Josephs, Keith A.

AbstractBackgroundMagnetic resonance brainstem measurements are useful structural biomarkers in the Richardson's syndrome variant of progressive supranuclear palsy (PSP). However, it is unclear how these biomarkers differ across the phenotypic spectrum of PSP and how they relate to underlying pathology.ObjectiveThe aim of this study was to compare brainstem imaging measures across clinical variants of PSP and determine sensitivity and specificity based on pathologically diagnosed cases.MethodsA total of 153 patients with PSP who represented eight clinical variants were recruited at Mayo Clinic (Rochester, MN, USA) and underwent structural magnetic resonance imaging (MRI). Midbrain and pons area and superior and middle cerebellar peduncle width measurements were performed, and midbrain/pons ratio and Magnetic Resonance Parkinsonism Index (MRPI) were calculated. Among the 43 patients who later died, PSP pathology was confirmed in 29, whereas 14 had other pathology.ResultsBrainstem measurements varied across PSP clinical variants and were most abnormal in PSP‐Richardson's syndrome and frontal variants, followed by PSP‐corticobasal, PSP‐speech/language, and PSP‐parkinsonism variants. All these variants showed abnormalities compared with controls. The PSP‐gait freezing variant and patients with prominent corticospinal tract signs showed normal brainstem measures. Among cases with confirmed PSP pathology, the midbrain area, midbrain/pons ratio, and MRPI were all more abnormal compared to those with other pathologies, with best differentiation obtained with the MRPI (sensitivity = 83%; specificity = 85%).ConclusionsMRI brainstem measures show utility as diagnostic biomarkers across PSP clinical variants and have the potential to be useful in predicting underlying pathology. © 2021 International Parkinson and Movement Disorder Society

ABSTRACTBackgroundApathy and depression commonly occur in patients with progressive supranuclear palsy (PSP)‐Richardson's syndrome variant; depression often requiring treatment. Little is known, however, about apathy and depression among other PSP variants.MethodsWe prospectively studied 97 newly diagnosed PSP patients. All were classified into a PSP variant using the 2017 Movement Disorder Society‐PSP criteria and administered the Geriatric Depression and Apathy Evaluation Scales. Differences in apathy and depression frequency and severity across six variants, and secondarily across PSP‐Richardson's syndrome, PSP‐Cortical and PSP‐Subcortical, were analyzed using ANCOVA and linear regression adjusting for disease severity.ResultsDepression (55%) was more common than apathy (12%). PSP‐Speech/Language (PSP‐SL) variant had the lowest depression frequency (13%) and lower depression scores than the other variants. No differences in apathy frequency/severity were identified.ConclusionPSP‐SL patients may have less depression compared to PSP‐Richardson's syndrome and other PSP variants.

Abstract 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.

Purpose This study compared performance on three-word fluency measures among individuals with primary progressive aphasia (PPA) and primary progressive apraxia of speech (PPAOS), and examined the relationship between word fluency and other measures of language and speech. Method This study included 106 adults with PPA and 30 adults with PPAOS. PPA participants were divided into three clinical subgroups: semantic (svPPA), logopenic (lvPPA), and nonfluent/agrammatic with or without apraxia of speech (nfPPA). Category fluency, letter fluency, and action/verb fluency tasks were administered to all participants. Results The four clinical groups performed abnormally on the word fluency measures, although not to a degree that represented high sensitivity to their PPA or PPAOS diagnosis. All PPA subgroups produced fewer words compared to individuals with PPAOS on all word fluency measures. Moderate correlations were found between word fluency and aphasia severity and naming performance in some of the clinical groups. Conclusions Word fluency measures are often challenging for individuals with PPA and PPAOS, but they are not of equal difficulty, with letter fluency being the most difficult. Differences among word fluency tests also vary to some degree as a function of the clinical group in question, with least impairment in PPAOS. However, the findings of this study do not support statistically significant differences in word fluency task performance among the PPA subgroups. Correlations suggest that word fluency performance in PPA is at least partly related to aphasia severity.

ABSTRACTBackgroundProgressive supranuclear palsy (PSP) may present as a speech/language disorder (PSP‐SL).ObjectiveWe assessed pathological correlates of patients with PSP‐SL who retained the suggestive of PSP‐SL (s.o. PSP‐SL) diagnosis versus those who progressed to possible/probable (poss./prob.) PSP.MethodsThirty‐four prospectively recruited patient with s.o. PSP‐SL completed comprehensive speech/language and neurological assessments longitudinally, died, and underwent autopsy.ResultsTwelve patients (35%) evolved to poss./prob PSP, while 22 (65%) remained as s.o. PSP‐SL. Pathological diagnoses differed across the groups (P = 0.025). Patients with s.o. PSP‐SL had four different neuropathologies (corticobasal degeneration [59%], PSP [13%], Pick's disease [14%], and frontotemporal lobar degeneration with TDP‐43 [14%]), while all patients with poss./prob. PSP had a 4R‐tauopathy (PSP [67%] and corticobasal degeneration [33%]). Development of poss./prob. PSP increased the chance of having PSP pathology by 2.38 times.ConclusionsPSP‐SL is associated with heterogenous pathologies. Evolution of PSP‐SL into poss./prob. PSP is more predictive of underlying PSP pathology than s.o. PSP‐SL. © 2021 International Parkinson and Movement Disorder Society

Purpose Individuals with primary progressive apraxia of speech have apraxia of speech (AOS) as the initial and predominant symptom. Many develop aphasia and/or dysarthria later in the disease course. It was previously demonstrated that patients with neurodegenerative AOS experience reduced participation in communication that is further exacerbated by co-occurring language deficits ( Utianski et al., 2020 ). Measures of disease severity did not necessarily correlate with measures of participation restrictions. The aim of this follow-up study was to describe changes in communication limitations in these patients, again measured by (a) the patient via the Communicative Participation Item Bank (CPIB) and (b) the speech-language pathologist via the American Speech-Language-Hearing Association's (ASHA's) Functional Communication Measures (FCMs) and an adapted motor speech disorder (MSD) severity rating to determine if there are significant changes in these and other objective speech and language measures at follow-up after 1 year. Method Of the 24 patients reported in the study of Utianski et al. (2020) , 17 (10 men, seven women) returned for a second visit approximately 1 year following the first visit. Identical procedures were utilized; the communication measures collected at each visit were statistically compared. Correlations were calculated between the participation ratings and other clinical assessment measures at the second visit and for the change in scores on those measures between the first and second visits. Results There were statistically significant differences in AOS and aphasia severity between visits. There were significant changes in clinical assessments, MSD severity rating, and all ASHA FCMs between visits, but not the CPIB. Correlation analyses suggest the relationships among clinical and participation measures are complex; overall, patients with more severe changes in AOS experienced greater changes in participation restrictions. Conclusions The findings of this study support the use of patient-reported outcome measures as they may better reflect the patient experience, including the influence of factors such as ongoing speech therapy and the emergence of neuropsychiatric features, and associated changes in day-to-day functioning, when other measures may simply index the progression of the disease. Supplemental Material https://doi.org/10.23641/asha.16528512

AbstractBackgroundDysphagia is a common symptom of progressive supranuclear palsy often leading to aspiration pneumonia and death.ObjectiveThe aim of this study was to examine how impairments of the oral and pharyngeal phases of the swallow and airway incursion during liquid swallows relate to gray and white matter integrity.MethodsThirty‐eight participants with progressive supranuclear palsy underwent videofluorographic swallowing assessment and structural and diffusion tensor head magnetic resonance imaging. Penalized linear regression models assessed relationships between swallowing metrics and regional gray matter volumes and white matter fractional anisotropy and mean diffusivity.ResultsOral phase impairments were associated with reduced superior parietal volumes and abnormal diffusivity in parietal and sensorimotor white matter, posterior limb of the internal capsule, and superior longitudinal fasciculus. Pharyngeal phase impairments were associated with disruption to medial frontal lobe, corticospinal tract, and cerebral peduncle. No regions were predictive of airway incursion.ConclusionsDifferential patterns of neuroanatomical impairment corresponded to oral and pharyngeal phase swallowing impairments. © 2021 International Parkinson and Movement Disorder Society

Abstract Posterior cortical atrophy is a neurodegenerative syndrome with a heterogeneous clinical presentation due to variable involvement of the left, right, dorsal and ventral parts of the visual system, as well as inconsistent involvement of other cognitive domains and systems. 18F-fluorodeoxyglucose (FDG)-PET is a sensitive marker for regional brain damage or dysfunction, capable of capturing the pattern of neurodegeneration at the single-participant level. We aimed to leverage these inter-individual differences on FDG-PET imaging to better understand the associations of heterogeneity of posterior cortical atrophy. We identified 91 posterior cortical atrophy participants with FDG-PET data and abstracted demographic, neurologic, neuropsychological and Alzheimer’s disease biomarker data. The mean age at reported symptom onset was 59.3 (range: 45–72 years old), with an average disease duration of 4.2 years prior to FDG-PET scan, and a mean education of 15.0 years. Females were more common than males at 1.6:1. After standard preprocessing steps, the FDG-PET scans for the cohort were entered into an unsupervised machine learning algorithm which first creates a high-dimensional space of inter-individual covariance before performing an eigen-decomposition to arrive at a low-dimensional representation. Participant values (‘eigenbrains’ or latent vectors which represent principle axes of inter-individual variation) were then compared to the clinical and biomarker data. Eight eigenbrains explained over 50% of the inter-individual differences in FDG-PET uptake with left (eigenbrain 1) and right (eigenbrain 2) hemispheric lateralization representing 24% of the variance. Furthermore, eigenbrain-loads mapped onto clinical and neuropsychological data (i.e. aphasia, apraxia and global cognition were associated with the left hemispheric eigenbrain 1 and environmental agnosia and apperceptive prosopagnosia were associated with the right hemispheric eigenbrain 2), suggesting that they captured important axes of normal and abnormal brain function. We used NeuroSynth to characterize the eigenbrains through topic-based decoding, which supported the idea that the eigenbrains map onto a diverse set of cognitive functions. These eigenbrains captured important biological and pathophysiologic data (i.e. limbic predominant eigenbrain 4 patterns being associated with older age of onset compared to frontoparietal eigenbrain 7 patterns being associated with younger age of onset), suggesting that approaches that focus on inter-individual differences may be important to better understand the variability observed within a neurodegenerative syndrome like posterior cortical atrophy.

TAR DNA binding protein‐43 (TDP‐43)‐immunoreactive neuronal cytoplasmic inclusions (NCIs), characteristically associated with frontotemporal lobar degenerations (FTLD‐U and FTLD‐MND), have been found in the hippocampal dentate granule cells of about 20% of cases with advanced Alzheimer disease (AD). The extent and distribution of TDP‐43 pathology in brain regions other than hippocampus in AD is not known, especially in AD cases without hippocampal NCIs. Sections of hippocampus, amygdala, neocortex, and medulla from patients with clinical dementia and pathologic features of AD were analyzed for the presence of TDP‐43‐immunoreactive NCIs. 22 cases of advanced AD (Braak Stage V‐VI) without hippocampal NCIs and 23 cases of advanced AD with hippocampal NCIs were included. 6 hippocampal‐negative cases (27%) had TDP‐43 positive NCIs in the amygdala. All 23 cases of hippocampal‐positive cases had numerous TDP‐43 NCIs in the amygdala, with decreasing density of NCIs in the other brain regions. In summary, TDP‐43 immunoreactive NCIs are found predominantly in the medial temporal structures in advanced AD, and the amygdala appears to be the area most vulnerable.