Whitwell, Jennifer L.

AbstractBackgroundOptimizing software to measure Flortaucipir (AV‐1451) tau PET SUVR change‐over‐time is crucial for longitudinal observational studies and potential trials of anti‐tau agents. Ideal measurements should have good repeatability (low noise), and should clearly separate clinical cognitive groups.MethodWe compared 456 software methods varying in their use of: two major packages, each with cross‐sectional and longitudinal variants (FreeSurfer and an in‐house pipeline using SPM12, MCALT, and ANTs); three temporal‐lobe target regions (each with/without adjacent WM); seven reference regions; five PVC methods; and two statistics (mean vs. median). We used linear mixed‐effects models to compare methods using scans from 88 Mayo Clinic participants (46 cognitively impaired, 42 impaired, excluding those with symptoms inconsistent with the AD pathology imaged by Flortaucipir), each with three visits with PET and MRI. From these models, we calculated two criteria for each pipeline: relative measurement error (residual from the linear mixed model), and the t‐statistic for testing differences in group‐wise rates of change (which has a Cohen’s d interpretation of effect size for longitudinal data). We plotted both criteria orthogonally, then ranked methods overall according to the average of their ranks on both individual criteria.ResultMethods using the entorhinal cortex target region performed poorly in both criteria (Figure 1). The top 10 methods by the combined criteria (top‐left in Figure 2) all used the Mayo SPM12‐based pipeline with an eroded supratentorial WM (eSWM) or composite (eSWM + pons + cerebellum) reference region. Among them, 9/10 used the longitudinal variant, 8/10 used 2‐compartment PVC, and 7/10 used median. Altogether, our results favored SUVR methods with a longitudinal design (simultaneously calculating all time‐points), a temporal‐lobe meta‐ROI including adjacent WM, a composite reference region, 2‐class voxel‐based (Meltzer) PVC, and median statistics. Methods using GTM‐Tau PVC (Baker et al., Data in Brief, 2017) had the highest group separation but relatively large measurement error, giving them ranks 197 and 199 out of 456 with the joint (average rank) criteria.ConclusionCompared with popular FreeSurfer‐based methods (ranks 176, 258; Figure 2), our top‐ranked approaches approximately halved error in SUVR measurements while maintaining or improving group separation.

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.

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

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 Aims To assess the burden of transactive response DNA‐binding protein of 43 kDa (TDP‐43) inclusions in a unique cohort of old‐age patients with genetic frontotemporal lobar degeneration (gFTLD‐TDP) and compare these patients with sporadic old‐age individuals with TDP‐43, either in the presence of Alzheimer's disease (AD‐TDP) or in isolation (pure‐TDP). Methods The brain bank at Mayo Clinic‐Jacksonville was searched for cases ≥75 years old at death with TDP‐43 extending into middle frontal cortex. Cases were split into the following groups: (1) gFTLD‐TDP ( n = 15) with progranulin ( GRN )/ C9ORF72 mutations; (2) AD‐TDP ( n = 10)—cases with median Braak neurofibrillary tangle (NFT) stage VI, Thal phase V; (3) pure‐TDP ( n = 10)—cases with median Braak NFT stage I, Thal phase I. Clinical data were abstracted; TDP‐43 burden was calculated using digital pathology. Results Amnestic Alzheimer's dementia was the clinical diagnosis in ≥50% patients in each group. The distribution of TDP‐43 burden in gFTLD‐TDP and AD‐TDP, but not pure‐TDP, was limbic‐predominant targeting CA1 and subiculum. Patients with gFTLD‐TDP had higher burden in entorhinal cortex compared to AD‐TDP. TDP‐43 burden in middle frontal cortex did not differ between the three groups. Conclusions In old age it is challenging to clinically and pathologically differentiate gFTLD‐TDP from AD‐TDP and pure‐TDP‐43 based on burden. Like AD‐TDP, old age gFTLD‐TDP have a limbic predominant TDP‐43 distribution. The finding that amnestic Alzheimer's dementia was the most common clinical diagnosis regardless of group suggests that TDP‐43 directly and indirectly targets limbic regions.

Purpose This study describes motor speech disorders and associated communication limitations in six variants of progressive supranuclear palsy (PSP). Method The presence, nature, and severity of dysarthria and apraxia of speech (AOS) were documented, along with scores on the Apraxia of Speech Rating Scale–Version 3 (ASRS-3) for 77 (40 male and 37 female) patients with PSP. Clinician-estimated and patient-estimated communication limitations were rated using the Motor Speech Disorders Severity Rating (MSDSR) Scale and the Communicative Effectiveness Survey (CES), respectively. Descriptive statistics were calculated for each of these dependent variables. One-tailed t tests were conducted to test mean differences in ASRS-3 and CES between participants with and without AOS and between participants with and without dysarthria. Spearman rank correlations were calculated between ASRS-3 scores and clinical judgments of AOS and dysarthria severity and between MSDSR and CES ratings. Results Nine participants (12%) had normal speech. Eighty-seven percent exhibited dysarthria; hypokinetic and mixed hypokinetic–spastic dysarthria were observed most frequently. AOS was observed in 19.5% of participants across all variants, but in only 10% exclusive of the PSP speech and language variant. Nearly half presented with AOS in which neither phonetic nor prosodic features clearly predominated. The mean ASRS-3 score for participants with AOS was significantly higher than for those without and correlated strongly with clinician judgment of AOS severity. Mean ASRS-3 was higher for participants with dysarthria than for those without but correlated weakly with dysarthria severity. Mean MSDSR and CES ratings were lower in participants with AOS compared to those without and moderately correlated with each other. Conclusions Motor speech disorders that negatively impact communicative effectiveness are common in PSP and occur in many variants. This is the first description of motor speech disorders across PSP variants, setting the stage for future research characterizing neuroanatomical correlates, progression of motor speech disorders, and benefits of targeted interventions. Supplemental Material https://doi.org/10.23641/asha.14111837

Background: Transactive response DNA-binding protein of 43 kDa (TDP-43) is associated with memory impairment and overall cognitive decline. It is unclear how TDP-43 contributes to the rate of clinical decline. Objective: To determine whether cross-sectional and longitudinal cognitive and functional decline are associated with anatomical distribution of TDP-43 in the brain. Methods: Longitudinal clinical-neuropathologic autopsy cohort study of 385 initially cognitively normal/mildly impaired older adults prospectively followed until death. We investigated how TDP-43, amyloid-β (Aβ), tau neurofibrillary tangles (NFT), Lewy body disease (LBD), age, sex, and genetics are associated with clinical scores and rates of their longitudinal decline. Results: Of 385 participants, 260 (68%) had no TDP-43, 32 (8%) had TDP-43 limited to amygdala, and 93 (24%) had TDP-43 in the hippocampus and beyond. Higher TDP-43 and Braak NFT stages independently were associated with faster decline in global cognition, functional performance measured by Clinical Dementia Rating scale, and naming and episodic memory, whereas older age was associated with slower rate of cognitive, psychiatric, and functional decline. Cross-sectionally the following associations were found: higher TDP-43 and Braak NFT - worse performance; higher Aβ burden - worse global cognition, more behavioral changes, the latter also with higher LBD; older age - worse naming, lower frequency of behavioral changes; female sex - more impaired naming and better preserved episodic memory. There were no genetic associations. Conclusion: The association of TDP-43 distribution with decline in cognitive and functional performance suggests that TDP-43 is playing a role in the clinical progression to dementia. Further characterization of clinical features associated with TDP-43 can facilitate establishment of antemortem diagnosis.