Frontotemporal lobar degeneration (FTLD) is defined neuropathologically by misfolded tau (FTLD-tau) or TAR DNA-binding protein of 43 kDa (FTLD-TDP). However, we lack biomarkers that can distinguish them in vivo which is a major barrier to effective disease-modifying treatment trials. Based on neuropathological evidence of distinct patterns of cellular degeneration, more prominent in white matter (WM) for FTLD-tau relative to FTLD-TDP, we hypothesized that diffusion MRI (dMRI) measures of white matter microstructure would help dissociate FTLD-tau and FTLD-TDP during life. We evaluated dMRI for 157 individuals with FTLD-Tau (n=66, autopsy-confirmed sporadic=51, MAPT=15) and FTLD-TDP (n=91, autopsy-confirmed sporadic=25, GRN=19, C9orf72=47) defined by a pathogenic genetic mutation or autopsy confirmation. Images were preprocessed using QSIprep and reconstructed using Generalized Q-sampling Imaging. Tensor-based scalar maps of fractional anisotropy (FA) and mean diffusivity (MD) were then calculated. Deterministic tractography was run and white matter bundles of pathogenic interest based on literature were segmented with DSIstudio using template-based tracking. Overall, FTLD-Tau individuals showed worse white matter integrity compared to those with FTLD-TDP with lower FA in the superior longitudinal fasciculus (SLF), uncinate fasciculus and fronto-parietal cingulum; and higher MD in the uncinate fasciculus. Even within sporadic autopsy-confirmed individuals, FTLD-Tau subtypes had significantly lower FA in the SLF, fronto-parietal cingulum, and left corticostriatal tract relative to FTLD-TDP. Our results demonstrate that white matter microstructure can distinguish between FTLD-Tau and FTLD-TDP pathologies in a tract-specific manner with greater evidence of white matter degeneration in disease-associated regions in FTLD-Tau. Future work examining longitudinal associations with disease progression and white matter microstructure could aid in non-invasive differentiation of these subtypes enabling more sensitive treatment monitoring.

BACKGROUND:The organization of the brain into distinct networks increases (i.e., differentiation) during development and decreases (i.e., de-differentiation) during healthy aging, changes that are associated with improvements and worsening of cognition, respectively. Given that behavioral variant frontotemporal degeneration (bvFTD) is a neurodegenerative disease associated with executive dysfunction and selective vulnerability of the salience network, we tested the hypotheses that bvFTD structural networks are de-differentiated compared to cognitively normal controls (CNC) and that network de-differentiation relates to worse executive function. METHODS:In a sample of 90 patients with bvFTD and 71 age-matched CNC with diffusion MRI data we generated probabilistic tractography maps and calculated system segregation, a metric that compares within-network to between-network connectivity, to reflect the extent to which brain networks were differentiated. Patients with bvFTD also completed tests of executive function (digit span backwards, phonemic fluency, category fluency) and a control task (lexical retrieval). We assessed group differences in system segregation, reflecting network differentiation, and, within bvFTD, associations between system segregation and neuropsychological test performance. RESULTS:Compared to CNC, patients with bvFTD exhibited lower system segregation of the salience (p < 0.001) and global brain network (p = 0.008). In bvFTD, lower salience network system segregation was associated with worse executive function (pcorrected = 0.021) but not lexical retrieval. CONCLUSIONS:Results demonstrate associations between executive dysfunction and salience network de-differentiation in patients with bvFTD. Our findings indicate that brain network de-differentiation, reflecting reduced neural capacity for specialized processing, may contribute to the emergence of executive dysfunction in bvFTD.

Background: Lewy body disorders (LBD), encompassing Parkinson disease (PD), PD dementia (PDD), and dementia with Lewy bodies (DLB), are characterized by alpha-synuclein pathology but often are accompanied by Alzheimer's disease (AD) neuropathological change (ADNC). The medial temporal lobe (MTL) is a primary locus of tau accumulation and associated neurodegeneration in AD. However, it is unclear the extent to which AD copathology in LBD (LBD/AD+) contributes to MTL-specific patterns of degeneration. We employ a MTL subregional segmentation strategy of T1-weighted (T1w) MRI in biomarker-supported or autopsy-confirmed LBD and LBD/AD+ to investigate the anatomic consequences of co-occurring LBD/AD+ pathology on neurodegeneration. Methods: We studied 167 individuals with clinical diagnoses of LBD (PD, n = 124 (74.3 %); PDD, n = 11 (6.6 %); DLB, n = 32 (19.2 %)) with available T1w MRI and AD biomarkers or autopsy evidence of ADNC. Individuals were further biologically classified as LBD/AD+ based on hierarchical evidence of ADNC pathology: 1) AD "intermediate" or "high" by ABC neuropathologic criteria (n = 39 (23.4 %)); 2) positive amyloid PET (n = 2 (1.2 %)); or 3) CSF beta-amyloid(1-42) < 185.7 pg/mL n = 126 (75.4 %)). The T1 Automated Segmentation of Hippocampal Subfields (ASHS) pipeline was used to compute volume and thickness measurements of MTL subregions in LBD/AD- and LBD/AD+. Linear regression tested the association of AD copathology and subregion volume/thickness, covarying for age and sex, and intracranial volume for volume measurements. Secondary analyses correlated MTL subregional volume/thickness with cognition and neuropathology. Results: LBD/AD+ had decreased volume/thickness compared to LBD/AD- in all MTL subregions except posterior hippocampus. The greatest effect sizes were seen in Brodmann Area 35 (BA35) (Cohen's d = 0.62, p = 0.002, beta = 0.107 +/- 0.034), and entorhinal cortex (ERC) (Cohen's d = 0.56, p = 0.006, beta = 0.088 +/- 0.031). Smaller differences were seen in the parahippocampal cortex (PHC) (Cohen's d = 0.5, p = 0.012, beta = 0.082 +/- 0.033), BA36 (Cohen's d = 0.47, p = 0.021, beta = 0.090 +/- 0.039) and anterior hippocampus (Cohen's d = 0.45, p = 0.029, beta = 111.790 +/- 50.595). Verbal memory scores positively correlated with volume/thickness in anterior and posterior hippocampus, BA35, ERC and PHC, while visuospatial memory positively correlated only in BA35. In the subset of participants with autopsy, lower ERC volume was associated with a higher tau load in ERC (adjusted odds ratio 0.013, 95 % CI [0.0002, 0.841], uncorrected p = 0.041). Conclusions: Relative to LBD/AD-, LBD/AD+ has greater T1w MRI evidence of atrophy in multiple MTL subregions. Atrophy in MTL subregions associates with memory performance and tau pathological load. The observed pattern of atrophy largely follows expectation from AD Braak stages, except for posterior hippocampus. Longitudinal studies are needed to validate the hypothesized spread of neurodegeneration.

Inter-modality image registration is a challenging problem in medical image analysis, primarily due to absence of robust energy minimization objective functions that can handle variations across modalities. In this work, we introduce a novel framework that reformulates the inter-modality registration task as an intra-modality problem via image synthesis. Specifically, we jointly optimize a 3D diffusion-based deep generative model for image translation and a classical, greedy non-parametric diffeomorphic deformable image registration algorithm based on the log domain demons algorithm. Our approach does not require perfectly aligned training pairs: the registration component helps preserve the geometrical structure of the source modality during translation, while the synthesis model generates realistic target modality images that facilitate improved alignment. Unlike existing deep learning-based methods that rely on complex multi-term loss functions or adversarial training, our framework simplifies optimization by requiring only one loss function for each task (translation and registration) making it more stable and interpretable. We evaluate our method on a novel inter-modality dataset consisting of high-resolution postmortem (exvivo) T2w MRI scans (7T, 0.3 mm ^3 ) and corresponding antemortem (invivo) T1w MRI scans (1.5T/3T/7T, 0.7–1.0 mm ^3 ) from individuals with Alzheimer’s disease and related dementias (ADRD), where substantial atrophy is present between scan acquisitions. We demonstrate that our method achieves superior registration accuracy in the presence of large anatomical and contrast discrepancies. We open-source our codebase at the .

Amnestic mild cognitive impairment and Alzheimer’s disease (aAD) exhibit degeneration of white matter (WM) tracts preceding overt cognitive decline. However, WM changes in non-amnestic AD (naAD) are understudied. We hypothesized patterns of WM degeneration would differ between aAD and naAD. We compared WM degeneration, assessed by 30-direction diffusion-weighted imaging (DWI), in 41 individuals with aAD; 67 with naAD diagnoses including logopenic-variant primary progressive aphasia (lvPPA), posterior cortical atrophy (PCA), behavioral variant AD (bvAD), and corticobasal syndrome (CBS); and 45 with normal cognition (Table 1). We performed deterministic tractography between 148 cortical/subcortical regions; connectivity was quantified by generalized fractional anisotropy (GFA). Tractwise GFA and regional grey matter (GM) volumes were converted to W-scores adjusting for age and sex. We contrasted GFA between groups using regression models covarying for MMSE score. A mixed effects model was used to assess associations between tractwise GFA and volume of GM endpoints. Additionally, we computed the number of connected components in each person’s brain graph (i.e., number of subgraphs created by progressively stricter thresholds) across 100 GFA values. We contrasted this topological metric between groups and assessed its associations with MMSE and disease duration. GM volume was lower in naAD and aAD than controls (both p<0.0001) but did not differ between patient groups (p=0.81). aAD and naAD patients had shared WM degeneration in corpus callosum, cingulum, and inferior/superior longitudinal fasciculi; however, WM degeneration was more severe in naAD (Figure 1). In lvPPA, WM degeneration was left-lateralized; in PCA, GFA was reduced in bilateral parietal, occipital, and temporal areas (Figure 2). Across groups, GM and WM degeneration were significantly associated [F(1,20442)=326.0, p<0.0001]. Topological analysis indicated naAD but not aAD patients had lower global connectivity than controls. A higher component number (indicating reduced connectivity) was associated with longer disease duration and lower MMSE. Associations between GM volume and GFA suggest WM degeneration in naAD is related to AD pathologic change and not an independent process. Greater WM disease in naAD than aAD was not attributable to GM atrophy or symptom severity. Finally, topological metrics may serve as objective markers of global disease progression.

IntroductionFrontotemporal lobar degeneration (FTLD) is associated with FTLD due to tau (FTLD-tau) or TDP (FTLD-TDP) inclusions found at autopsy. Arterial Spin Labeling (ASL) MRI is often acquired in the same session as a structural T1-weighted image (T1w), enabling detection of regional changes in cerebral blood flow (CBF). We hypothesize that ASL-T1w registration with more degrees of freedom using boundary-based registration (BBR) will better align ASL and T1w images and show increased sensitivity to regional hypoperfusion differences compared to manual registration in patient participants. We hypothesize that hypoperfusion will be associated with a clinical measure of disease severity, the FTLD-modified clinical dementia rating scale sum-of-boxes (FTLD-CDR).Materials and methodsPatients with sporadic likely FTLD-tau (sFTLD-tau; N = 21), with sporadic likely FTLD-TDP (sFTLD-TDP; N = 14), and controls (N = 50) were recruited from the Connectomic Imaging in Familial and Sporadic Frontotemporal Degeneration project (FTDHCP). Pearson’s Correlation Coefficients (CC) were calculated on cortical vertex-wise CBF between each participant for each of 3 registration methods: (1) manual registration, (2) BBR initialized with manual registration (manual+BBR), (3) and BBR initialized using FLIRT (FLIRT+BBR). Mean CBF was calculated in the same regions of interest (ROIs) for each registration method after image alignment. Paired t-tests of CC values for each registration method were performed to compare alignment. Mean CBF in each ROI was compared between groups using t-tests. Differences were considered significant at p < 0.05 (Bonferroni-corrected). We performed linear regression to relate FTLD-CDR to mean CBF in patients with sFTLD-tau and sFTLD-TDP, separately (p < 0.05, uncorrected).ResultsAll registration methods demonstrated significant hypoperfusion in frontal and temporal regions in each patient group relative to controls. All registration methods detected hypoperfusion in the left insular cortex, middle temporal gyrus, and temporal pole in sFTLD-TDP relative to sFTLD-tau. FTLD-CDR had an inverse association with CBF in right temporal and orbitofrontal ROIs in sFTLD-TDP. Manual+BBR performed similarly to FLIRT+BBR.DiscussionASL is sensitive to distinct regions of hypoperfusion in patient participants relative to controls, and in patients with sFTLD-TDP relative to sFTLD-tau, and decreasing perfusion is associated with increasing disease severity, at least in sFTLD-TDP. BBR can register ASL-T1w images adequately for controls and patients.

INTRODUCTION:Screening for Alzheimer's disease neuropathologic change (ADNC) in individuals with atypical presentations is challenging but essential for clinical management. We trained automatic speech-based classifiers to distinguish frontotemporal dementia (FTD) patients with ADNC from those with frontotemporal lobar degeneration (FTLD). METHODS:We trained automatic classifiers with 99 speech features from 1 minute speech samples of 179 participants (ADNC = 36, FTLD = 60, healthy controls [HC] = 89). Patients' pathology was assigned based on autopsy or cerebrospinal fluid analytes. Structural network-based magnetic resonance imaging analyses identified anatomical correlates of distinct speech features. RESULTS:Our classifier showed 0.88 ± $ \pm $ 0.03 area under the curve (AUC) for ADNC versus FTLD and 0.93 ± $ \pm $ 0.04 AUC for patients versus HC. Noun frequency and pause rate correlated with gray matter volume loss in the limbic and salience networks, respectively. DISCUSSION:Brief naturalistic speech samples can be used for screening FTD patients for underlying ADNC in vivo. This work supports the future development of digital assessment tools for FTD. HIGHLIGHTS:We trained machine learning classifiers for frontotemporal dementia patients using natural speech. We grouped participants by neuropathological diagnosis (autopsy) or cerebrospinal fluid biomarkers. Classifiers well distinguished underlying pathology (Alzheimer's disease vs. frontotemporal lobar degeneration) in patients. We identified important features through an explainable artificial intelligence approach. This work lays the groundwork for a speech-based neuropathology screening tool.

IntroductionMultimodal evidence indicates Alzheimer’s disease (AD) is characterized by early white matter (WM) changes that precede overt cognitive impairment. WM changes have overwhelmingly been investigated in typical, amnestic mild cognitive impairment and AD; fewer studies have addressed WM change in atypical, non-amnestic syndromes. We hypothesized each non-amnestic AD syndrome would exhibit WM differences from amnestic and other non-amnestic syndromes.Materials and methodsParticipants included 45 cognitively normal (CN) individuals; 41 amnestic AD patients; and 67 patients with non-amnestic AD syndromes including logopenic-variant primary progressive aphasia (lvPPA, n = 32), posterior cortical atrophy (PCA, n = 17), behavioral variant AD (bvAD, n = 10), and corticobasal syndrome (CBS, n = 8). All had T1-weighted MRI and 30-direction diffusion-weighted imaging (DWI). We performed whole-brain deterministic tractography between 148 cortical and subcortical regions; connection strength was quantified by tractwise mean generalized fractional anisotropy. Regression models assessed effects of group and phenotype as well as associations with grey matter volume. Topological analyses assessed differences in persistent homology (numbers of graph components and cycles). Additionally, we tested associations of topological metrics with global cognition, disease duration, and DWI microstructural metrics.ResultsBoth amnestic and non-amnestic patients exhibited lower WM connection strength than CN participants in corpus callosum, cingulum, and inferior and superior longitudinal fasciculi. Overall, non-amnestic patients had more WM disease than amnestic patients. LvPPA patients had left-lateralized WM degeneration; PCA patients had reductions in connections to bilateral posterior parietal, occipital, and temporal areas. Topological analysis showed the non-amnestic but not the amnestic group had more connected components than controls, indicating persistently lower connectivity. Longer disease duration and cognitive impairment were associated with more connected components and fewer cycles in individuals’ brain graphs.DiscussionWe have previously reported syndromic differences in GM degeneration and tau accumulation between AD syndromes; here we find corresponding differences in WM tracts connecting syndrome-specific epicenters. Determining the reasons for selective WM degeneration in non-amnestic AD is a research priority that will require integration of knowledge from neuroimaging, biomarker, autopsy, and functional genetic studies. Furthermore, longitudinal studies to determine the chronology of WM vs. GM degeneration will be key to assessing evidence for WM-mediated tau spread.

Background:Excessive daytime sleepiness (EDS) is a disabling symptom of Lewy body disorders (LBD). The hypothalamus is a key sleep-wake regulator, but its contribution to EDS in LBD remains unclear. Objectives:Use diffusion MRI to evaluate the relationship of hypothalamic microstructure to EDS symptoms in LBD. Methods:We studied 102 patients with clinically-defined LBD (Parkinson's disease, n=93; Parkinson's disease dementia, n=4; and dementia with Lewy bodies, n=5) and Epworth Sleepiness Scale (ESS) within 2 years of MRI. Mean diffusivity (MD) was compared between EDS+ (ESS≥10, n=37) and EDS- (ESS<10, n=65) groups in the whole hypothalamus and three subregions, covarying for age and sex. Secondary analyses tested correlations between subregion MD and continuous ESS, global cognition, and motor scores; and between subregion volume and continuous ESS. Results:MD was increased in EDS+ compared to EDS- only in the inferior tuberal subregion (Cohen's d=0.43, p=0.043, β=0.117±0.057), with trend level differences in the whole hypothalamus (Cohen's d=0.39, p=0.064, β=0.070±0.037) and superior tuberal subregion (Cohen's d=0.38, p=0.073, β=0.063±0.035). No difference was seen in the posterior subregion (Cohen's d=0.1, p=0.628, β=0.019±0.038). Significant correlations with continuous ESS were seen in MD of whole hypothalamus (r2=0.074, p=0.0057), superior tuberal (r2=0.081, p=0.0038), and inferior tuberal (r2=0.073, p=0.0059) subregions. There was no correlation of hypothalamic MD with global cognition or motor scores, and no correlation of whole/subregional hypothalamic volumes with ESS. Conclusions:Daytime sleepiness associates with increased MD in the inferior tuberal hypothalamus in an LBD cohort. This suggests degeneration within this region could contribute to EDS symptoms.

Regional cerebral blood flow (CBF) changes quantified using arterial spin labeling (ASL) are altered in neurodegenerative disorders such as frontotemporal lobar degeneration due to tau (FTLD-tau), but the relationship between ASL CBF and pathologic burden has not been assessed. Our objective was to determine whether regional ASL CBF acquired antemortem in patients with FTLD-tau is related to pathologic burden measured at autopsy in those same regions in the same patients to directly test the imaging-pathology relationship. In this case-control study, data were acquired between 3/4/2010 and 12/16/2018. Data processing and analysis were completed in 2023. Twenty-one participants with autopsy-confirmed FTLD-tau (N = 10 women, mean[SD] age 67.9[7.56] years) along with 25 control participants (N = 15 women, age 64.7[7.53]) were recruited through the cognitive neurology clinic at the University of Pennsylvania. All participants had ASL and T1-weighted images collected antemortem. ASL images were processed to estimate CBF and T1-weighted images were processed to estimate gray matter (GM) volumes in regions corresponding to regions sampled postmortem. Digital quantification of pathologic burden was performed to find the percent area occupied (%AO) of pathologic FTLD-tau at autopsy. Regional CBF and GM volumes were both related to pathologic burden in the same regions from the same participants. Strengths of model fits of imaging measures to pathologic burden were compared. CBF in FTLD-tau and controls were compared, with results considered significant at p < 0.05 after Bonferroni correction. We found that relative to controls, FTLD-tau displayed hypoperfusion in anterior cingulate, orbitofrontal, middle frontal, and superior temporal regions, as well as angular gyrus. For patients with FTLD-tau regional CBF was significantly associated with pathologic burden (beta = -1.07, t = -4.80, p < 0.005). Models including both GM volume and CBF provided significantly better fits to pathologic burden data than single modality models (p < 0.05, Bonferroni-corrected). Our results indicate that reduced CBF measured using ASL MRI is associated with increased pathologic burden in FTLD-tau and adds complementary predictive value of pathologic burden to structural MRI.

ABSTRACT Background and objectives Patients with ALS-FTD spectrum disorders (ALS-FTSD) have mixed motor and cognitive impairments and require valid and quantitative assessment tools to support diagnosis and tracking of bulbar motor disease. This study aimed to validate a novel automated digital speech tool that analyzes vowel acoustics from natural, connected speech as a marker for impaired articulation due to bulbar motor disease in ALS-FTSD. Methods We used an automatic algorithm called Forced Alignment Vowel Extraction (FAVE) to detect spoken vowels and extract vowel acoustics from 1 minute audio-recorded picture descriptions. Using automated acoustic analysis scripts, we derived two articulatory-acoustic measures: vowel space area (VSA, in Bark 2 ) which represents tongue range-of-motion (size), and average second formant slope of vowel trajectories (F2 slope) which represents tongue movement speed. We compared vowel measures between ALS with and without clinically-evident bulbar motor disease (ALS+bulbar vs. ALS-bulbar), behavioral variant frontotemporal dementia (bvFTD) without a motor syndrome, and healthy controls (HC). We correlated impaired vowel measures with bulbar disease severity, estimated by clinical bulbar scores and perceived listener effort, and with MRI cortical thickness of the orobuccal part of the primary motor cortex innervating the tongue (oralPMC). We also tested correlations with respiratory capacity and cognitive impairment. Results Participants were 45 ALS+bulbar (30 males, mean age=61±11), 22 ALS-nonbulbar (11 males, age=62±10), 22 bvFTD (13 males, age=63±7), and 34 HC (14 males, age=69±8). ALS+bulbar had smaller VSA and shallower average F2 slopes than ALS-bulbar (VSA: | d |=0.86, p =0.0088; F2 slope: | d |=0.98, p =0.0054), bvFTD (VSA: | d |=0.67, p =0.043; F2 slope: | d |=1.4, p <0.001), and HC (VSA: | d |=0.73, p =0.024; F2 slope: | d |=1.0, p <0.001). Vowel measures declined with worsening bulbar clinical scores (VSA: R=0.33, p =0.033; F2 slope: R=0.25, p =0.048), and smaller VSA was associated with greater listener effort (R=-0.43, p =0.041). Shallower F2 slopes were related to cortical thinning in oralPMC (R=0.50, p =0.03). Neither vowel measure was associated with respiratory nor cognitive test scores. Conclusions Vowel measures extracted with automatic processing from natural speech are sensitive to bulbar motor disease in ALS-FTD and are robust to cognitive impairment.

BACKGROUND AND OBJECTIVES:Clinical trials developing therapeutics for frontotemporal degeneration (FTD) focus on pathogenic variant carriers at preclinical stages. Objective, quantitative clinical assessment tools are needed to track stability and delayed disease onset. Natural speech can serve as an accessible, cost-effective assessment tool. We aimed to identify early changes in the natural speech of FTD pathogenic variant carriers before they become symptomatic. METHODS:In this cohort study, speech samples of picture descriptions were collected longitudinally from healthy participants in observational studies at the University of Pennsylvania and Columbia University between 2007 and 2020. Participants were asymptomatic but at risk for familial FTD. Status as "carrier" or "noncarrier" was based on screening for known pathogenic variants in the participant's family. Thirty previously validated digital speech measures derived from automatic speech processing pipelines were selected a priori based on previous studies in patients with FTD and compared between asymptomatic carriers and noncarriers cross-sectionally and longitudinally. RESULTS:A total of 105 participants, all asymptomatic, included 41 carriers: 12 men [30%], mean age 43 ± 13 years; education, 16 ± 2 years; MMSE 29 ± 1; and 64 noncarriers: 27 men [42%]; mean age, 48 ± 14 years; education, 15 ± 3 years; MMSE 29 ± 1. We identified 4 speech measures that differed between carriers and noncarriers at baseline: mean speech segment duration (mean difference -0.28 seconds, 95% CI -0.55 to -0.02, p = 0.04); word frequency (mean difference 0.07, 95% CI 0.008-0.14, p = 0.03); word ambiguity (mean difference 0.02, 95% CI 0.0008-0.05, p = 0.04); and interjection count per 100 words (mean difference 0.33, 95% CI 0.07-0.59, p = 0.01). Three speech measures deteriorated over time in carriers only: particle count per 100 words per month (β = -0.02, 95% CI -0.03 to -0.004, p = 0.009); total narrative production time in seconds per month (β = -0.24, 95% CI -0.37 to -0.12, p < 0.001); and total number of words per month (β = -0.48, 95% CI -0.78 to -0.19, p = 0.002) including in 3 carriers who later converted to symptomatic disease. DISCUSSION:Using automatic processing pipelines, we identified early changes in the natural speech of FTD pathogenic variant carriers in the presymptomatic stage. These findings highlight the potential utility of natural speech as a digital clinical outcome assessment tool in FTD, where objective and quantifiable measures for abnormal behavior and language are lacking.

Frontotemporal dementia (FTD) is a spectrum of clinically and pathologically heterogenous neurodegenerative dementias. Clinical and anatomical variants of FTD have been described and associated with underlying frontotemporal lobar degeneration (FTLD) pathology, including tauopathies (FTLD-tau) or TDP-43 proteinopathies (FTLD-TDP). FTD patients with predominant degeneration of anterior temporal cortices often develop a language disorder of semantic knowledge loss and/or a social disorder often characterized by compulsive rituals and belief systems corresponding to predominant left or right hemisphere involvement, respectively. The neural substrates of these complex social disorders remain unclear. Here, we present a comparative imaging and postmortem study of two patients, one with FTLD-TDP (subtype C) and one with FTLD-tau (subtype Pick disease), who both developed new rigid belief systems. The FTLD-TDP patient developed a complex set of values centered on positivity and associated with specific physical and behavioral features of pigs, while the FTLD-tau patient developed compulsive, goal-directed behaviors related to general themes of positivity and spirituality. Neuroimaging showed left-predominant temporal atrophy in the FTLD-TDP patient and right-predominant frontotemporal atrophy in the FTLD-tau patient. Consistent with antemortem cortical atrophy, histopathologic examinations revealed severe loss of neurons and myelin predominantly in the anterior temporal lobes of both patients, but the FTLD-tau patient showed more bilateral, dorsolateral involvement featuring greater pathology and loss of projection neurons and deep white matter. These findings highlight that the regions within and connected to anterior temporal lobes may have differential vulnerability to distinct FTLD proteinopathies and serve important roles in human belief systems.

Despite well-articulated hypotheses of spreading pathology in animal models of neurodegenerative disease, the basis for spreading neurodegenerative pathology in humans has been difficult to ascertain. In this study, we used graph theoretic analyses of structural networks in antemortem, multimodal MRI from autopsy-confirmed cases to examine spreading pathology in sporadic frontotemporal lobar degeneration. We defined phases of progressive cortical atrophy on T-1-weighted MRI using a published algorithm in autopsied frontotemporal lobar degeneration with tau inclusions or with transactional DNA binding protein of similar to 43 kDa inclusions. We studied global and local indices of structural networks in each of these phases, focusing on the integrity of grey matter hubs and white matter edges projecting between hubs. We found that global network measures are compromised to an equal degree in patients with frontotemporal lobar degeneration with tau inclusions and frontotemporal lobar degeneration-transactional DNA binding protein of similar to 43 kDa inclusions compared to healthy controls. While measures of local network integrity were compromised in both frontotemporal lobar degeneration with tau inclusions and frontotemporal lobar degeneration-transactional DNA binding protein of similar to 43 kDa inclusions, we discovered several important characteristics that distinguished between these groups. Hubs identified in controls were degraded in both patient groups, but degraded hubs were associated with the earliest phase of cortical atrophy (i.e. epicentres) only in frontotemporal lobar degeneration with tau inclusions. Degraded edges were significantly more plentiful in frontotemporal lobar degeneration with tau inclusions than in frontotemporal lobar degeneration-transactional DNA binding protein of similar to 43 kDa inclusions, suggesting that the spread of tau pathology involves more significant white matter degeneration. Weakened edges were associated with degraded hubs in frontotemporal lobar degeneration with tau inclusions more than in frontotemporal lobar degeneration-transactional DNA binding protein of similar to 43 kDa inclusions, particularly in the earlier phases of the disease, and phase-to-phase transitions in frontotemporal lobar degeneration with tau inclusions were characterized by weakened edges in earlier phases projecting to diseased hubs in subsequent phases of the disease. When we examined the spread of pathology from a region diseased in an earlier phase to physically adjacent regions in subsequent phases, we found greater evidence of disease spreading to adjacent regions in frontotemporal lobar degeneration-transactional DNA binding protein of similar to 43 kDa inclusions than in frontotemporal lobar degeneration with tau inclusions. We associated evidence of degraded grey matter hubs and weakened white matter edges with quantitative measures of digitized pathology from direct observations of patients' brain samples. We conclude from these observations that the spread of pathology from diseased regions to distant regions via weakened long-range edges may contribute to spreading disease in frontotemporal dementia-tau, while spread of pathology to physically adjacent regions via local neuronal connectivity may play a more prominent role in spreading disease in frontotemporal lobar degeneration-transactional DNA binding protein of similar to 43 kDa inclusions. Chen et al. utilize graph-theoretic analyses of antemortem, multimodal MRIs to examine spreading pathology in structural networks of those with autopsy-confirmed frontotemporal lobar degeneration with either tau or transactional DNA binding protein of similar to 43 kDa inclusions. They report distinct patterns of long-range and short-range network degradation between the two pathologies, suggesting different mechanisms for their spread.

Background: In previous studies of patients with frontotemporal lobar degeneration due to tau (FTLD-tau) and FTLD due to TDP (FTLD-TDP), cortical volumes derived from T1-weighted MRI have been used to identify a sequence of volume loss according to arbitrary volumetric criteria. Event-based modeling (EBM) is a probabilistic, generative machine learning model that determines the characteristic sequence of changes, or “events”, occurring during disease progression. EBM also estimates an individual patient’s disease “stage” by identifying which events have already occurred. In the present study, we use an EBM analysis to derive stages of regional anatomic atrophy in FTLD-tau and FTLD-TDP, and validated these stages against pathologic burden. Methods: Sporadic autopsy-confirmed patients with FTLD-tau (N = 42) and FTLD-TDP (N = 21), and 167 healthy controls with available T1-weighted images were identified. A subset of patients had quantitative digital histopathology of cortex performed at autopsy (FTLD-tau = 30, FTLD-TDP = 17). MRI images were processed, producing regional measures of cortical volumes. K-means clustering was used to find cortical regions with similar amounts of GM volume changes (n = 5 clusters). EBM was used to determine the characteristic sequence of cortical atrophy of identified clusters in autopsy-confirmed FTLD-tau and FTLD-TDP, and estimate each patient’s disease stage by cortical volume biomarkers. Linear regressions related pathologic burden to EBM-estimated disease stages. Results: EBM for cortical volume biomarkers generated statistically robust characteristic sequences of cortical atrophy in each group of patients. Cortical volume-based EBM-estimated disease stage was associated with pathologic burden in FTLD-tau (R2 = 0.16, p = 0.017) and FTLD-TDP (R2 = 0.51, p = 0.0008). Conclusions: We provide evidence that EBM can identify sequences of pathologically-confirmed cortical atrophy in sporadic FTLD-tau and FTLD-TDP.

Frontotemporal lobar degeneration (FTLD) includes clinically similar FTLD-tau or FTLD-TDP proteinopathies which lack in vivo markers for accurate antemortem diagnosis. To identify early distinguishing sites of cortical atrophy between groups, we retrospectively analyzed in vivo volumetric MRI from 42 FTLD-Tau and 21 FTLD-TDP patients and validated these findings with postmortem measures of pathological burden. Our frequency-based staging model revealed distinct loci of maximal early cortical atrophy in each group, including dorsolateral and medial frontal regions in FTLD-Tau and ventral frontal and anterior temporal regions in FTLD-TDP. Sørenson-Dice calculations between proteinopathy groups showed little overlap of phases. Conversely, within-group subtypes showed good overlap between 3R- and 4R-tauopathies, and between TDP-43 Types A and C for early regions with subtle divergence between subtypes in subsequent phases of atrophy. Postmortem validation found an association of imaging phases with pathologic burden within FTLD-tau (F(4, 238) = 17.44, p < 0.001) and FTLD-TDP (F(4,245) = 42.32, p < 0.001). These results suggest that relatively early, distinct markers of atrophy may distinguish FTLD proteinopathies during life.

Arterial spin labeled (ASL) magnetic resonance imaging (MRI) is the primary method for non-invasively measuring regional brain perfusion in humans. We introduce ASLPrep, a suite of software pipelines that ensure the reproducible and generalizable processing of ASL MRI data.

Longitudinal positron emission tomography (PET) studies of tau accumulation in Alzheimer’s disease (AD) have noted reduced increases or frank decreases in tau signal. It is unclear whether these reductions reflect measurement/processing error or biological changes in advanced neurodegeneration.

ABSTRACTBehavioral variant frontotemporal degeneration (bvFTD) is clinically characterized by progressive decline in social and executive domains. Previous work suggests that early lifestyle factors such as education and occupational attainment may relate to structural integrity and moderate the rate of cognitive decline in bvFTD, but the role of other cognitively stimulating activities is understudied. We sought to investigate the effect of such activities on cortical thickness (CT) in bvFTD. bvFTD patients (n=31) completed a baseline MRI scan, and informants for the patients completed the Lifetime of Experiences Questionnaire (LEQ), which measures specific activities considered to be undertaken primarily within one particular life phase, such as education (young-life), occupation (mid-life), and social/leisure activity (late-life). At baseline, linear models assessed the effect of LEQ scores from each life phase on regional CT. A subset (n=19) of patients completed longitudinal MRI, and to evaluate the association of LEQ with longitudinal rates of CT decline, we derived individualized slopes of decline using linear mixed effects models and these were related to LEQ scores from each life phase. At baseline, a higher late-life LEQ score was associated with less atrophy in bilateral superior anterior temporal regions. Longitudinally, we observed that higher late-life LEQ scores were associated with an attenuated rate of CT loss in insular cortex. Late-life LEQ score was positively associated with both relatively preserved CT early in bvFTD and a slower rate of cortical loss in regions important for social functioning. These findings suggest that social and leisure activities may contribute to a form of resilience against pathologic effects of disease.

Behavioral variant frontotemporal degeneration (bvFTD) is clinically characterized by progressive decline in social and executive domains. Previous work suggests that early lifestyle factors such as education and occupational attainment may relate to structural integrity and moderate the rate of cognitive decline in bvFTD, but the role of other cognitively stimulating activities is understudied. We sought to investigate the effect of such activities on cortical thickness (CT) in bvFTD. bvFTD patients (n = 31) completed a baseline MRI scan, and informants for the patients completed the Lifetime of Experiences Questionnaire (LEQ), which measures specific activities considered to be undertaken primarily within one particular life phase, such as education (young-life), occupation (mid-life), and social/leisure activity (late-life). At baseline, linear models assessed the effect of LEQ scores from each life phase on regional CT. A subset (n = 19) of patients completed longitudinal MRI, and to evaluate the association of LEQ with longitudinal rates of CT decline, we derived individualized slopes of decline using linear mixed effects models and these were related to LEQ scores from each life phase. At baseline, a higher late-life LEQ score was associated with less atrophy in left superior and inferior anterior temporal regions as well as right middle temporal gyrus. Longitudinally, we observed that higher late-life LEQ scores were associated with an attenuated rate of CT loss in insular cortex. Late-life LEQ score was positively associated with both relatively preserved CT early in bvFTD and a slower rate of cortical loss in regions important for social functioning. These findings suggest that social and leisure activities may contribute to a form of resilience against pathologic effects of disease.