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Background: Increasing evidence suggests that TAR DNA-binding protein 43 (TDP-43) pathology in Alzheimer’s disease (AD), or AD-TDP, can be diffuse or limbic-predominant. Understanding whether diffuse AD-TDP has genetic, clinical, and pathological features that differ from limbic AD-TDP could have clinical and research implications. Objective: To better characterize the clinical and pathologic features of diffuse AD-TDP and differentiate it from limbic AD-TDP. Methods: 363 participants from the Mayo Clinic Study of Aging, Alzheimer’s Disease Research Center, and Neurodegenerative Research Group with autopsy confirmed AD and TDP-43 pathology were included. All underwent genetic, clinical, neuropsychologic, and neuropathologic evaluations. AD-TDP pathology distribution was assessed using the Josephs 6-stage scale. Stages 1–3 were classified as limbic, those 4–6 as diffuse. Multivariable logistic regression was used to identify clinicopathologic features that independently predicted diffuse pathology. Results: The cohort was 61% female and old at onset (median: 76 years [IQR:70–82]) and death (median: 88 years [IQR:82–92]). Fifty-four percent were limbic and 46% diffuse. Clinically, ∼10–20% increases in odds of being diffuse associated with 5-year increments in age at onset (p = 0.04), 1-year longer disease duration (p = 0.02), and higher Neuropsychiatric Inventory scores p = 0.03), while 15-s longer Trailmaking Test-B times (p = 0.02) and higher Block Design Test scores (p = 0.02) independently decreased the odds by 10–15%. There was evidence for association of APOE ɛ4 allele with limbic AD-TDP and of TMEM106B rs3173615C allele with diffuse AD-TDP. Pathologically, widespread amyloid-β plaques (Thal phases: 3–5) decreased the odds of diffuse TDP-43 pathology by 80–90%, while hippocampal sclerosis increased it sixfold (p

Purpose: The purpose of this study was to examine the interrater reliability and validity of the Apraxia of Speech Rating Scale (ASRS-3.5) as an index of the presence and severity of apraxia of speech (AOS) and the prominence of several of its important features. Method: Interrater reliability was assessed for 27 participants. Validity was examined in a cohort of 308 participants (120 with and 188 without progressive AOS) through item analysis; item-Total score correlations; correlations among ASRS Total score and component subscores and independent clinical ratings of AOS, dysarthria and aphasia severity, intelligibility, and articulatory errors, as well as years postonset and age; and regression models assessing item and Total score prediction of AOS presence. Results: Interrater reliability was good or excellent for most items and excellent for the Total score. Item and Total score analyses revealed good separation of participants with versus without AOS. Inter-item and item-Total score correlations were generally moderately high as were correlations between the ASRS Total score and independent ratings of AOS severity, intelligibility, and articulatory errors. The Total score was not meaningfully correlated with ratings of aphasia and dysarthria severity, years postonset, or age. Total scores below 7 and above 10 revealed excellent diagnostic sensitivity and specificity for AOS. The presence of eight or more abnormal features was also highly predictive of AOS presence. Conclusions: The ASRS-3.5 is a reliable and valid scale for identifying the presence and severity of AOS and its predominant features. It has excellent sensitivity to AOS presence and excellent specificity relative to aphasia and dysarthria in patients with neurodegenerative disease. Supplemental Material: https://doi.org/10.23641/asha.21817584

Purpose: The purpose of this study was to describe, compare, and understand speech modulation capabilities of patients with varying motor speech disorders (MSDs) in a paradigm in which patients made highly cued attempts to speak faster or slower. Method: Twenty-nine patients, 12 with apraxia of speech (AOS; four phonetic and eight prosodic subtype), eight with dysarthria (six hypokinetic and two spastic subtype), and nine patients without any neurogenic MSD completed a standard motor speech evaluation where they were asked to repeat words and sentences, which served as their “natural” speaking rate. They were then asked to repeat lower complexity (counting 1–5; repeating “cat” and “catnip” 3 times each) and higher complexity stimuli (repeating “catastrophe” and “stethoscope” 3 times each and “My physician wrote out a prescription” once) as fast/slow as possible. Word durations and interword intervals were measured. Linear mixed-effects models were used to assess differences related to MSD subtype and stimuli complexity on bidirectional rate modulation capacity as indexed by word duration and interword interval. Articulatory accuracy was also judged and compared. Results: Patients with prosodic AOS demonstrated a reduced ability to go faster; while they performed similarly to patients with spastic dysarthria when counting, patients with spastic dysarthria were able to increase rate similar to controls during sentence repetition; patients with prosodic AOS could not and made increased articulatory errors attempting to increase rate. AOS patients made more articulatory errors relative to other groups, regardless of condition; however, their percentage of errors reduced with an intentionally slowed speaking rate. Conclusions: The findings suggest comparative rate modulation abilities in conjunction with their impact on articulatory accuracy may support differential diagnosis between healthy and abnormal speech and among subtypes of MSDs (i.e., type of dysarthria or AOS). Findings need to be validated in a larger, more representative cohort encompassing several types of MSDs. Supplemental Material: https://doi.org/10.23641/asha.22044632

Purpose: Prior studies have shown that communication-related participation restrictions in patients with degenerative disease do not always match clinician judgment or objective indices of symptom severity. Although there is a growing body of literature documenting that discrepancies between patients with dementia and their care partners' perception of participation restrictions exist, it is not known how care partner perceptions of communication participation restrictions specifically match or diverge from the patients' experiences, which may inform the use of care partner proxy in the context of degenerative diseases. Method: Thirty-eight patients with progressive neurologic conditions (progressive supranuclear palsy, corticobasal syndrome, and primary progressive aphasia or apraxia of speech) and, in most instances, focal cognitive-communication disorders were included. The patients and their accompanying care partners independently completed the Communicative Participation Item Bank, short form, a 10-question survey about communication participation restrictions in different contexts. Care partners were instructed to complete the form with their perception of the patient's experience. The difference between patient and care partner total scores were calculated and analyzed relative to clinical and demographic variables of interest. Results: Care partner ratings modestly tracked with patient experience and objective indices of symptom severity but did not exactly match patient ratings. The presence of aphasia increased, but did not fully account for, the likelihood of a discrepancy between care partner and patient ratings. Conclusion: Although careful consideration should be given prior to using care-partner report as a proxy for patient experience, it is worthwhile to include care partner ratings as a means of supporting conversations about differing perceptions, guiding joint intervention planning, and monitoring care-partner perceptions of change along with the implementation of supported conversation strategies.

Primary progressive apraxia of speech (PPAOS) is a neurodegenerative motor speech disorder affecting the ability to produce speech. If agrammatic aphasia is present, it can be referred to as the non-fluent/agrammatic variant of primary progressive aphasia (nfvPPA). We investigated whether resting-state functional MRI (rs-fMRI) connectivity from disease ‘epicenters’ correlated with longitudinal grey matter atrophy and hypometabolism in nfvPPA and PPAOS. Eighteen nfvPPA and 23 PPAOS patients underwent clinical assessment, structural MRI, rs-fMRI, and [(18)F] fluorodeoxyglucose (FDG)-PET at baseline and ~2 years follow-up. Rates of neurodegeneration in nfvPPA and PPAOS correlated with functional connectivity to the premotor, motor, and frontal cortex. Connectivity to the caudate and thalamus was more strongly associated with rates of hypometabolism than atrophy. Connectivity to the left Broca’s area was more strongly associated with rates of atrophy and hypometabolism in nfvPPA. Finally, functional connectivity to a network of regions, and not to a single epicenter, correlated with rates of neurodegeneration in PPAOS and nfvPPA, suggesting similar biological mechanisms driving disease progression, with regional differences related to language.

This study was undertaken to assess cross-sectional and longitudinal [One hundred forty-three participants who had completed at least one flortaucipir PET and had autopsy-confirmed FTLD (n = 52) or high (n = 58) or low ADNC (n = 33) based on Braak neurofibrillary tangle stages 0-IV versus V-VI were included. Flortaucipir standard uptake value ratios (SUVRs) were calculated for 9 regions of interest (ROIs): an FTLD meta-ROI, midbrain, globus pallidum, an AD meta-ROI, entorhinal, inferior temporal, orbitofrontal, precentral, and medial parietal. Linear mixed effects models were used to compare mean baseline SUVRs and annual rate of change in SUVR by group. Sensitivity and specificity to distinguish FTLD from high and low ADNC were calculated.Baseline uptake in the FTLD meta-ROI, midbrain, and globus pallidus was greater in FTLD than high and low ADNC. No region showed a greater rate of flortaucipir accumulation in FTLD. Baseline uptake in the AD-related regions and orbitofrontal and precentral cortices was greater in high ADNC, and all showed greater rates of accumulation compared to FTLD. Baseline differences were superior to longitudinal rates in differentiating FTLD from high and low ADNC. A simple baseline metric of midbrain/inferior temporal ratio of flortaucipir uptake provided good to excellent differentiation between FTLD and high and low ADNC (sensitivities/specificities = 94%/95% and 71%/70%).There are cross-sectional and longitudinal differences in flortaucipir uptake between FTLD and high and low ADNC. However, optimum differentiation between FTLD and ADNC was achieved with baseline uptake rather than longitudinal rates. ANN NEUROL 2022;92:1016-1029.

Posterior cortical atrophy (PCA) and logopenic progressive aphasia (LPA) are clinical syndromes that commonly have underlying Alzheimer’s disease (AD), although non-AD pathologies have also been reported. PET imaging allows for identification of beta-amyloid (Aβ) and tau in AD, so we aimed to assess these in a large cohort to identify patients that do not have evidence for biomarker-defined AD. Eight-one patients, 47 PCA and 34 LPA, underwent extensive neurological and neuropsychological testing, [(11)C] Pittsburgh compound B, [(18)F] flortaucipir and [(18)F] fluorodeoxyglucose PETs. Global Aβ and tau-PET standardized uptake value ratios (SUVRs) were plotted for all patients and outliers, and patients with abnormally low SUVRs compared to the biomarker-classic cohort were identified. Six (7.4%) biomarker-outlier cases were identified, and three patterns were observed: i) negative/borderline Aβ-PET and striking widespread tau-PET uptake (two LPA); ii) negative/borderline Aβ-PET and low tau-PET uptake (three PCA) and iii) elevated Aβ-PET uptake but mild focal tau-PET uptake (one LPA). Among the unusual patients in group ii, two patients showed no abnormal tau uptake suggesting non-AD pathology, with one developing features of corticobasal syndrome and the other dementia with Lewy bodies. The remaining patient showed very mild focal tau uptake. This study demonstrates that a small minority (~8%) of PCA and LPA patients do not show the typical striking patterns of Aβ and tau PET uptake, with only 2% showing absence of both proteins. These findings will help inform the use of molecular PET in clinical treatment trials that include patients with atypical phenotypes of AD.

Background: The hippocampus and temporal lobe are atrophic in typical amnestic Alzheimer’s disease (tAD) and are used as imaging biomarkers in treatment trials. However, a better understanding of how temporal structures differ across atypical AD phenotypes and relate to cognition is needed. Objective: Our goal was to compare temporal lobe regions between tAD and two atypical AD phenotypes (logopenic progressive aphasia (LPA) and posterior cortical atrophy (PCA)), and assess cognitive associations. Methods: We age and gender-matched 77 tAD participants to 50 LPA and 27 PCA participants, all of which were amyloid-positive. We used linear mixed-effects models to compare FreeSurfer-derived hippocampal volumes and cortical thickness of entorhinal, inferior and middle temporal, and fusiform gyri, and to assess relationships between imaging and memory, naming, and visuospatial function across and within AD phenotype. Results: Hippocampal volume and entorhinal thickness were smaller bilaterally in tAD than LPA and PCA. PCA showed greater right inferior temporal and bilateral fusiform thinning and LPA showed greater left middle and inferior temporal and left fusiform thinning. Atypical AD phenotypes differed with greater right hemisphere thinning in PCA and greater left hemisphere thinning in LPA. Verbal and visual memory related most strongly to hippocampal volume; naming related to left temporal thickness; and visuospatial related to bilateral fusiform thickness. Fewer associations remained when examined within AD group. Conclusion: Atypical AD phenotypes are associated with greater thinning of lateral temporal structures, with relative sparing of medial temporal lobe, compared to tAD. These findings may have implications for future clinical trials in AD.

INTRODUCTION: Multiple system atrophy (MSA) typically presents with parkinsonism, ataxia and/or autonomic dysfunction. Occasionally, clinically atypical (ca-MSA) cases masquerade as progressive supranuclear palsy (PSP). We aimed to investigate whether different neuroimaging modalities could facilitate differentiation and whether histopathologic characteristics could explain the atypical presentation. METHODS: We identified 3 neuropathologically-defined ca-MSA patients with clinically diagnosed PSP who underwent various antemortem brain imaging: MRI and PET imaging using (11)C-Pittsburgh compound B, (18)F-flortaucipir, and (18)F-fluorodeoxyglucose. We compared clinical features, brainstem planimetry, and radiotracer standardized uptake value ratios in ca-MSA to 10 autopsy-confirmed PSP patients and 10 healthy controls (imaging only). We also compared histologic count of neuronal loss, iron deposition and α-synuclein-immunoreactive glial cytoplasmic inclusion burden to 10 autopsy-confirmed MSA-parkinsonism (MSA-P) cases. RESULTS: Ca-MSA had better PSP Saccadic Impairment Scale scores (p=0.003) and more frequent good levodopa response (p=0.061) than PSP. Ca-MSA showed higher midbrain-to-pons ratio and lower Magnetic Resonance Parkinsonism Index than PSP (each, p=0.036) and exhibited lower glucose metabolism in the putamen and globus pallidus versus PSP (p=0.017) and controls (p=0.007). These same regions showed higher flortaucipir uptake in ca-MSA than PSP (p=0.007 for putamen, p=0.049 for pallidum) and controls (p=0.012). Lower flortaucipir retention was observed in the subthalamic nucleus versus PSP (p=0.007). The putamen-to-subthalamic ratio distinguished ca-MSA from PSP. No histopathological differences were observed for ca-MSA versus typical MSA-P. CONCLUSION: Severity of saccadic impairment, levodopa responsiveness, MRI planimetric measurements, and different patterns of fluorodeoxyglucose and flortaucipir uptake can help improve antemortem differentiation of MSA masquerading as PSP from true PSP.

A 57-year-old man presented with dynamic aphasia with evolving agrammatism and anomia. Additionally, he exhibited emerging atypical parkinsonism and features of behavioral variant frontotemporal dementia. Insights pertinent to this complex clinical presentation are discussed.

Corticobasal syndrome (CBS) is a clinical syndrome characterised by progressive asymmetric limb rigidity and apraxia with dystonia, myoclonus, cortical sensory loss and alien limb phenomenon. Corticobasal degeneration (CBD) is one of the most common underlying pathologies of CBS, but other disorders, such as progressive supranuclear palsy (PSP), Alzheimer’s disease (AD) and frontotemporal lobar degeneration with TDP-43 inclusions, are also associated with this syndrome.In this review, we describe common and rare neuropathological findings in CBS, including tauopathies, synucleinopathies, TDP-43 proteinopathies, fused in sarcoma proteinopathy, prion disease (Creutzfeldt-Jakob disease) and cerebrovascular disease, based on a narrative review of the literature and clinicopathological studies from two brain banks. Genetic mutations associated with CBS, includingGRNandMAPT, are also reviewed. Clinicopathological studies on neurodegenerative disorders associated with CBS have shown that regardless of the underlying pathology, frontoparietal, as well as motor and premotor pathology is associated with CBS. Clinical features that can predict the underlying pathology of CBS remain unclear. Using AD-related biomarkers (ie, amyloid and tau positron emission tomography (PET) and fluid biomarkers), CBS caused by AD often can be differentiated from other causes of CBS. Tau PET may help distinguish AD from other tauopathies and non-tauopathies, but it remains challenging to differentiate non-AD tauopathies, especially PSP and CBD. Although the current clinical diagnostic criteria for CBS have suboptimal sensitivity and specificity, emerging biomarkers hold promise for future improvements in the diagnosis of underlying pathology in patients with CBS.

BACKGROUND: Parkinson’s disease (PD)-associated psychosis is a well-known non-motor complication, occurring years after diagnosis of PD. Incidence data vary across different studies highlighting a need for long-term observation and clinical definition. OBJECTIVE: To determine the incidence of psychosis in patients with PD and to investigate their survival in an incident cohort study from 1991–2010 in Olmsted County, MN. METHODS: We used the Rochester Epidemiology Project to define an incident-cohort study of parkinsonism (1991–2010) in Olmsted County, MN. A movement-disorder specialist reviewed the electronic medical records and applied diagnosis criteria to PD. Psychosis was diagnosed using of NINDS/NIMH unified criteria. RESULTS: We identified 669 cases of parkinsonism; 297 patients were clinically diagnosed with PD. 114/297 (38.4%) patients had evidence of psychosis (60% male); the median onset age of psychosis was 79.4 years. The incidence of Parkinson’s disease psychosis (PDP) was 4.28/100 person-years. PDP patients had a 71% increased risk of death compared to PD patients. In PD patients without psychosis, men had 73.4% increased risk of death compared to women, whereas no significant sex difference was observed among PDP men vs. women. Of 114 patients diagnosed with psychosis, 59 were treated with antipsychotics. There was no significant difference in survival between treated and untreated patients. CONCLUSION: PDP increased the odds of death compared to PD patients. Men with PD without psychosis had greater odds of death compared to women; however, in PD with psychosis the odds of death were comparable among sexes. Lastly, treatment with anti-psychotics did not significantly affect survival.

Posterior cortical atrophy (PCA) is one of the atypical Alzheimer's disease variants, characterized by predominant visuospatial and visuoperceptual deficits, with established dorsal and ventral subtypes. A third primary occipital (caudal) variant has been suggested. We aimed to determine its demographics, clinical manifestations, and biomarker findings.Fifty-two PCA patients were investigated. Patients underwent neuropsychological assessment, magnetic resonance imaging, and fluorodeoxyglucose (FDG)-, amyloid-, and tau-positron emission tomography (tau-PET) scans. Normalized regional FDG-PET values were represented as z-scores relative to a control population. Patients were divided into "primary occipital" and "other PCA" subgroups according to FDG-PET-defined criteria, with primary occipital defined as patients in which the z-scores for occipital subregions were at least one standard deviation lower (SD) (i.e., more abnormal) than the z-scores in all other brain regions. Global amyloid-PET, temporo-parietal FDG-PET, and temporal tau-PET regions-of-interest (ROIs) were calculated.Nine patients were classified as primary occipital; they were older (p = 0.034) and had more years of education (p = 0.007) than other PCA patients. The primary occipital group performed worse on the Ishihara test for color perception (p 0.001), while other PCA patients performed worse on the Western Aphasia Battery (WAB) praxis scale (p = 0.005). Overall neuropsychiatric symptom burden was lower in the primary occipital group (p 0.001). The FDG-PET meta-ROI was higher in the primary occipital subtype (p = 0.006), but no differences were observed in amyloid- and tau-PET.Our findings suggest that primary occipital PCA is characterized by an older age at onset, more color perception dysfunction, less severe ideomotor apraxia, and less hypometabolism in temporo-parietal meta-ROI compared to established phenotypes.

BackgroundPick’s disease (PiD) is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. PiD is pathologically defined by argyrophilic inclusion Pick bodies and ballooned neurons in the frontal and temporal brain lobes. PiD is characterised by the presence of Pick bodies which are formed from aggregated, hyperphosphorylated, 3-repeat tau proteins, encoded by theMAPTgene. TheMAPTH2 haplotype has consistently been associated with a decreased disease risk of the 4-repeat tauopathies of progressive supranuclear palsy and corticobasal degeneration, however its role in susceptibility to PiD is unclear. The primary aim of this study was to evaluate the association betweenMAPTH2 and risk of PiD.MethodsWe established the Pick’s disease International Consortium (PIC) and collected 338 (60.7% male) pathologically confirmed PiD brains from 39 sites worldwide. 1,312 neurologically healthy clinical controls were recruited from Mayo Clinic Jacksonville, FL (N=881) or Rochester, MN (N=431). For the primary analysis, subjects were directly genotyped forMAPTH1-H2 haplotype-defining variant rs8070723. In secondary analysis, we genotyped and constructed the six-variantMAPTH1 subhaplotypes (rs1467967, rs242557, rs3785883, rs2471738, rs8070723, and rs7521).FindingsOur primary analysis found that theMAPTH2 haplotype was associated with increased risk of PiD (OR: 1.35, 95% CI: 1.12-1.64 P=0.002). In secondary analysis involving H1 subhaplotypes, a protective association with PiD was observed for the H1f haplotype (0.0% vs. 1.2%, P=0.049), with a similar trend noted for H1b (OR: 0.76, 95% CI: 0.58-1.00, P=0.051). The 4-repeat tauopathy risk haplotypeMAPTH1c was not associated with PiD susceptibility (OR: 0.93, 95% CI: 0.70-1.25, P=0.65).InterpretationThe PIC represents the first opportunity to perform relatively large-scale studies to enhance our understanding of the pathobiology of PiD. This study demonstrates that in contrast to its protective role in 4R tauopathies, theMAPTH2 haplotype is associated with an increased risk of PiD. This finding is critical in directing isoform-related therapeutics for tauopathies.FundingSee funding section

In the context of Alzheimer disease phenotypes, patients may present with symptoms and signs that do not exclusively fit into one of the existing phenotypic categories, which often delays timely diagnosis and initiation of services to optimize patient awareness and coping.A 74-year-old woman presented with the complaint of progressive word-finding difficulty, raising our suspicion for primary progressive aphasia. Clinical evaluations, however, also revealed emerging cortical visual deficits consistent with posterior cortical atrophy. During evaluation 1 year later, Gerstmann syndrome was evident. Her in vivo neuroimaging was positive for beta-amyloid and tau biomarkers of Alzheimer disease pathology.In addition to contributing to the literature on the heterogeneity of the clinical manifestations of Alzheimer disease, this report highlights that a breakdown in the visual-lexical interface can account for anomia in posterior cortical atrophy at least in some cases. Other relevant clinical insights pertinent to this case are discussed.

Introduction: Progressive agrammatic aphasia (PAA) can be associated with abnormal behaviors; however, it is unknown whether behaviors occur and/or are different in patients with primary progressive apraxia of speech (PPAOS). We aimed to compare baseline and longitudinal behavioral symptomatology between PPAOS, patients with PAA, and patients with both apraxia of speech and PAA (AOS-PAA). Methods: We recruited 89 patients for this study, 40 with PPAOS, 11 with PAA, and 38 with AOS-PAA. Behavioral disturbances were evaluated using the frontal behavior inventory (FBI) which was also split into negative behaviors and disinhibition, and the 20-item behavioral assessment scale (20-BAS). Data analysis was performed using linear regression and linear mixed models. Results: Of the 89 patients in the study, 54% were women and the mean age at onset was 68 years. All patients, regardless of diagnosis, endorsed at least one symptom on the FBI at baseline, most frequently verbal apraxia (100%), logopenia (95.6%), irritability (55.9%), and apathy (42.6%). On the 20-BAS, 47.6% of the patients endorsed at least one symptom, most commonly “crying more easily” (19.5%) and personality change (18.3%). PPAOS was the least behaviorally affected group, with differences between PPAOS and AOS-PAA mainly driven by negative behaviors as opposed to disinhibition for PPAOS and PAA. The behavioral metrics showed average sensitivity and specificity to distinguish between groups. Behavioral disturbances worsened over time although rate of behavioral change across groups was similar. Conclusion: Behavioral disturbances are more common and severe in patients with agrammatic aphasia with or without AOS compared to patients with isolated apraxia of speech.

Background and ObjectivesMRI connectomics is an ideal tool to test a network-based model of pathologic propagation from a disease epicenter in neurodegenerative disorders. In this study, we used a novel graph theory-based MRI paradigm to explore functional connectivity reorganization, discerning between direct and indirect connections from disease epicenters, and its relationship with neurodegeneration across clinical presentations of the frontotemporal dementia (FTD) spectrum, including behavioral variant of FTD (bvFTD), nonfluent variant of primary progressive aphasia (nfvPPA), and semantic variant of primary progressive aphasia (svPPA).MethodsIn this observational cross-sectional study, disease epicenters were defined as the peaks of atrophy of a cohort of patients with high confidence of frontotemporal lobar degeneration pathology (Mayo Clinic). These were used as seed regions for stepwise functional connectivity (SFC) analyses in an independent (Milan) set of patients with FTD to assess connectivity in regions directly and indirectly connected to the epicenters. Correlations between SFC architecture in healthy conditions and atrophy patterns in patients with FTD were also tested.ResultsAs defined by comparing the 42 Mayo Clinic patients with 15 controls, disease epicenters were the left anterior insula for bvFTD, left supplementary motor area for nfvPPA, and left inferior temporal gyrus (ITG) for svPPA. Compared with 94 age-matched controls, patients with bvFTD (n = 64) and nfvPPA (n = 34) of the Milan cohort showed widespread decreased SFC in bilateral cortical regions with direct/indirect connections with epicenters and increased SFC either in directly connected regions, physically close to the respective seed region, or in more distant cortical/cerebellar areas with indirect connections. Across all link steps, svPPA (n = 36) showed SFC decrease mostly within the temporal lobes, with co-occurrent SFC increase in cerebellar regions at indirect link steps. The average stepwise topological distance from the left ITG in a reference group of 50 young healthy controls correlated with regional gray matter volume in svPPA, consistent with network-based degeneration.DiscussionOur findings demonstrate that each FTD syndrome is associated with a characteristic interplay of decreased and increased functional connectivity with the disease epicenter, affecting both direct and indirect connections. SFC revealed novel insights regarding the topology of functional disconnection across FTD syndromes, holding the promise to be used to model disease progression in future longitudinal studies.

Prior studies have shown communication-related participation restrictions in patients with degenerative disease do not always match clinician judgment of symptom severity. Relatedly, there is a growing body of literature documenting discrepancies between patients with dementia and care partner perception of participation restrictions. However, it is not known how care partner perceptions of communication participation restrictions match or diverge from the patient's experience, which was the topic of this study. Toward that end, 28 patients with apraxia of speech and/or dysarthria associated with primary progressive apraxia of speech, nonfluent/agrammatic primary progressive aphasia, or progressive supranuclear palsy, all types of frontotemporal dementia, were seen for speech-language examinations. The patients and their care partners were asked to independently complete the Communication Participation Item Bank (CPIB), short form, which is a 10-question survey about communication in different contexts; higher scores reflect less interference from their condition on communication. Care partners were instructed to complete the form with their perception of the patient's restrictions. The total CPIB score (maximum 30) and difference scores were calculated and visualized. The data (Figure) suggest mismatches exist in care partner and patient ratings of communication participation restrictions. Of 28 patients, only 1 pair had identical scores, each rating severe interference in all communication contexts. 57% of patients rated communication as less impacted (higher scores) compared to their family member, leaving 39% of family members rating communication as less impacted than their loved one's perception. This study lays the foundation for future research to include patient and care partner ratings when examining the benefit of impairment-based therapy, utilization of compensatory speech strategies, effectiveness of such strategies, and impact of other augmentative or alternative means of communication. The CPIB may be useful to document reduced psychosocial impact of disease and diminished burden and burnout on care partners with different intervention options. Future studies will explore possible differences between FTD phenotypes and, more specifically, whether 1) the motor speech disorder (MSD) disorder is primary or secondary to other motor impairment, 2) the nature or severity of the MSD, or 3) concomitant cognitive-communication impairment predict the existence of and/or direction of a discrepancy.

Alzheimer's disease (AD) patients ≥70 years show smaller medial temporal volumes despite lessSeventy-seven participants with flortaucipir-PET and volumetric magnetic resonance imaging underwent postmortem AD and TDP-43 pathology assessments. Bivariate-response linear regression estimated the effect of age and TDP-43 pathology on volume and/or flortaucipir standardized uptake volume ratios of the hippocampus, amygdala, entorhinal, inferior temporal, and midfrontal cortices.Older participants had lower hippocampal volumes and overall flortaucipir uptake. TDP-43-immunoreactivity correlated with reduced medial temporal volumes but was unrelated to flortaucipir uptake. TDP-43 effect size was consistent across the age spectrum. However, at older ages, the cohort mean volumes moved toward those of TDP-43-positives, reflecting the increasing TDP-43 pathology frequency with age.TDP-43 pathology is a relevant contributor driving the volume-uptake mismatch in older AD participants.TDP-43 pathology affects medial temporal volume loss but not tau radiotracer uptake. Greater TDP-43 pathology effect is seen in old age due to its increasing frequency. TDP-43 pathology is a relevant driver of the volume-uptake mismatch in old AD patients.

BACKGROUND: Globular glial tauopathy (GGT) has been associated with frontotemporal dementia syndromes; little is known about the clinical and imaging characteristics of GGT and how they differ from other non-globular glial 4-repeat tauopathies (N4GT) such as progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD). METHODS: For this case-control study the Mayo Clinic brain banks were queried for all cases with an autopsy-confirmed diagnosis of GGT between 01/01/2011 and 31/10/2021. Fifty patients with N4GT (30 PSP, 20 CBD) were prospectively recruited and followed at Mayo Clinic, Minnesota. MR imaging was used to characterize patterns of gray/white matter atrophy, MR-parkinsonism index, midbrain volume, and white matter hyperintensities.(18)F-Fluorodeoxyglucose-, (11)C Pittsburg compound-, and (18)F-flortaucipir-PET scans were reviewed. RESULTS: Twelve patients with GGT were identified: 83% were women compared to 42% in NG4T (P=0.02) with median age at death 76.5 years (range: 55–87). The most frequent clinical features were eye movement abnormalities, parkinsonism, behavioral changes, cognitive impairment followed by pyramidal tract signs and speech abnormalities. Lower motor neuron involvement was present in 17% and distinguished GGT from NG4T, P=0.035. Primary progressive apraxia of speech was the most frequent initial diagnosis (25%); 50% had a Parkinson-plus syndrome before death. Most GGT patients had asymmetric frontotemporal atrophy with matching hypometabolism. GGT patients had more gray matter atrophy in temporal lobes, normal MR-parkinsonism index, and larger midbrain volumes. CONCLUSIONS: Female sex, lower motor neuron involvement in the context of a frontotemporal dementia syndrome and asymmetric brain atrophy with preserved midbrain might be suggestive of underlying GGT.

Background: Dementia, vascular disease, and cancer increase with age, enabling complex comorbid interactions. Understanding vascular and cancer contributions to dementia risk and neuropathology in oldest-old may improve risk modification and outcomes. Objective: Investigate the contributions of vascular factors and cancer to dementia and neuropathology. Methods: Longitudinal clinicopathologic study of prospectively followed Mayo Clinic participants dying≥95 years-old who underwent autopsy. Participants were stratified by dementia status and compared according to demographics, vascular risk factors, cancer, and neuropathology. Results: Participants (n = 161; 83% female; 99% non-Hispanic whites)≥95 years (95–106 years-old) with/without dementia did not differ based on demographics. APOE ɛ2 frequency was higher in no dementia (20/72 [28%]) versus dementia (11/88 [12%]; p = 0.03), but APOE ɛ4 frequency did not differ. Coronary artery disease was more frequent in no dementia (31/72 [43%]) versus dementia (23/89 [26%]; p = 0.03) associated with 56% lower dementia odds (odds ratio [OR] = 0.44 [confidence interval (CI) = 0.19–0.98]; p = 0.04) and fewer neuritic/diffuse plaques. Diabetes had an 8-fold increase in dementia odds (OR = 8.42 [CI = 1.39–163]; p = 0.02). Diabetes associated with higher cerebrovascular disease (Dickson score; p = 0.05). Cancer associated with 63% lower dementia odds (OR = 0.37 [CI = 0.17–0.78]; p

Background and ObjectivesThe aims of this work were to compare rates of longitudinal change in neurologic and neuropsychological test performance between the logopenic progressive aphasia (LPA) and posterior cortical atrophy (PCA) variants of atypical Alzheimer disease (AD) and to use unbiased principal component analysis to assess heterogeneity in patterns of change and relationships to demographics and concurrent brain atrophy.MethodsPatients with PCA or LPA who were positive for amyloid and tau AD biomarkers and had undergone serial neurologic and neuropsychological assessments and structural MRI were identified. Rates of change in 13 clinical measures were compared between groups in a case-control design, and principal component analysis was used to assess patterns of clinical change unbiased by clinical phenotype. Components were correlated with rates of regional brain atrophy with tensor-based morphometry.ResultsTwenty-eight patients with PCA and 27 patients with LPA were identified. Those with LPA showed worse baseline performance and faster rates of decline in naming, repetition, and working memory, as well as faster rates of decline in verbal episodic memory, compared to those with PCA. Conversely, patients with PCA showed worse baseline performance in tests of visuospatial and perceptual function and on the Clinical Dementia Rating Scale and faster rates of decline in visuoperceptual function compared to those with LPA. Principal component analysis showed that patterns of clinical decline were highly heterogeneous across the cohort, with 10 principal components required to explain >90% of the variance. The first principal component reflected overall severity, with higher scores in LPA than PCA reflecting faster decline in LPA, and was related to left temporoparietal atrophy. The second and third principal components were not related to clinical phenotype but showed some relationship to regional atrophy. No relationships were identified between the principal components and age, sex, disease duration, amyloid PET findings, or apolipoprotein genotype.DiscussionLongitudinal patterns of clinical decline differ between LPA and PCA but are heterogeneous and related to different patterns of topographic spread. PCA is associated with a more slowly progressive course than LPA.

Apolipoprotein E (APOE) ε4 is an important genetic risk factor for typical Alzheimer's disease (AD), influencing brain volume and tau burden. Little is known about its influence in atypical presentations of AD.An atypical AD cohort of 140 patients diagnosed with either posterior cortical atrophy or logopenic progressive aphasia underwent magnetic resonance imaging and positron emission tomography. Linear mixed effects models were fit to assess the influence of APOE ε4 on cross-sectional and longitudinal regional metrics.At baseline, APOE ε4 carriers had smaller hippocampal and amygdala volumes and greater tau standardized uptake volume ratio in the hippocampus and entorhinal cortex compared to non-carriers while longitudinally, APOE ε4 non-carriers showed faster rates of atrophy and tau accumulation in the entorhinal cortex, with faster tau accumulation in the hippocampus.APOE ε4 influences patterns of neurodegeneration and tau deposition and was associated with more medial temporal involvement, although there is evidence that non-carriers may be catching up over time.

Frontotemporal lobar degeneration (FTLD) with TDP-43-immunoreactive inclusions (FTLD-TDP) is a neurodegenerative disease associated with clinical, genetic, and neuropathological heterogeneity. An association between TDP-43, FTLD and amyotrophic lateral sclerosis (ALS) was first described in 2006. However, a century before immunohistochemistry existed, atypical dementias displaying behavioral, language and/or pyramidal symptoms and showing non-specific FTLD with superficial cortical neuronal loss, gliosis and spongiosis were often confused with Alzheimer's or Pick's disease. Initially this pathology was termed dementia lacking distinctive histopathology (DLDH), but this was later renamed when ubiquitinated inclusions originally found in ALS were also discovered in (DLDH), thus warranting a recategorization as FTLD-U (ubiquitin). Finally, the ubiquitinated protein was identified as TDP-43, which aggregates in cortical, subcortical, limbic and brainstem neurons and glial cells. The topography and morphology of TDP-43 inclusions associate with specific clinical syndromes and genetic mutations which implies different pathomechanisms that are yet to be discovered; hence, the TDP-43 journey has actually just begun. In this review, we describe how FTLD-TDP was established and defined clinically and neuropathologically throughout the past century.

Primary four-repeat tauopathies are characterized by depositions of the four-repeat isoform of the microtubule binding protein, tau. The two most common sporadic four-repeat tauopathies are progressive supranuclear palsy and corticobasal degeneration. Because tau PET tracers exhibit poor binding affinity to four-repeat pathology, determining how well in vivo MRI findings relate to underlying pathology is critical to evaluating their utility as surrogate markers to aid in diagnosis and as outcome measures for clinical trials. We studied the relationship of cross-sectional imaging findings, such as MRI volume loss and diffusion tensor imaging white matter tract abnormalities, to tau histopathology in four-repeat tauopathies. Forty-seven patients with antemortem 3 T MRI volumetric and diffusion tensor imaging scans plus post-mortem pathological diagnosis of a four-repeat tauopathy (28 progressive supranuclear palsy; 19 corticobasal degeneration) were included in the study. Tau lesion types (pretangles/neurofibrillary tangles, neuropil threads, coiled bodies, astrocytic lesions) were semiquantitatively graded in disease-specific cortical, subcortical and brainstem regions. Antemortem regional volumes, fractional anisotropy and mean diffusivity were modelled using linear regression with post-mortem tau lesion scores considered separately, based on cellular type (neuronal versus glial), or summed (total tau). Results showed that greater total tau burden was associated with volume loss in the subthalamic nucleus (P = 0.001), midbrain (P

Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) is a complex heterogeneous neurodegenerative disorder for which mechanisms are poorly understood. To explore transcriptional changes underlying FTLD-TDP, we performed RNA-sequencing on 66 genetically unexplained FTLD-TDP patients, 24 FTLD-TDP patients with GRN mutations and 24 control participants. Using principal component analysis, hierarchical clustering, differential expression and coexpression network analyses, we showed that GRN mutation carriers and FTLD-TDP-A patients without a known mutation shared a common transcriptional signature that is independent of GRN loss-of-function. After combining both groups, differential expression as compared to the control group and coexpression analyses revealed alteration of processes related to immune response, synaptic transmission, RNA metabolism, angiogenesis and vesicle-mediated transport. Deconvolution of the data highlighted strong cellular alterations that were similar in FTLD-TDP-A and GRN mutation carriers with NSF as a potentially important player in both groups. We propose several potentially druggable pathways such as the GABAergic, GDNF and sphingolipid pathways. Our findings underline new disease mechanisms and strongly suggest that affected pathways in GRN mutation carriers extend beyond GRN and contribute to genetically unexplained forms of FTLD-TDP-A.

Transactive response DNA-binding protein of ∼43 kDa (TDP-43), a primary pathologic substrate in tau-negative frontotemporal lobar degeneration (FTLD), is also often found in the brains of elderly individuals without FTLD and is a key player in the process of neurodegeneration in brains with and without FTLD. It is unknown how rates and trajectories of TDP-43-associated brain atrophy compare between these two groups. Additionally, non-FTLD TDP-43 inclusions are not homogeneous and can be divided into two morphologic types: type-α and neurofibrillary tangle-associated type-β. Therefore, we explored whether neurodegeneration also varies due to the morphologic type. In this longitudinal retrospective study of 293 patients with 843 MRI scans spanning over ∼10 years, we used a Bayesian hierarchical linear model to quantify similarities and differences between the non-FTLD TDP-43 (type-α/type-β) and FTLD-TDP (n = 68) in both regional volume at various timepoints before death and annualized rate of atrophy. Since Alzheimer's disease (AD) is a frequent co-pathology in non-FTLD TDP-43, we further divided types α/β based on presence/absence of intermediate-high likelihood AD: AD-TDP type-β (n = 90), AD-TDP type-α (n = 104), and Pure-TDP (n = 31, all type-α). FTLD-TDP was associated with faster atrophy rates in the inferior temporal lobe and temporal pole compared to all non-FTLD TDP-43 groups. The atrophy rate in the frontal lobe was modulated by age with younger FTLD-TDP having the fastest rates. Older FTLD-TDP showed a limbic predominant pattern of neurodegeneration. AD-TDP type-α showed faster rates of hippocampal atrophy and smaller volumes of amygdala, temporal pole, and inferior temporal lobe compared to AD-TDP type-β. Pure-TDP was associated with slowest rates and less atrophy in all brain regions. The results suggest that there are differences and similarities in longitudinal brain volume loss between FTLD-TDP and non-FTLD TDP-43. Within FTLD-TDP age plays a role in which brain regions are the most affected. Additionally, brain atrophy regional rates also vary by non-FTLD TDP-43 type.