Single-nucleus multiome analysis of human cerebellum in Alzheimer's disease-related dementia.

Although human cerebellum is known to be neuropathologically impaired in Alzheimer's disease (AD) and AD-related dementias (ADRD), the cell type-specific transcriptional and epigenomic changes that contribute to this pathology are not well understood. Here, we report single-nucleus multiome (snRNA-seq and snATAC-seq) analysis of 103,861 nuclei isolated from cerebellum from 9 human cases of AD/ADRD and 8 controls, and with frontal cortex of 6 AD donors for additional comparison. Using peak-to-gene linkage analysis, we identified 431,834 significant linkages between gene expression and cell subtype-specific chromatin accessibility regions enriched for candidate cis-regulatory elements (cCREs). These cCREs were associated with AD/ADRD-specific transcriptomic changes and disease-related gene regulatory networks, especially for RAR Related Orphan Receptor A (RORA) and E74 Like ETS Transcription Factor 1 (ELF1) in cerebellar Purkinje cells and granule cells, respectively. Trajectory analysis of granule cell populations further identified disease-relevant transcription factors, such as RORA, and their regulatory targets. Finally, we prioritized two likely causal genes, including Seizure Related 6 Homolog Like 2 (SEZ6L2) in Purkinje cells and KAT8 Regulatory NSL Complex Subunit 1 (KANSL1) in granule cells, through integrative analysis of cCREs derived from snATAC-seq, genome-wide AD/ADRD loci, and Hi-C looping data. This first cell subtype-specific regulatory landscape in the human cerebellum identified here offer novel genomic and epigenomic insights into the neuropathology and pathobiology of AD/ADRD and other neurological disorders if broadly applied.

Progressive verbal apraxia of reading.

We identified a syndrome characterized by a relatively isolated progressive impairment of reading words that the patient was able to understand and repeat but without other components of speech apraxia. This cluster of symptoms fits a new syndrome designated Progressive Verbal Apraxia of Reading. A right-handed man (AB) came with a 2.5-year history of increasing difficulties in reading aloud. He was evaluated twice, 2 years apart, using multimodal neuroimaging techniques and quantitative neurolinguistic assessment. In the laboratory, reading difficulties arose in the context of intact visual and auditory word recognition as well as intact ability to understand and repeat words he was unable to read aloud. The unique feature was the absence of dysarthria or speech apraxia in tasks other than reading. Initial imaging did not reveal statistically significant atrophy. Structural magnetic resonance and FDG-PET imaging at the second assessment revealed atrophy and hypometabolism in the right posterior cerebellum, in areas shown to be part of his language network by task-based functional neuroimaging at initial assessment. This syndromic cluster can be designated Progressive Verbal Apraxia of Reading, an entity that has not been reported previously to the best of our knowledge. We hypothesize a selective disconnection of the visual word recognition system from the otherwise intact articulatory apparatus, a disconnection that appears to reflect the disruption of multisynaptic cerebello-cortical circuits.

Calming effect of Clinically Designed Improvisatory Music for patients admitted to the epilepsy monitoring unit during the COVID-19 pandemic: a pilot study.

Background: Epilepsy monitoring requires simulating seizure-inducing conditions which frequently causes discomfort to epilepsy monitoring unit (EMU) patients. COVID-19 hospital restrictions added another layer of stress during hospital admissions. The purpose of this pilot study was to provide evidence that live virtual Clinically Designed Improvisatory Music (CDIM) brings relief to EMU patients for their psychological distress. Methods: Five persons with epilepsy (PWEs) in the EMU during the COVID-19 lockdown participated in the study (average age ± SD = 30.2 ± 6 years). Continuous electroencephalogram (EEG) and electrocardiogram (EKG) were obtained before, during, and after live virtual CDIM. CDIM consisted of 40 minutes of calming music played by a certified clinical music practitioner (CMP) on viola. Post-intervention surveys assessed patients' emotional state on a 1-10 Likert scale. Alpha/beta power spectral density ratio was calculated for each subject across the brain and was evaluated using one-way repeated analysis of variance, comparing 20 minutes before, during, and 20 minutes after CDIM. Post-hoc analysis was performed using paired t-test at the whole brain level and regions with peak changes. Results: Patients reported enhanced emotional state (9 ± 1.26), decrease in tension (9.6 ± 0.49), decreased restlessness (8.6 ± 0.80), increased pleasure (9.2 ± 0.98), and likelihood to recommend (10 ± 0) on a 10-point Likert scale. Based on one-way repeated analysis of variance, alpha/beta ratio increased at whole-brain analysis (F3,12 = 5.01, P = 0.018) with a peak in midline (F3,12 = 6.63, P = 0.0068 for Cz) and anterior medial frontal region (F3,12 = 6.45, P = 0.0076 for Fz) during CDIM and showed a trend to remain increased post-intervention. Conclusion: In this pilot study, we found positive effects of CDIM as reported by patients, and an increased alpha/beta ratio with meaningful electroencephalographic correlates due to the calming effects in response to CDIM. Our study provides proof of concept that live virtual CDIM offered demonstrable comfort with biologic correlations for patients admitted in the EMU during the COVID-19 pandemic.

AD-BERT: Using pre-trained language model to predict the progression from mild cognitive impairment to Alzheimer's disease.

OBJECTIVE: We develop a deep learning framework based on the pre-trained Bidirectional Encoder Representations from Transformers (BERT) model using unstructured clinical notes from electronic health records (EHRs) to predict the risk of disease progression from Mild Cognitive Impairment (MCI) to Alzheimer's Disease (AD). METHODS: We identified 3657 patients diagnosed with MCI together with their progress notes from Northwestern Medicine Enterprise Data Warehouse (NMEDW) between 2000 and 2020. The progress notes no later than the first MCI diagnosis were used for the prediction. We first preprocessed the notes by deidentification, cleaning and splitting into sections, and then pre-trained a BERT model for AD (named AD-BERT) based on the publicly available Bio+Clinical BERT on the preprocessed notes. All sections of a patient were embedded into a vector representation by AD-BERT and then combined by global MaxPooling and a fully connected network to compute the probability of MCI-to-AD progression. For validation, we conducted a similar set of experiments on 2563 MCI patients identified at Weill Cornell Medicine (WCM) during the same timeframe. RESULTS: Compared with the 7 baseline models, the AD-BERT model achieved the best performance on both datasets, with Area Under receiver operating characteristic Curve (AUC) of 0.849 and F1 score of 0.440 on NMEDW dataset, and AUC of 0.883 and F1 score of 0.680 on WCM dataset. CONCLUSION: The use of EHRs for AD-related research is promising, and AD-BERT shows superior predictive performance in modeling MCI-to-AD progression prediction. Our study demonstrates the utility of pre-trained language models and clinical notes in predicting MCI-to-AD progression, which could have important implications for improving early detection and intervention for AD.

Lower Cerebrospinal Fluid Amyloid-ß42 Predicts Sooner Time to Antipsychotic Use in Alzheimer's Disease.

Background: Cerebrospinal fluid (CSF) biomarkers of amyloid-ß42 (Aß42) and phosphorylated-tau help clinicians accurately diagnose Alzheimer's disease (AD). Whether biomarkers help prognosticate behavioral and psychological symptoms of dementia (BPSD) is unclear. Objective: Determine whether CSF biomarker levels aid prognostication of BPSD in AD. Methods: This retrospective cohort study included patients over 65 with a diagnosis of AD based on CSF biomarkers. We measured time from CSF testing to the first antipsychotic use in the following months. We then analyzed time to antipsychotic (AP) use with respect to Aß42, total tau, phosphorylated tau, and amyloid-to-tau index using a survival analysis approach. Results: Of 86 AD patients (average 72±5 years, 46.5% male), 11 patients (12.7%) received APs following CSF testing. Patients with Aß42 below the median had sooner time-to-AP use. This was significant on a log-rank test (p = 0.04). There was no difference in time-to-AP use if the group was stratified by levels of total tau, phosphorylated tau, or amyloid-to-tau index. Conclusion: These results suggest a relationship between lower CSF Aß42 levels and sooner AP use. This supports prior reports suggesting a correlation between BPSD and Aß deposition on PET. These results highlight the need for further prospective studies on Aß levels and BPSD.

Cognitive Impairment in Liver Transplant Recipients With a History of Cirrhosis: A Systematic Review.

Cognitive impairment is common among patients with cirrhosis and may persist post-transplantation. This systematic review seeks to (1) describe the prevalence of cognitive impairment in liver transplant (LT) recipients with a history of cirrhosis, (2) describe risk factors for this population, and (3) describe associations between post-transplant cognitive impairment and quality outcome measures. Methods: Studies in PubMed, Embase, Scopus, PsychINFO, and the Cochrane Database of Controlled Trials were included through May 2022. Inclusion criteria included (1) population - LT recipient, age ≥18 y, (2) exposure - history of cirrhosis before transplant, and (3) outcome - cognitive impairment after transplant (per validated cognitive testing). Exclusion criteria included (1) wrong study type, (2) abstract-only publication, (3) full-text unavailable, (4) wrong population, (5) wrong exposure, and (6) wrong outcome. The risk of bias was assessed using the Newcastle-Ottawa Scale and the Appraisal tool for Cross-Sectional Studies. The Grading of Recommendations, Assessment, Development, and Evaluations system was used to assess evidence certainty. Data from individual tests were categorized into six cognitive domains: attention, executive function, working memory, long-term memory, visuospatial, and language. Results: Twenty-four studies were included covering 847 patients. Follow-up ranged from 1 mo to 1.8 y after LT. Studies had a median of 30 (interquartile range 21.5-50.5) patients. The prevalence of cognitive impairment after LT ranged from 0% to 36%. Forty-three unique cognitive tests were used, the most common being the Psychometric Hepatic Encephalopathy Score. The most frequently assessed cognitive domains were attention (10 studies) and executive function (10 studies). Conclusions: The prevalence of cognitive impairment after LT varied across studies depending on cognitive tests utilized and follow-up duration. Attention and executive function were most impacted. Generalizability is limited due to small sample size and heterogeneous methodology. Further studies are needed to examine differences in the prevalence of post-LT cognitive impairment by etiology, risk factors, and ideal cognitive measures.

Brain Networks, Clinical Manifestations, and Neuroimaging of Cognitive Disorders: The Role of Computed Tomography (CT), Magnetic Resonance Imaging (MRI), Positron Emission Tomography (PET), and Other Advanced Neuroimaging Tests.

In this article, we briefly discuss imaging modalities used in clinical settings for neuroanatomical characterization and for diagnosis of the underlying disease. We then discuss how each neuroimaging tool can be used in the context of clinical syndromes. The major underlying causes relevant to our discussion include Alzheimer disease, Lewy body disease, cerebrovascular disease, frontotemporal degeneration, autoimmune diseases, and systemic or metabolic derangements.

Stimulation of distinct parietal locations differentiates frontal versus hippocampal network involvement in memory formation.

Adjacent regions of parietal cortex are thought to affiliate with distinct large-scale networks and thereby make different contributions to memory formation. We directly tested this putative functional segregation within parietal cortex by perturbing activity of anterior versus posterior parietal areas. We applied noninvasive theta-burst transcranial magnetic stimulation to these locations immediately before a semantic encoding task, and subsequently tested recollection memory. Consistent with previous findings, fMRI activity in left inferior frontal gyrus during semantic encoding correlated with subsequent high memory accuracy and strong subjective recollection. Stimulation of the posterior parietal cortex decoupled its network - the hippocampal-cortical network - from left inferior frontal gyrus. Furthermore, posterior parietal stimulation reduced highly accurate subjective recollection. Critically, both of these changes occurred relative to stimulation of the anterior parietal cortex. Stimulating anterior versus posterior parietal cortex therefore differentiated hippocampal network involvement in episodic memory. This provides direct evidence that distinct territories within close proximity of each other in parietal cortex make functionally distinct contributions to memory formation. Further, noninvasive stimulation has the spatial resolution required to differentially modulate the interaction of these adjacent parietal locations with distributed large-scale brain networks.

Musical Bridges to Memory: A Pilot Dyadic Music Intervention to Improve Social Engagement in Dementia.

BACKGROUND: Music-based psychosocial interventions may provide effective management of behavioral symptoms in persons with dementia (PWDs). However, there has been a paucity of studies that measured their effect on social engagement. This proof-of-concept study evaluates efficacy of the Musical Bridges to Memory (MBM) intervention on PWD's social engagement, behavioral symptoms, and associated caregiver distress. METHODS: Twenty-nine PWDs and caregivers (8 control dyads, 21 intervention) participated in this dyadically designed, prospective, blinded, 12-week controlled interventional study. The intervention consisted of weekly MBM sessions, led by board-certified music therapists and performers, including caregiver training, live performances, and social breakout groups. Outcomes were measured by the Verbal and Nonverbal Interaction Scale for Care Receivers (VNVIS-CR) to code interactions between PWDs and caregivers for verbal and nonverbal sociable and unsociable behaviors. Symptom severity and caregiver distress were measured using Neuropsychiatric Inventory. RESULTS: Nonverbal sociable interactions significantly increased ( P =0.012) in those who completed the MBM program as compared with a decrease observed in the control group. Family/caregiver distress associated with PWDs neuropsychiatric symptoms showed significant improvement in the experimental group as compared with controls ( P =0.045). CONCLUSIONS: This study provides proof-of-concept that MBM improves nonverbal sociable content of PWDs interactions and reduces caregivers' distress.

Neurology Telemusic Program at the Time of the COVID-19 Pandemic: Turning Hospital Time Into Aesthetic Time During Crisis.

Strict precautions during the COVID-19 pandemic left patients isolated during already stressful hospital stays. Research indicates that listening to music recruits regions in the brain involved with social interaction and reduces feelings of loneliness. We formed a team of clinicians and clinical musicians to bring music to the bedside, as "psychological first aid." Our goal was to reduce feelings of anxiety and isolation in patients admitted to the Northwestern Memorial Hospital's neurosciences unit. Participants were offered 30-40-min live music sessions over FaceTime by a violist in consultation with a music therapist and a certified music practitioner. Music used for the interventions was personalized. Participants were evaluated with the Music Assessment Tool where they indicated their musical preferences and music to which they objected. Following the intervention, participants answered a questionnaire assessing how music impacted their emotional state based on a 1-10 Likert scale. Scores were then averaged across all patients and were calculated as percentages. Eighty-seven sessions were completed during a 3-month period. Despite different degrees of disability, most patients engaged aesthetically with the music. The likelihood to recommend (LTR) for the program was 98%; participants tended to highly agree that the intervention improved their emotional state (92%); that it provided a pleasurable experience (92.4%); and that it reduced their stress and anxiety (89.5%). This pilot project showed that the telemusic intervention was feasible for our neurosciences patients during the COVID-19 pandemic. Our results are consistent with previous in-person hospital-based music interventions and highlight the importance of such programs when in-person interventions are not possible. This pilot project serves as a prelude to further investigate mechanisms by which music interventions can support admitted neurology patients.

Treatment for Anomia in Bilingual Speakers with Progressive Aphasia.

Anomia is an early and prominent feature of primary progressive aphasia (PPA) and other neurodegenerative disorders. Research investigating treatment for lexical retrieval impairment in individuals with progressive anomia has focused primarily on monolingual speakers, and treatment in bilingual speakers is relatively unexplored. In this series of single-case experiments, 10 bilingual speakers with progressive anomia received lexical retrieval treatment designed to engage relatively spared cognitive-linguistic abilities and promote word retrieval. Treatment was administered in two phases, with one language targeted per phase. Cross-linguistic cognates (e.g., rose and rosa) were included as treatment targets to investigate their potential to facilitate cross-linguistic transfer. Performance on trained and untrained stimuli was evaluated before, during, and after each phase of treatment, and at 3, 6, and 12 months post-treatment. Participants demonstrated a significant treatment effect in each of their treated languages, with maintenance up to one year post-treatment for the majority of participants. Most participants showed a significant cross-linguistic transfer effect for trained cognates in both the dominant and nondominant language, with fewer than half of participants showing a significant translation effect for noncognates. A gradual diminution of translation and generalization effects was observed during the follow-up period. Findings support the implementation of dual-language intervention approaches for bilingual speakers with progressive anomia, irrespective of language dominance.

Nosology of Primary Progressive Aphasia and the Neuropathology of Language.

Primary progressive aphasia (PPA) is a dementia syndrome associated with several neuropathologic entities, including Alzheimer's disease (AD) and all major forms of frontotemporal lobar degeneration (FTLD). It is classified into subtypes defined by the nature of the language domain that is most impaired. The asymmetric neurodegeneration of the hemisphere dominant for language (usually left) is one consistent feature of all PPA variants. This feature offers unique opportunities for exploring mechanisms of selective vulnerability in neurodegenerative diseases and the neuroanatomy of language. This chapter reviews some of the current trends in PPA research as well as the challenges that remain to be addressed on the nosology, clinicopathologic correlations, and therapy of this syndrome.

Common and distinct neural substrates of sentence production and comprehension.

Functional neuroimaging and lesion-symptom mapping investigations implicate a left frontal-temporal-parietal network for sentence processing. The majority of studies have focused on sentence comprehension, with fewer in the domain of sentence production, which have not fully elucidated overlapping and/or unique brain structures associated with the two domains, particularly for sentences with noncanonical word order. Using voxel-based lesion symptom mapping (VLSM) we examined the relationship between lesions within the left hemisphere language network and both sentence comprehension and production of simple and complex syntactic structures in 76 participants with chronic stroke-induced aphasia. Results revealed shared regions across domains in the anterior and posterior superior temporal gyri (aSTG, pSTG), and the temporal pole (adjusted for verb production/comprehension). Additionally, comprehension was associated with lesions in the anterior and posterior middle temporal gyri (aMTG, pMTG), the MTG temporooccipital regions, SMG/AG, central and parietal operculum, and the insula. Subsequent VLSM analyses (production versus comprehension) revealed critical regions associated with each domain: anterior temporal lesions were associated with production; posterior temporo-parietal lesions were associated with comprehension, implicating important roles for regions within the ventral and dorsal stream processing routes, respectively. Processing of syntactically complex, noncanonical (adjusted for canonical), sentences was associated with damage to the pSTG across domains, with additional damage to the pMTG and IPL associated with impaired sentence comprehension, suggesting that the pSTG is crucial for computing noncanonical sentences across domains and that the pMTG, and IPL are necessary for re-analysis of thematic roles as required for resolution of long-distance dependencies. These findings converge with previous studies and extend our knowledge of the neural mechanisms of sentence comprehension to production, highlighting critical regions associated with both domains, and further address the mechanism engaged for syntactic computation, controlled for the contribution of verb processing.

Familial language network vulnerability in primary progressive aphasia.

OBJECTIVE: To investigate evidence of the potential role of early cortical vulnerability in the development of primary progressive aphasia (PPA). METHOD: A woman with a diagnosis of PPA and her 9 adult siblings, 7 with developmental language disabilities, underwent neuropsychological testing, structural MRI, and resting-state fMRI. Whole-exome sequencing was conducted for genes associated with dyslexia or with neurodegenerative dementia. RESULTS: The siblings demonstrated lower verbal than nonverbal cognitive test scores in a developmental dyslexia pattern. On structural MRI, although the siblings did not differ from controls in total brain volume, the left hemisphere language area volume was significantly smaller than the right. Furthermore, cortical connectivity between the left superior temporal area, previously identified as the region of peak atrophy in the proband early in the course of illness, and adjacent language network components, including the planum temporale, was decreased in the siblings. No distinctive genetic signatures were identified. CONCLUSION: This report further supports the hypothesis that at least some cases of PPA may be based on a familial language network vulnerability that interferes with the acquisition of language in some members and that makes the language network a locus of least resistance to the effects of an independently late-arising neurodegenerative disease in others. This association offers a conceptual model to explain why identical neurodegenerative diseases may selectively target the language network in some individuals while targeting networks that regulate memory or behavior in others. The genetic basis for this vulnerability remains to be determined.

Challenges in diagnosis of primary progressive aphasia.

Two 68-year-old men presented to the behavioral neurology clinic with memory complaints. The clinical picture was complicated by bilingualism and psychiatric comorbidities. Based on a combination of cognitive and language testing, 5-fluorodeoxyglucose positron emission tomography (FDG-PET), and/or magnetic resonance imaging (MRI) of the brain, both cases were initially diagnosed as having mild cognitive impairment (MCI). At follow-up, however, both cases' language profiles and neuroimaging had evolved to clearly indicate primary progressive aphasia (PPA) as the underlying condition rather than MCI. These cases underscore the importance of careful observation of clinical and neuroimaging data over time to reach an accurate diagnosis.

Perturbations of language network connectivity in primary progressive aphasia.

Aphasias are caused by disruption in structural integrity and interconnectivity within a large-scale distributed language network. We investigated the distribution and behavioral consequences of altered functional connectivity in three variants of primary progressive aphasia (PPA). The goal was to clarify relationships among atrophy, resting connectivity, and the resulting behavioral changes in 73 PPA and 33 control participants. Three core regions of the left perisylvian language network: the inferior frontal gyrus (IFG), middle temporal gyrus (MTG), and anterior temporal lobe (ATL) were evaluated in agrammatic (PPA-G), logopenic (PPA-L), and semantic (PPA-S) PPA variants. All PPA groups showed decreased connectivity between IFG and MTG. The PPA-S group also showed additional loss of connectivity strength between ATL and the other language regions. Decreased connectivity between the IFG and MTG nodes in PPA-G remained significant even when controlled for the effect of atrophy. In the PPA group as a whole, IFG-MTG connectivity strength correlated with repetition and grammar scores, whereas MTG-ATL connectivity correlated with picture naming and single-word comprehension. There was no significant change in the connectivity of homologous regions in the right hemisphere. These results show that language impairments in PPA are associated with perturbations of functional connectivity within behaviorally concordant components of the language network. Altered connectivity in PPA may reflect not only the irreversible loss of cortical components indexed by atrophy, but also the dysfunction of remaining neurons.

Sleep talking and primary progressive aphasia: case study and autopsy findings in a patient with logopenic primary progressive aphasia and dementia with Lewy bodies.

This case study highlights the parasomnia behaviours of an individual with primary progressive aphasia, a type of dementia known for decline in language abilities. Despite a paucity of speech during the day, this individual had concurrent sleep talking at night; a combination which, to our knowledge, has never been reported before. Post-mortem pathology confirmed clinical suspicion of both Alzheimer and Lewy body diseases, both asymmetric to the left side. Given this rare left-sided asymmetrical pathology, we hypothesise that the relatively preserved right hemisphere may have allowed for access to intact overlearned phrases which usually originate from the right hemisphere to appear while asleep. A second hypothesis is also presented which postulates that bottom-up processing may have overridden top-down apathy during sleep and allowed for speech output in this case.

Combined Pathologies in FTLD-TDP Types A and C.

This study investigated the presence of combined pathologies in a large cohort of autopsies that show a primary pathologic diagnosis of phosphorylated 43-kDa TAR DNA-binding protein (FTLD-TDP), the majority of which portrayed clinical phenotypes consistent with primary progressive aphasia or behavioral variant frontotemporal dementia (bvFTD). Thirty-eight cases with FTLD-TDP (30 type-A and 8 type-C) were identified to determine characteristic differences between cases with and without combined pathologies. Findings indicated that combined pathologies co-occur with FTLD-TDP type-A at a high frequency (50%)-greater than when compared to FTLD-TDP type-C cases (12.5%). Those with FTLD-TDP type-A and combined pathologies showed significantly longer lifespans (p < 0.05), and longer disease durations (p < 0.05), than those with only FTLD-TDP type-A. Cases with FTLD-TDP type-A and known genetic mutations tended not to show combined pathology. Those with the GRN mutation and FTLD-TDP type-A showed a significantly younger age of onset (p < 0.05) and younger age at death (p < 0.01) compared to noncarriers. In 1 bvFTD case, we highlight the rare presence of "triple" FTLD-TDP type-A, FTLD-tau, and Alzheimer pathology. The ante- and post-mortem features associated with combined pathologies in FTLD-related disorders are of useful consideration in the stratification of patients to drug trials, and in the development of therapeutic targets for FTLD.

Functional Connectivity is Reduced in Early-stage Primary Progressive Aphasia When Atrophy is not Prominent.

Primary progressive aphasia (PPA) is a clinical syndrome of language decline caused by neurodegenerative pathology. Although language impairments in PPA are typically localized via the morphometric assessment of atrophy, functional changes may accompany or even precede detectable structural alterations, in which case resting state functional connectivity (RSFC) could provide an alternative approach. The goal of this study was to determine whether language network RSFC is reduced in early-stage PPA when atrophy is not prominent. We identified 10 individuals with early-stage agrammatic variant of PPA with no prominent cortical thinning compared with nonaphasic controls. RSFC between 2 nodes of the language network and 2 nodes of the default mode network were compared between agrammatic variant of PPA and healthy control participants. Language network connectivity was comparable with controls among patients with milder agrammatism, but was significantly reduced in patients with more pronounced agrammatism. No group differences were observed in default mode network connectivity, demonstrating specificity of findings. In early stages of PPA when cortical atrophy is not prominent, RSFC provides an alternative method for probing the neuroanatomic substrates of language impairment. RSFC may be of particular utility in studies on early interventions for neurodegenerative disease, either to identify anatomic targets for intervention or as an outcome measure of therapeutic efficacy.