation should be coupled with clinical history, biochemical analysis, and skeletal radiographs to facilitate early treatment and prevention complications, acknowledging its limited specificity., (© 2024. The Author(s).)

With the arrival of disease-modifying drugs, neurodegenerative diseases will require an accurate diagnosis for optimal treatment. Convolutional neural networks are powerful deep learning techniques that can provide great help to physicians in image analysis. The purpose of this study is to introduce and validate a 3D neural network for classification of Alzheimer's disease (AD), frontotemporal dementia (FTD) or cognitively normal (CN) subjects based on brain glucose metabolism. Retrospective [18F]-FDG-PET scans of 199 CE, 192 FTD and 200 CN subjects were collected from our local database, Alzheimer's disease and frontotemporal lobar degeneration neuroimaging initiatives. Training and test sets were created using randomization on a 90 %-10 % basis, and training of a 3D VGG16-like neural network was performed using data augmentation and cross-validation. Performance was compared to clinical interpretation by three specialists in the independent test set. Regions determining classification were identified in an occlusion experiment and Gradient-weighted Class Activation Mapping. Test set subjects were age- and sex-matched across categories. The model achieved an overall 89.8 % accuracy in predicting the class of test scans. Areas under the ROC curves were 93.3 % for AD, 95.3 % for FTD, and 99.9 % for CN. The physicians' consensus showed a 69.5 % accuracy, and there was substantial agreement between them (kappa = 0.61, 95 % CI: 0.49-0.73). To our knowledge, this is the first study to introduce a deep learning model able to discriminate AD and FTD based on [18F]-FDG PET scans, and to isolate CN subjects with excellent accuracy. These initial results are promising and hint at the potential for generalization to data from other centers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Objective: Alzheimer's disease (AD) and frontotemporal dementia (FTD) show different patterns of cortical thickness (CTh) loss compared with healthy controls (HC), even though there is relevant heterogeneity between individuals suffering from each of these diseases. Thus, we developed CTh models to study individual variability in AD, FTD, and HC., Methods: We used the baseline CTh measures of 379 participants obtained from the structural MRI processed with FreeSurfer. A total of 169 AD patients (63 ± 9 years, 65 men), 88 FTD patients (64 ± 9 years, 43 men), and 122 HC (62 ± 10 years, 47 men) were studied. We fitted region-wise temporal models of CTh using Support Vector Regression. Then, we studied associations of individual deviations from the model with cerebrospinal fluid levels of neurofilament light chain (NfL) and 14-3-3 protein and Mini-Mental State Examination (MMSE). Furthermore, we used real longitudinal data from 144 participants to test model predictivity., Results: We defined CTh spatiotemporal models for each group with a reliable fit. Individual deviation correlated with MMSE for AD and with NfL for FTD. AD patients with higher deviations from the trend presented higher MMSE values. In FTD, lower NfL levels were associated with higher deviations from the CTh prediction. For AD and HC, we could predict longitudinal visits with the presented model trained with baseline data. For FTD, the longitudinal visits had more variability., Conclusion: We highlight the value of CTh models for studying AD and FTD longitudinal changes and variability and their relationships with cognitive features and biomarkers., (© 2023. The Author(s).)

Introduction: Sleep and rest-activity rhythm alterations are common in neurodegenerative diseases. However, their characterization in patients with behavioral variant frontotemporal dementia (bvFTD) has proven elusive. We investigated rest-activity rhythm alterations, sleep disturbances, and their neural correlates in bvFTD., Methods: Twenty-seven bvFTD patients and 25 healthy controls completed sleep questionnaires and underwent 7 days of actigraphy while concurrently maintaining a sleep diary. Cortical complexity and thickness were calculated from T1-weighted magnetic resonance (MR) images., Results: Compared to controls, bvFTD patients showed longer time in bed (95% confidence interval [CI]: 79.31, 321.83) and total sleep time (95% CI: 24.38, 321.88), lower sleep efficiency (95% CI: -12.58, -95.54), and rest-activity rhythm alterations in the morning and early afternoon. Increased sleep duration was associated with reduced cortical thickness in frontal regions., Discussion: Patients with bvFTD showed longer sleep duration, lower sleep quality, and rest-activity rhythm alterations. Actigraphy could serve as a cost-effective and accessible tool for ecologically monitoring changes in sleep duration in bvFTD patients., Highlights: We assessed sleep and circadian rhythms in behavioral variant frontotemporal dementia (bvFTD) using actigraphy. Patients with bvFTD show increased sleep duration and reduced sleep quality. Patients with bvFTD show rest-activity alterations in the morning and early afternoon. Sleep duration is associated with reduced cortical thickness in frontal regions. These alterations may represent an early sign of neurodegeneration., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

We report a patient with behavioral variant frontotemporal dementia who developed agraphia, irritability, perseverative and stereotyped behavior, and dietary changes. MRI revealed bilateral frontal convexity atrophy. Neuropsychological examination showed fluent aphasia with perseverative allographic agraphia, mild semantic impairment, and dysexecutive syndrome. Allographic agraphia featured unidirectional conversion from hiragana (cursive form of Japanese phonograms) and kanji (Japanese morphograms) to katakana (square form of Japanese phonograms), as opposed to mutual (bidirectional) conversion between hiragana and katakana in parieto-occipital gyri lesions. Furthermore, all letters of the word were converted and this whole-word conversion may be characteristic of perseverative behavior in frontotemporal dementia.

Abstract: Frontotemporal dementia is a clinical syndrome that is characterized by a progressive deterioration in behavior, personality, and/or language, with relative preservation of memory, and its phenotype and molecular basis are heterogeneous. We present a case of a 62-year-old female patient who underwent 18 F-FDG PET/CT and 18 F-FP-CIT PET/CT for differential diagnosis of psychiatric disease and types of dementia. 18 F-FDG PET/CT image showed a compatible finding for frontotemporal dementia, and 18 F-FP-CIT PET/CT image showed dominantly decreased dopamine transporter activity in the bilateral caudate nucleus., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Diminished basal parasympathetic nervous system activity is a feature of frontotemporal dementia that relates to left frontoinsula dysfunction and empathy impairment. Individuals with a pathogenic expansion of the hexanucleotide repeat in chromosome 9 open reading frame 72 (C9orf72), the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis, provide a unique opportunity to examine whether parasympathetic activity is disrupted in genetic forms of frontotemporal dementia and to investigate when parasympathetic deficits manifest in the pathophysiological cascade. We measured baseline respiratory sinus arrhythmia, a parasympathetic measure of heart rate variability, over two minutes in a sample of 102 participants that included 19 asymptomatic expansion carriers (C9 + asymp), 14 expansion carriers with mild cognitive impairment (C9 + MCI), 16 symptomatic expansion carriers with frontotemporal dementia (C9 + FTD), and 53 expansion-negative healthy controls (C9 - HC) who also underwent structural magnetic resonance imaging. In follow-up analyses, we compared baseline respiratory sinus arrhythmia in the C9 + FTD group with an independent age-, sex-, and clinical severity-matched group of 26 people with sporadic behavioral variant frontotemporal dementia. The Frontotemporal Lobar Degeneration-modified Clinical Dementia Rating-Sum of Boxes score was used to quantify behavioral symptom severity, and informant ratings on the Interpersonal Reactivity Index provided measures of participants' current emotional (empathic concern) and cognitive (perspective-taking) empathy. Results indicated that the C9 + FTD group had lower baseline respiratory sinus arrhythmia than the C9 + MCI, C9 + asymp, and C9 - HC groups, a deficit that was comparable to that of sporadic behavioral variant frontotemporal dementia. Linear regression analyses indicated that lower baseline respiratory sinus arrhythmia was associated with worse behavioral symptom severity and lower empathic concern and perspective-taking across the C9orf72 expansion carrier clinical spectrum. Whole-brain voxel-based morphometry analyses in participants with C9orf72 pathogenic expansions found that lower baseline respiratory sinus arrhythmia correlated with smaller gray matter volume in the left frontoinsula and bilateral thalamus, key structures that support parasympathetic function, and in the bilateral parietal lobes, occipital lobes, and cerebellum, regions that are also vulnerable in individuals with C9orf72 expansions. This study provides novel evidence that basal parasympathetic functioning is diminished in FTD due to C9orf72 expansions and suggests that baseline respiratory sinus arrhythmia may be a potential non-invasive biomarker that is sensitive to behavioral symptoms in the early stages of disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Genetic mutations causative of frontotemporal lobar degeneration (FTLD) are highly predictive of a specific proteinopathy, but there exists substantial inter-individual variability in their patterns of network degeneration and clinical manifestations. We collected clinical and 18 Fluorodeoxyglucose-positron emission tomography (FDG-PET) data from 39 patients with genetic FTLD, including 11 carrying the C9orf72 hexanucleotide expansion, 16 carrying a MAPT mutation and 12 carrying a GRN mutation. We performed a spectral covariance decomposition analysis between FDG-PET images to yield unbiased latent patterns reflective of whole brain patterns of metabolism ("eigenbrains" or EBs). We then conducted linear discriminant analyses (LDAs) to perform EB-based predictions of genetic mutation and predominant clinical phenotype (i.e., behavior/personality, language, asymptomatic). Five EBs were significant and explained 58.52 % of the covariance between FDG-PET images. EBs indicative of hypometabolism in left frontotemporal and temporo-parietal areas distinguished GRN mutation carriers from other genetic mutations and were associated with predominant language phenotypes. EBs indicative of hypometabolism in prefrontal and temporopolar areas with a right hemispheric predominance were mostly associated with predominant behavioral phenotypes and distinguished MAPT mutation carriers from other genetic mutations. The LDAs yielded accuracies of 79.5 % and 76.9 % in predicting genetic status and predominant clinical phenotype, respectively. A small number of EBs explained a high proportion of covariance in patterns of network degeneration across FTLD-related genetic mutations. These EBs contained biological information relevant to the variability in the pathophysiological and clinical aspects of genetic FTLD, and for offering valuable guidance in complex clinical decision-making, such as decisions related to genetic testing., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Behavioral variant frontotemporal dementia (bvFTD) typically involves subtle changes in personality that can delay a timely diagnosis., Objective: Here, we report the case of a patient diagnosed of GRN-positive bvFTD at the age of 52 presenting with a 7-year history of narcissistic personality disorder, accordingly to DSM-5 criteria., Methods: The patient was referred to neurological and neuropsychological examination. She underwent 3 Tesla magnetic resonance imaging (MRI) and genetic studies., Results: The neuropsychological examination revealed profound deficits in all cognitive domains and 3T brain MRI showed marked fronto-temporal atrophy. A mutation in the GRN gene further confirmed the diagnosis., Conclusions: The present case documents an unusual onset of bvFTD and highlights the problematic nature of the differential diagnosis between prodromal psychiatric features of the disease and primary psychiatric disorders. Early recognition and diagnosis of bvFTD can lead to appropriate management and support for patients and their families. This case highlights the importance of considering neurodegenerative diseases, such as bvFTD, in the differential diagnosis of psychiatric disorders, especially when exacerbations of behavioral traits manifest in adults.

Background: TDP-43 proteinopathies represent a spectrum of neurological disorders, anchored clinically on either end by amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). The ALS-FTD spectrum exhibits a diverse range of clinical presentations with overlapping phenotypes, highlighting its heterogeneity. This study was aimed to use disease progression modeling to identify novel data-driven spatial and temporal subtypes of brain atrophy and its progression in the ALS-FTD spectrum., Methods: We used a data-driven procedure to identify 13 anatomic clusters of brain volume for 57 behavioral variant FTD (bvFTD; with either autopsy-confirmed TDP-43 or TDP-43 proteinopathy-associated genetic variants), 103 ALS, and 47 ALS-FTD patients with likely TDP-43. A Subtype and Stage Inference (SuStaIn) model was trained to identify subtypes of individuals along the ALS-FTD spectrum with distinct brain atrophy patterns, and we related subtypes and stages to clinical, genetic, and neuropathological features of disease., Results: SuStaIn identified three novel subtypes: two disease subtypes with predominant brain atrophy in either prefrontal/somatomotor regions or limbic-related regions, and a normal-appearing group without obvious brain atrophy. The limbic-predominant subtype tended to present with more impaired cognition, higher frequencies of pathogenic variants in TBK1 and TARDBP genes, and a higher proportion of TDP-43 types B, E and C. In contrast, the prefrontal/somatomotor-predominant subtype had higher frequencies of pathogenic variants in C9orf72 and GRN genes and higher proportion of TDP-43 type A. The normal-appearing brain group showed higher frequency of ALS relative to ALS-FTD and bvFTD patients, higher cognitive capacity, higher proportion of lower motor neuron onset, milder motor symptoms, and lower frequencies of genetic pathogenic variants. The overall SuStaIn stages also correlated with evidence for clinical progression including longer disease duration, higher King's stage, and cognitive decline. Additionally, SuStaIn stages differed across clinical phenotypes, genotypes and types of TDP-43 pathology., Conclusions: Our findings suggest distinct neurodegenerative subtypes of disease along the ALS-FTD spectrum that can be identified in vivo, each with distinct brain atrophy, clinical, genetic and pathological patterns., (© 2023. The Author(s).)

Background: Language deficits are cardinal manifestations of some frontotemporal dementia (FTD) phenotypes and also increasingly recognized in sporadic and familial amyotrophic lateral sclerosis (ALS). They have considerable social and quality-of-life implications, and adaptive strategies are challenging to implement. While the neuropsychological profiles of ALS-FTD phenotypes are well characterized, the neuronal underpinnings of language deficits are less well studied., Methods: A multiparametric, quantitative neuroimaging study was conducted to characterize the involvement of language-associated networks, tracts, and cortical regions with a panel of structural, diffusivity, and functional magnetic resonance imaging (MRI) metrics. Seven study groups were evaluated along the ALS-FTD spectrum: healthy controls (HC), individuals with ALS without cognitive impairment (ALSnci), C9orf72-negative ALS-FTD, C9orf72-positive ALS-FTD, behavioral-variant FTD (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), and semantic variant PPA (svPPA). The integrity of the Broca's area, Wernicke's area, frontal aslant tract (FAT), arcuate fascicle (AF), inferior occipitofrontal fascicle (IFO), inferior longitudinal fascicle (ILF), superior longitudinal fascicle (SLF), and uncinate fascicle (UF) was quantitatively evaluated. The functional connectivity (FC) between Broca's and Wernicke' areas and FC along the FAT was also specifically assessed., Results: Patients with nfvPPA and svPPA exhibit distinctive patterns of gray and white matter degeneration in language-associated brain regions. Individuals with bvFTD exhibit Broca's area, right FAT, right IFO, and UF degeneration. The ALSnci group exhibits Broca's area atrophy and decreased FC along the FAT. Both ALS-FTD cohorts, irrespective of C9orf72 status, show bilateral FAT, AF, and IFO pathology. Interestingly, only C9orf72-negative ALS-FTD patients exhibit bilateral uncinate and right ILF involvement, while C9orf72-positive ALS-FTD patients do not., Conclusions: Language-associated tracts and networks are not only affected in language-variant FTD phenotypes but also in ALS and bvFTD. Language domains should be routinely assessed in ALS irrespective of the genotype., (© 2023 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Behavioral variant frontotemporal dementia is characterized by heterogeneous frontal, insular, and anterior temporal atrophy patterns that vary along left-right and dorso-ventral axes. Little is known about how these structural imbalances impact clinical symptomatology. The goal of this study was to assess the frequency of frontotemporal asymmetry (right- or left-lateralization) and dorsality (ventral or dorsal predominance of atrophy) and to investigate their clinical correlates. Neuropsychiatric symptoms and structural images were analyzed for 250 patients with behavioral variant frontotemporal dementia. Frontotemporal atrophy was most often symmetric while left-lateralized (9%) and right-lateralized (17%) atrophy were present in a minority of patients. Atrophy was more often ventral (32%) than dorsal (3%) predominant. Patients with right-lateralized atrophy were characterized by higher severity of abnormal eating behavior and hallucinations compared to those with left-lateralized atrophy. Subsequent analyses clarified that eating behavior was associated with right atrophy to a greater extent than a lack of left atrophy, and hallucinations were driven mainly by right atrophy. Dorsality analyses showed that anxiety, euphoria, and disinhibition correlated with ventral-predominant atrophy. Agitation, irritability, and depression showed greater severity with a lack of regional atrophy, including in dorsal regions. Aberrant motor behavior and apathy were not explained by asymmetry or dorsality. This study provides additional insight into how anatomical heterogeneity influences the clinical presentation of patients with behavioral variant frontotemporal dementia. Behavioral symptoms can be associated not only with the presence or absence of focal atrophy, but also with right/left or dorsal/ventral imbalance of gray matter volume., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)