Incidence of Primary Progressive Apraxia of Speech and Primary Progressive Aphasia in Olmsted County, MN, 2011-2022.

BACKGROUND AND OBJECTIVE: No epidemiologic studies have formally assessed the incidence of primary progressive aphasia (PPA) and primary progressive apraxia of speech (PPAOS). Thus, we decided to assess the incidence of these disorders in Olmsted County, MN, between 2011 and 2022, and to characterize clinical, radiographic, and pathologic characteristics of these patients. METHODS: This was a retrospective examination of data from a population-based cohort of patients with PPA and PPAOS prospectively identified in Olmsted County, MN, from 2011 to 2022. The incidence of PPA among adults (older than 18 years) was calculated for Olmsted County as the number of patients per 100,000 person-years during the study period. The adult population of Olmsted County was determined by the annual catchment population reported by the Rochester Epidemiological Project for each year 2011-2022. A behavioral neurologist verified the clinical diagnoses and determined subtypes. RESULTS: We identified 10 patients (60% female) within the study period (median age of symptoms onset: 70 years; range: 66-73), 8 with PPA and 2 with PPAOS. Of the 8 patients with PPA (6 female patients, 2 male patients), 2 met criteria for non-fluent variant PPA (nfvPPA), 3 for logopenic variant PPA (lvPPA), and 3 for semantic variant (svPPA). Speech evaluation confirmed the clinical diagnoses in all patients and all showed typical imaging findings consistent with their respective subtype. Six patients (2 PPAOS, 2 nfvPPA, 2 lvPPA) died and 3 underwent autopsy (2 PPAOS, 1 nfvPPA), confirming the pathologic diagnosis of progressive supranuclear palsy. The incidence of PPA + PPAOS was 0.70 persons per 100,000 person-years (95% CI 0.34-1.29 persons per 100,000) during the study period. The incidence of PPAOS was 0.14 persons per 100,000 person-years (95% CI 0.02-0.55 persons per 100,000), whereas for the 8 patients with PPA, the incidence was 0.56 persons per 100,000 person-years (95% CI 0.24-1.10 cases per 100,000). The incidence of nfvPPA was 0.14 persons per 100,000 person-years (95% CI 0.02-0.55), 0.21 persons per 100,000 person-years (95% CI 0.04-0.61) for lvPPA, and 0.21 persons per 100,000 person-years (95% CI 0.04-0.61) for svPPA. DISCUSSION: As a group, PPA and PPAOS are a relatively rare group of diseases. PPAOS has a slightly lower incidence than PPA as a group but similar incidence to the individual PPA variants.

Clinicopathologic and Neuroimaging Correlations of Nonverbal Oral Apraxia in Patients With Neurodegenerative Disease.

BACKGROUND AND OBJECTIVES: Nonverbal oral apraxia (NVOA) is the inability to plan, sequence, and execute voluntary oromotor movements in the absence of weakness. In the context of neurodegenerative disease, it remains unclear whether it is linked to a specific underlying pathologic, clinical, or neuroimaging finding. Thus, we aimed to assess the clinicopathologic and neuroimaging associations of NVOA. METHODS: We conducted a retrospective study of autopsy-confirmed patients previously assessed through an NVOA evaluation tool with a previously published cutpoint to screen for NVOA. We compared demographic and clinical characteristics and postmortem pathology between those who developed NVOA and those who did not. We also compared clinicopathologic characteristics in mild vs greater than mild NVOA and early vs late-emerging NVOA. SPM12 was used to assess patterns of gray matter loss in NVOA vs non-NVOA with age and sex included as covariates. RESULTS: A total of 104 patients (median age at symptom onset 63 years, 43% female) were included in the study. 63 (60.6%) developed NVOA. NVOA appeared at a median of 4.3 years from symptom onset. 29% developed NVOA within the first 3 years. Primary progressive apraxia of speech and the nonfluent variant of primary progressive aphasia were the most common baseline diagnoses in the NVOA group while progressive supranuclear palsy (PSP) syndrome and logopenic progressive aphasia (LPA) were the most common in patients without NVOA. Atrophy of the left lateral and medial posterior frontal cortex was related to NVOA. The most common pathologies associated with NVOA were PSP (36.5%) and corticobasal degeneration (CBD) (33.3%). In patients without NVOA, PSP (26.8%) and other pathologies (26.8%) were the most frequent. 11% of patients with NVOA had persistently mild NVOA and were more likely to have baseline diagnoses of LPA, PSP syndrome, or semantic dementia. The most frequent pathologies in this group were Alzheimer disease and PSP. The pathologic associations of greater than mild NVOA were CBD and PSP. DISCUSSION: NVOA is present in several clinical syndromes. It is most associated with PSP and CBD. NVOA is a manifestation of left lateral and medial posterior frontal cortex damage rather than a particular pathology.

Patterns of brain volume and metabolism predict clinical features in the progressive supranuclear palsy spectrum.

Progressive supranuclear palsy (PSP) is a neurodegenerative tauopathy that presents with highly heterogenous clinical syndromes. We perform cross-sectional data-driven discovery of independent patterns of brain atrophy and hypometabolism across the entire PSP spectrum. We then use these patterns to predict specific clinical features and to assess their relationship to phenotypic heterogeneity. We included 111 patients with PSP (60 with Richardson syndrome and 51 with cortical and subcortical variant subtypes). Ninety-one were used as the training set and 20 as a test set. The presence and severity of granular clinical variables such as postural instability, parkinsonism, apraxia and supranuclear gaze palsy were noted. Domains of akinesia, ocular motor impairment, postural instability and cognitive dysfunction as defined by the Movement Disorders Society criteria for PSP were also recorded. Non-negative matrix factorization was used on cross-sectional MRI and fluorodeoxyglucose-positron emission tomography (FDG-PET) scans. Independent models for each as well as a combined model for MRI and FDG-PET were developed and used to predict the granular clinical variables. Both MRI and FDG-PET were better at predicting presence of a symptom than severity, suggesting identification of disease state may be more robust than disease stage. FDG-PET predicted predominantly cortical abnormalities better than MRI such as ideomotor apraxia, apraxia of speech and frontal dysexecutive syndrome. MRI demonstrated prediction of cortical and more so sub-cortical abnormalities, such as parkinsonism. Distinct neuroanatomical foci were predictive in MRI- and FDG-PET-based models. For example, vertical gaze palsy was predicted by midbrain atrophy on MRI, but frontal eye field hypometabolism on FDG-PET. Findings also differed by scale or instrument used. For example, prediction of ocular motor abnormalities using the PSP Saccadic Impairment Scale was stronger than with the Movement Disorders Society Diagnostic criteria for PSP oculomotor impairment designation. Combination of MRI and FDG-PET demonstrated enhanced detection of parkinsonism and frontal syndrome presence and apraxia, cognitive impairment and bradykinesia severity. Both MRI and FDG-PET patterns were able to predict some measures in the test set; however, prediction of global cognition measured by Montreal Cognitive Assessment was the strongest. MRI predictions generalized more robustly to the test set. PSP leads to neurodegeneration in motor, cognitive and ocular motor networks at cortical and subcortical foci, leading to diverse yet overlapping clinical syndromes. To advance understanding of phenotypic heterogeneity in PSP, it is essential to consider data-driven approaches to clinical neuroimaging analyses.

Deciphering Distinct Genetic Risk Factors for FTLD-TDP Pathological Subtypes via Whole-Genome Sequencing.

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) is a fatal neurodegenerative disorder with only a limited number of risk loci identified. We report our comprehensive genome-wide association study as part of the International FTLD-TDP Whole-Genome Sequencing Consortium, including 985 cases and 3,153 controls, and meta-analysis with the Dementia-seq cohort, compiled from 26 institutions/brain banks in the United States, Europe and Australia. We confirm UNC13A as the strongest overall FTLD-TDP risk factor and identify TNIP1 as a novel FTLD-TDP risk factor. In subgroup analyses, we further identify for the first time genome-wide significant loci specific to each of the three main FTLD-TDP pathological subtypes (A, B and C), as well as enrichment of risk loci in distinct tissues, brain regions, and neuronal subtypes, suggesting distinct disease aetiologies in each of the subtypes. Rare variant analysis confirmed TBK1 and identified VIPR1 , RBPJL , and L3MBTL1 as novel subtype specific FTLD-TDP risk genes, further highlighting the role of innate and adaptive immunity and notch signalling pathway in FTLD-TDP, with potential diagnostic and novel therapeutic implications.

Clinical recognition of frontotemporal dementia with right anterior temporal predominance: A multicenter retrospective cohort study.

INTRODUCTION: Although frontotemporal dementia (FTD) with right anterior temporal lobe (RATL) predominance has been recognized, a uniform description of the syndrome is still missing. This multicenter study aims to establish a cohesive clinical phenotype. METHODS: Retrospective clinical data from 18 centers across 12 countries yielded 360 FTD patients with predominant RATL atrophy through initial neuroimaging assessments. RESULTS: Common symptoms included mental rigidity/preoccupations (78%), disinhibition/socially inappropriate behavior (74%), naming/word-finding difficulties (70%), memory deficits (67%), apathy (65%), loss of empathy (65%), and face-recognition deficits (60%). Real-life examples unveiled impairments regarding landmarks, smells, sounds, tastes, and bodily sensations (74%). Cognitive test scores indicated deficits in emotion, people, social interactions, and visual semantics however, lacked objective assessments for mental rigidity and preoccupations. DISCUSSION: This study cumulates the largest RATL cohort unveiling unique RATL symptoms subdued in prior diagnostic guidelines. Our novel approach, combining real-life examples with cognitive tests, offers clinicians a comprehensive toolkit for managing these patients. HIGHLIGHTS: This project is the first international collaboration and largest reported cohort. Further efforts are warranted for precise nomenclature reflecting neural mechanisms. Our results will serve as a clinical guideline for early and accurate diagnoses.

Speech-language within and between network disruptions in primary progressive aphasia variants.

Primary progressive aphasia (PPA) variants present with distinct disruptions in speech-language functions with little known about the interplay between affected and spared regions within the speech-language network and their interaction with other functional networks. The Neurodegenerative Research Group, Mayo Clinic, recruited 123 patients with PPA (55 logopenic (lvPPA), 44 non-fluent (nfvPPA) and 24 semantic (svPPA)) who were matched to 60 healthy controls. We investigated functional connectivity disruptions between regions within the left-speech-language network (Broca, Wernicke, anterior middle temporal gyrus (aMTG), supplementary motor area (SMA), planum temporale (PT) and parietal operculum (PO)), and disruptions to other networks (visual association, dorsal-attention, frontoparietal and default mode networks (DMN)). Within the speech-language network, multivariate linear regression models showed reduced aMTG-Broca connectivity in all variants, with lvPPA and nfvPPA findings remaining significant after Bonferroni correction. Additional loss in Wernicke-Broca connectivity in nfvPPA, Wernicke-PT connectivity in lvPPA and greater aMTG-PT connectivity in svPPA were also noted. Between-network connectivity findings in all variants showed reduced aMTG-DMN and increased aMTG-dorsal-attention connectivity, with additional disruptions between aMTG-visual association in both lvPPA and svPPA, aMTG-frontoparietal in lvPPA, and Wernicke-DMN breakdown in svPPA. These findings suggest that aMTG connectivity breakdown is a shared feature in all PPA variants, with lvPPA showing more extensive connectivity disruptions with other networks.

Flortaucipir PET uncovers relationships between tau and amyloid-ß in primary age-related tauopathy and Alzheimer's disease.

[18F]-Flortaucipir positron emission tomography (PET) is considered a good biomarker of Alzheimer's disease. However, it is unknown how flortaucipir is associated with the distribution of tau across brain regions and how these associations are influenced by amyloid-ß. It is also unclear whether flortaucipir can detect tau in definite primary age-related tauopathy (PART). We identified 248 individuals at Mayo Clinic who had undergone [18F]-flortaucipir PET during life, had died, and had undergone an autopsy, 239 cases of which also had amyloid-ß PET. We assessed nonlinear relationships between flortaucipir uptake in nine medial temporal and cortical regions, Braak tau stage, and Thal amyloid-ß phase using generalized additive models. We found that flortaucipir uptake was greater with increasing tau stage in all regions. Increased uptake at low tau stages in medial temporal regions was only observed in cases with a high amyloid-ß phase. Flortaucipir uptake linearly increased with the amyloid-ß phase in medial temporal and cortical regions. The highest flortaucipir uptake occurred with high Alzheimer's disease neuropathologic change (ADNC) scores, followed by low-intermediate ADNC scores, then PART, with the entorhinal cortex providing the best differentiation between groups. Flortaucipir PET had limited ability to detect PART, and imaging-defined PART did not correspond with pathologically defined PART. In summary, spatial patterns of flortaucipir mirrored the histopathological tau distribution, were influenced by the amyloid-ß phase, and were useful for distinguishing different ADNC scores and PART.

Multimodal cross-examination of progressive apraxia of speech by diffusion tensor imaging-based tractography and Tau-PET scans.

Progressive apraxia of speech (PAOS) is a 4R tauopathy characterized by difficulties with motor speech planning. Neurodegeneration in PAOS targets the premotor cortex, particularly the supplementary motor area (SMA), with degeneration of white matter (WM) tracts connecting premotor and motor cortices and Broca's area observed on diffusion tensor imaging (DTI). We aimed to assess flortaucipir uptake across speech-language-related WM tracts identified using DTI tractography in PAOS. Twenty-two patients with PAOS and 26 matched healthy controls were recruited by the Neurodegenerative Research Group (NRG) and underwent MRI and flortaucipir-PET. The patient population included patients with primary progressive apraxia of speech (PPAOS) and non-fluent variant/agrammatic primary progressive aphasia (agPPA). Flortaucipir PET scans and DTI were coregistered using rigid registration with a mutual information cost function in subject space. Alignments between DTI and flortaucipir PET were inspected in all cases. Whole-brain tractography was calculated using deterministic algorithms by a tractography reconstruction tool (DSI-studio) and specific tracts were identified using an automatic fiber tracking atlas-based method. Fractional anisotropy (FA) and flortaucipir standardized uptake value ratios (SUVRs) were averaged across the frontal aslant tract, arcuate fasciculi, inferior frontal-occipital fasciculus, inferior and middle longitudinal fasciculi, as well as the SMA commissural fibers. Reduced FA (p < .0001) and elevated flortaucipir SUVR (p = .0012) were observed in PAOS cases compared to controls across all combined WM tracts. For flortaucipir SUVR, the greatest differentiation of PAOS from controls was achieved with the SMA commissural fibers (area under the receiver operator characteristic curve [AUROC] = 0.83), followed by the left arcuate fasciculus (AUROC = 0.75) and left frontal aslant tract (AUROC = 0.71). Our findings demonstrate that flortaucipir uptake is increased across WM tracts related to speech/language difficulties in PAOS.

Relationships between PET and blood plasma biomarkers in corticobasal syndrome.

INTRODUCTION: Corticobasal syndrome (CBS) can result from underlying Alzheimer's disease (AD) pathologies. Little is known about the utility of blood plasma metrics to predict positron emission tomography (PET) biomarker-confirmed AD in CBS. METHODS: A cohort of eighteen CBS patients (8 amyloid beta [Aß]+; 10 Aß-) and 8 cognitively unimpaired (CU) individuals underwent PET imaging and plasma analysis. Plasma concentrations were compared using a Kruskal-Wallis test. Spearman correlations assessed relationships between plasma concentrations and PET uptake. RESULTS: CBS Aß+ group showed a reduced Aß42/40 ratio, with elevated phosphorylated tau (p-tau)181, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) concentrations, while CBS Aß- group only showed elevated NfL concentration compared to CU. Both p-tau181 and GFAP were able to differentiate CBS Aß- from CBS Aß+ and showed positive associations with Aß and tau PET uptake. DISCUSSION: This study supports use of plasma p-tau181 and GFAP to detect AD in CBS. NfL shows potential as a non-specific disease biomarker of CBS regardless of underlying pathology. HIGHLIGHTS: Plasma phosphorylated tau (p-tau)181 and glial fibrillary acidic protein (GFAP) concentrations differentiate corticobasal syndrome (CBS) amyloid beta (Aß)- from CBS Aß+. Plasma neurofilament light concentrations are elevated in CBS Aß- and Aß+ compared to controls. Plasma p-tau181 and GFAP concentrations were associated with Aß and tau positron emission tomography (PET) uptake. Aß42/40 ratio showed a negative correlation with Aß PET uptake.

Identifying and Addressing Functional Communication Challenges in Patients With Behavioral Variant Frontotemporal Dementia.

PURPOSE: We describe the communication challenges of four patients with a neurodegenerative disorder consistent with behavioral variant frontotemporal dementia (bvFTD), characterized by early behavioral and personality changes. By describing their clinical profiles, we identify common barriers to functional communication in this population and provide recommendations for how speech-language pathologists (SLPs) might contribute to minimizing them. METHOD: Four patients with bvFTD were selected from a cohort of patients with progressive communication impairments. Three of them returned for at least one follow-up visit. Case histories are presented along with the results of comprehensive speech and language, neuropsychological, and neurological testing. RESULTS: At the time of initial evaluation, patients were between the ages of 54 and 66 years and had been experiencing symptoms for 1.5-6 years. Consistent with their bvFTD diagnoses, all patients had prominent behavioral and personality changes that impacted communication. Patients 1 and 2 also had mild aphasia at enrollment, primarily characterized by anomia and loss of word meaning. Patients 3 and 4 both had apraxia of speech and moderate-to-severe aphasia at enrollment with prominent anomia and agrammatism. All four patients had impaired executive functioning and relative sparing of visuospatial skills; episodic memory was also impaired for Patients 2 and 4. Even though functional communication was progressively limited for all patients, none of them received regular support from an SLP. CONCLUSIONS: This case series adds to a scant, but growing, literature demonstrating that patients with bvFTD have communication impairments. SLPs are uniquely positioned to identify barriers to functional communication and to provide tailored strategy training to the patients and their care partners over the course of their disease. Systematic evaluation of the efficacy of treatment in this population would be valuable. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.25933762.

Stepwise Functional Brain Architecture Correlates with Atrophy in Progressive Supranuclear Palsy.

BACKGROUND: Stepwise functional connectivity (SFC) detects whole-brain functional couplings of a selected region of interest at increasing link-step topological distances. OBJECTIVE: This study applied SFC to test the hypothesis that stepwise architecture propagating from the disease epicenter would shape patterns of brain atrophy in patients with progressive supranuclear palsy-Richardson's syndrome (PSP-RS). METHODS: Thirty-six patients with PSP-RS and 44 age-matched healthy control subjects underwent brain magnetic resonance imaging on a 3-T scanner. The disease epicenter was defined as the peak of atrophy observed in an independent cohort of 13 cases with postmortem confirmation of PSP pathology and used as seed region for SFC analysis. First, we explored SFC rearrangements in patients with PSP-RS, as compared with age-matched control subjects. Subsequently, we tested SFC architecture propagating from the disease epicenter as a determinant of brain atrophy distribution. RESULTS: The disease epicenter was identified in the left midbrain tegmental region. Compared with age-matched control subjects, patients with PSP-RS showed progressively widespread decreased SFC of the midbrain with striatal and cerebellar regions through direct connections and sensorimotor cortical regions through indirect connections. A correlation was found between average link-step distance from the left midbrain in healthy subjects and brain volumes in patients with PSP-RS (r = 0.38, P < 0.001). CONCLUSIONS: This study provides comprehensive insights into the topology of functional network rearrangements in PSP-RS and demonstrates that the brain architectural topology, as described by SFC propagating from the disease epicenter, shapes the pattern of atrophic changes in PSP-RS. Our findings support the view of a network-based pathology propagation in this primary tauopathy. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The yes-no reversal phenomenon in patients with primary progressive apraxia of speech.

Patients who have a yes-no reversal respond "yes" when they mean no and vice versa. The unintentional response can be made both verbally and with gestures (e.g., head shake or nod, thumbs up or down). Preliminary reports associate this phenomenon with 4-repeat tauopathies including primary progressive apraxia of speech (PPAOS), nonfluent/agrammatic primary progressive aphasia, and corticobasal syndrome; however, the significance and timing of this symptom relative to others are not well understood. Whereas some accounts associate yes-no reversals with other binary reversals (e.g., up/down, hot/cold) and attribute the reversals to disturbances of selection within the language system, others implicate more general inhibitory control processes. Here, we compared clinical and neuroimaging findings across 30 patients with PPAOS (apraxia of speech in the absence of aphasia), 15 of whom had a yes-no reversal complaint and 15 who did not. The two groups did not differ on any of the language or motor speech measures; however, patients who had the yes-no reversal received lower scores on the Frontal Assessment Battery and motor assessments. They also had greater hypometabolism in the left supplementary motor area and bilateral caudate nuclei on [18F]-fluorodeoxyglucose PET, but only the right caudate nucleus cluster survived correction for multiple comparisons. We interpret these results to suggest that the yes-no reversal phenomenon is associated with cognitive abilities that are supported by the frontostriatal network; more specifically, impaired response inhibition.

Comparing classic-onset corticobasal syndrome to speech/language-onset corticobasal syndrome.

INTRODUCTION: Patients with classic-onset corticobasal syndrome (CBS) present with asymmetric limb apraxia and parkinsonism. We have, however, observed patients who initially present with speech and/or language (SL) problems and several years later develop CBS (i.e., SL-onset CBS). We aimed to compare clinical, neuroimaging and pathological characteristics of classic-onset CBS with SL-onset CBS. METHODS: We conducted a retrospective cohort study of 62 patients who met criteria for CBS (17 presented with classic-onset CBS and 45 had SL-onset CBS). We compared demographics, clinical characteristics, and grey and white matter volume loss with SPM12 between groups and assessed pathology and corticobasal degeneration (CBD) pathological lesion counts in patients who had died and undergone autopsy. RESULTS: Median age at CBS diagnosis was 66.4 years in classic-onset CBS and 73.6 years in SL-onset CBS. Classic-onset CBS had higher frequencies of dystonia, myoclonus, and alien limb phenomenon, while SL-onset CBS had a higher frequency of vertical supranuclear gaze palsy. Both groups showed smaller frontoparietal volumes than controls, with SL-onset CBS having greater volume loss in the left supplementary motor area than classic-onset CBS. All three classic-onset CBS cases with autopsy (100 %) had CBD pathology while 8/21 of SL-onset CBS cases (38 %) had CBD. Pathological lesion burden (including astrocytic plaques) did not differ between classic-onset and SL-onset CBS. CONCLUSION: Classic-onset and SL-onset CBS appear to be different syndromes, with the former being a more profuse motor syndrome. The more widespread volume loss in SL-onset CBS likely reflects longer disease course.

TDP-43 Is Associated with Subiculum and Cornu Ammonis 1 Hippocampal Subfield Atrophy in Primary Age-Related Tauopathy.

Background: TAR DNA binding protein 43 (TDP-43) has been shown to be associated with whole hippocampal atrophy in primary age-related tauopathy (PART). It is currently unknown which subregions of the hippocampus are contributing to TDP-43 associated whole hippocampal atrophy in PART. Objective: To identify which specific hippocampal subfield regions are contributing to TDP-43-associated whole hippocampal atrophy in PART. Methods: A total of 115 autopsied cases from the Mayo Clinic Alzheimer Disease Research Center, Neurodegenerative Research Group, and the Mayo Clinic Study of Aging were analyzed. All cases underwent antemortem brain volumetric MRI, neuropathological assessment of the distribution of Aß (Thal phase), and neurofibrillary tangle (Braak stage) to diagnose PART, as well as assessment of TDP-43 presence/absence in the amygdala, hippocampus and beyond. Hippocampal subfield segmentation was performed using FreeSurfer version 7.4.1. Statistical analyses using logistic regression were performed to assess for associations between TDP-43 and hippocampal subfield volumes, accounting for potential confounders. Results: TDP-43 positive patients (n = 37, 32%), of which 15/15 were type-α, had significantly smaller whole hippocampal volumes, and smaller volumes of the body and tail of the hippocampus compared to TDP-43 negative patients. Subfield analyses revealed an association between TDP-43 and the molecular layer of hippocampal body and the body of cornu ammonis 1 (CA1), subiculum, and presubiculum regions. There was no association between TDP-43 stage and subfield volumes. Conclusions: Whole hippocampal volume loss linked to TDP-43 in PART is mainly due to volume loss occurring in the molecular layer, CA1, subiculum and presubiculum of the hippocampal body.

A multimodal clinical diagnostic approach using MRI and 18F-FDG-PET for antemortem diagnosis of TDP-43 in cases with low-intermediate Alzheimer's disease neuropathologic changes and primary age-related tauopathy.

OBJECTIVE: To evaluate the utility of clinical assessment scales for MRI and 18F-FDG-PET as potential in vivo predictive diagnostic tools for TAR DNA-binding protein of 43 kDa (TDP-43) proteinopathy in cases with low-intermediate Alzheimer's disease neuropathologic changes (ADNC) and primary age-related tauopathy (PART). METHODS: We conducted a cross-sectional analysis on patients with antemortem MRI and 18F-FDG-PET scans and postmortem diagnosis of low-intermediate ADNC or PART (Braak stage ≤ III; Thal ß-amyloid phase 0-5). We employed visual imaging scales to grade structural changes on MRI and metabolic changes on 18F-FDG-PET and statistically compared demographic and clinicopathological characteristics between TDP-43 positive and negative cases. Independent regression analyses were performed to assess further influences of pathological characteristics on imaging outcomes. Within-reader repeatability and inter-reader reliability were calculated (CI = 0.95). Additional quantitative region-of-interest analyses of MRI gray matter volumes and PET ligand uptake were performed. RESULTS: Of the 64 cases in the study, 20 (31%) were TDP-43 ( +), of which 12 (60%) were female. TDP-43 ( +) cases were more likely to have hippocampal sclerosis (HS) (p = 0.014) and moderate-severe medial temporal lobe atrophy on MRI (p = 0.048). TDP-43( +) cases also showed a trend for less parietal atrophy on MRI (p = 0.086) and more medial temporal lobe hypometabolism on 18F-FDG-PET (p = 0.087) than TDP-43( - ) cases. Regression analysis showed an association between medial temporal hypometabolism and HS (p = 0.0113). ICC values for MRI and PET within one reader were 0.75 and 0.91; across two readers were 0.79 and 0.82. The region-of-interest-based analysis confirmed a significant difference between TDP-43( +) and TDP-43( - ) cases for medial temporal lobe gray matter volume on MRI (p = 0.014) and medial temporal metabolism on PET (p = 0.011). CONCLUSION: Visual inspection of the medial temporal lobe on MRI and FDG-PET may help to predict TDP-43 status in the context of low-intermediate ADNC and PART.

Progression to corticobasal syndrome: a longitudinal study of patients with nonfluent primary progressive aphasia and primary progressive apraxia of speech.

BACKGROUND AND OBJECTIVES: Nonfluent variant primary progressive aphasia (nfvPPA) and primary progressive apraxia of speech (PPAOS) can be precursors to corticobasal syndrome (CBS). Details on their progression remain unclear. We aimed to examine the clinical and neuroimaging evolution of nfvPPA and PPAOS into CBS. METHODS: We conducted a retrospective longitudinal study in 140 nfvPPA or PPAOS patients and applied the consensus criteria for possible and probable CBS for every visit, evaluating limb rigidity, akinesia, limb dystonia, myoclonus, ideomotor apraxia, alien limb phenomenon, and nonverbal oral apraxia (NVOA). Given the association of NVOA with AOS, we also modified the CBS criteria by excluding NVOA and assigned every patient to either a progressors or non-progressors group. We evaluated the frequency of every CBS feature by year from disease onset, and assessed gray and white matter volume loss using SPM12. RESULTS: Asymmetric akinesia, NVOA, and limb apraxia were the most common CBS features that developed; while limb dystonia, myoclonus, and alien limb were rare. Eighty-two patients progressed to possible CBS; only four to probable CBS. nfvPPA and PPAOS had a similar proportion of progressors, although nfvPPA progressed to CBS earlier (p-value = 0.046), driven by an early appearance of limb apraxia (p-value = 0.0041). The non-progressors and progressors both showed premotor/motor cortex involvement at baseline, with spread into prefrontal cortex over time. DISCUSSION: An important proportion of patients with nfvPPA and PPAOS progress to possible CBS, while they rarely develop features of probable CBS even after long follow-up.

Frontal hypometabolism in the diagnosis of progressive supranuclear palsy clinical variants.

OBJECTIVE: Frontal hypometabolism on FDG-PET is observed in progressive supranuclear palsy (PSP), although it is unclear whether it is a feature of all PSP clinical variants and hence whether it is a useful diagnostic feature. We aimed to compare the frequency, severity, and pattern of frontal hypometabolism across PSP variants and determine whether frontal hypometabolism is related to clinical dysfunction. METHODS: Frontal hypometabolism in prefrontal, premotor, and sensorimotor cortices was visually graded on a 0-3 scale using CortexID Z-score images in 137 PSP patients. Frontal asymmetry was recorded. Severity scores were used to categorize patients as premotor-predominant, prefrontal-predominant, sensorimotor-predominant, mixed-predominance, or no regional predominance. Frontal ratings were compared across PSP clinical variants, and Spearman correlations were used to assess relationships with the Frontal Assessment Battery (FAB). RESULTS: 97% showed evidence of frontal hypometabolism which was most common (100%) in the speech-language (PSP-SL), corticobasal (PSP-CBS), and frontal (PSP-F) variants and least common in the progressive gait freezing (PSP-PGF) variant (73%). PSP-SL and PSP-CBS showed more severe hypometabolism than Richardson's syndrome (PSP-RS), Parkinsonism (PSP-P), and PSP-PGF. A premotor-predominant pattern was most common in PSP-SL and PSP-CBS, with more mixed patterns in the other variants. Hypometabolism was most commonly asymmetric in PSP-SL, PSP-P, PSP-F and PSP-CBS. Worse hypometabolism in nearly all frontal regions correlated with worse scores on the FAB. CONCLUSIONS: Frontal hypometabolism is a common finding in PSP, although it varies in severity and pattern across PSP variants and will likely be the most diagnostically useful in PSP-SL and PSP-CBS.

Clinical and neuroimaging characteristics of primary lateral sclerosis with overlapping features of progressive supranuclear palsy.

BACKGROUND AND PURPOSE: Primary lateral sclerosis (PLS) is a neurodegenerative disorder that primarily affects the central motor system. In rare cases, clinical features of PLS may overlap with those of progressive supranuclear palsy (PSP). We investigate neuroimaging features that can help distinguish PLS with overlapping features of PSP (PLS-PSP) from PSP. METHODS: Six patients with PLS-PSP were enrolled between 2019 and 2023. We compared their clinical and neuroimaging characteristics with 18 PSP-Richardson syndrome (PSP-RS) patients and 20 healthy controls. Magnetic resonance imaging, 18F-flortaucipir positron emission tomography (PET), quantitative susceptibility mapping, and diffusion tensor imaging tractography (DTI) were performed to evaluate eight brain regions of interest. Area under the receiver operating characteristic curve (AUROC) was calculated. RESULTS: Five of the six PLS-PSP patients (83.3%) were male. Median age at symptom onset was 61.5 (52.5-63) years, and all had mixed features of PLS and PSP. Volumes of the pallidum, caudate, midbrain, and cerebellar dentate were smaller in PSP-RS than PLS-PSP, providing good discrimination (AUROC = 0.75 for all). The susceptibilities in pallidum, midbrain, and cerebellar dentate were greater in PSP-RS compared to PLS-PSP, providing excellent discrimination (AUROC ≥ 0.90 for all). On DTI, fractional anisotropy (FA) in the posterior limb of the internal capsule from the corticospinal tract was lower in PLS-PSP compared to PSP-RS (AUROC = 0.86), but FA in the superior cerebellar peduncle was lower in PSP-RS (AUROC = 0.95). Pallidum flortaucipir PET uptake was greater in PSP-RS compared to PLS-PSP (AUROC = 0.74). CONCLUSIONS: Regional brain volume, tractography, and magnetic susceptibility, but not tau-PET, are useful in distinguishing PLS-PSP from PSP.