Whitwell, Jennifer

ObjectiveThis study was undertaken to assess cross‐sectional and longitudinal [18F]‐flortaucipir positron emission tomography (PET) uptake in pathologically confirmed frontotemporal lobar degeneration (FTLD) and to compare FTLD to cases with high and low levels of Alzheimer disease (AD) neuropathologic changes (ADNC).MethodsOne 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.ResultsBaseline 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%).InterpretationThere 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

Abstract 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 < 0.001), substantia nigra (P = 0.03) and red nucleus (P = 0.004), with glial lesions substantially driving the associations. Decreased fractional anisotropy and increased mean diffusivity in the superior cerebellar peduncle correlated with glial tau in the cerebellar dentate (P = 0.04 and P = 0.02, respectively) and red nucleus (P < 0.001 for both). Total tau and glial pathology also correlated with increased mean diffusivity in the midbrain (P = 0.02 and P < 0.001, respectively). Finally, increased subcortical white matter mean diffusivity was associated with total tau in superior frontal and precentral cortices (each, P = 0.02). Overall, results showed clear relationships between antemortem MRI changes and pathology in four-repeat tauopathies. Our findings show that brain volume could be a useful surrogate marker of tau pathology in subcortical and brainstem regions, whereas white matter integrity could be a useful marker of tau pathology in cortical regions. Our findings also suggested an important role of glial tau lesions in the pathogenesis of neurodegeneration in four-repeat tauopathies. Thus, development of tau PET tracers selectively binding to glial tau lesions could potentially uncover mechanisms of disease progression.

AbstractBackgroundPosterior 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.MethodsFifty‐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.ResultsNine 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.ConclusionsOur 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.

Background: It has been hypothesized that medial temporal sparing may be related to preserved posterior cingulate metabolism and the cingulate island sign (CIS) on [18F]fluorodeoxyglucose (FDG) PET in posterior cortical atrophy (PCA). Objective: To assess the severity of medial temporal atrophy in PCA and determine whether the presence of a CIS is related to medial temporal sparing. Methods: Fifty-five PCA patients underwent MRI and FDG-PET. The degree and symmetry of medial temporal atrophy on MRI was visually assessed using a five-point scale for both hemispheres. Visual assessments of FDG-PET coded the presence/absence of a CIS and whether the CIS was symmetric or asymmetric. Hippocampal volumes and a quantitative CIS were also measured. Results: Medial temporal atrophy was most commonly mild or moderate, was symmetric in 55% of patients, and when asymmetric was most commonly worse on the right (76%). Older age and worse memory performance were associated with greater medial temporal atrophy. The CIS was observed in 44% of the PCA patients and was asymmetric in 50% of these. The patients with a CIS showed greater medial temporal asymmetry, but did not show lower medial temporal atrophy scores, compared to those without a CIS. Hippocampal volumes were not associated with quantitative CIS. Conclusion: Mild medial temporal atrophy is a common finding in PCA and is associated with memory impairment. However, medial temporal sparing was not related to the presence of a CIS in PCA.

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

AbstractBackgroundAlthough semantic dementia (SMD) presents with language decline, patients often develop behavioral changes. Behavioral symptoms in SMD are attributed to both cortical (orbitofrontal cortex atrophy) and subcortical (nucleus accumbens) degeneration in imaging and neuropathological studies. The caudate nucleus has been implicated in early behavioral changes in some phenotypes of frontotemporal dementia. The objective of this study was to determine whether asymmetric ipsilateral caudate nucleus hypometabolism on [18F]‐fluorodeoxyglucose positron emission tomography (FDG‐PET) is associated with early behavioral changes in the absence of frontal hypometabolism in SMD.MethodFifteen patients with a diagnosis of SMD evaluated by the Neurodegenerative Research Group (NRG) at the Mayo Clinic, Rochester from 2006‐2016, who had FDG‐PET, were included in this study. Clinical data was extracted from the medical records including age at presentation, sex, behavioral symptoms and duration of symptoms. Automated average Z‐scores generated from CortexID (GE Healthcare, WI, USA) using 3D stereotactic surface projections were obtained for the following regions bilaterally: temporal lobes, frontal lobes and caudate nucleus. Patients were categorized as left or right hemisphere lateralized based on the higher temporal lobe Z‐scores. Caudate nucleus and frontal lobe Z‐scores were then compared between the two sides for each patient. Hypometabolism was considered present if Z‐scores were greater than 2.ResultOf our cohort, 9/15 (60%) were females with a median age of 68 at presentation and had 3.5 years symptom duration. 13/15 had at least 1 behavioral symptom at presentation. Eleven patients were considered to have left‐lateralized whereas 4 were right‐lateralized in their temporal lobe hypometabolism. Median Z‐scores were significantly different for ipsilateral and contralateral caudate nuclei at 2.5 and 1.6, respectively (p=0.02, Wilcoxon nonparametric test). Frontal lobe median Z‐scores were 1.2 (ipsilateral) and 0.59 (contralateral) with no statistical difference between two sides (p=0.13).ConclusionIn SMD patients who exhibit behavioral symptoms with no frontal hypometabolism on FDG‐PET, asymmetric caudate nuclei hypometabolism should be explored as a possible imaging marker. This implicates abnormal frontal‐striatal circuitry in the development of behavioral symptoms even in the absence of frontal hypometabolism in early behavioral changes in SMD.

AbstractBackgroundPast research has demonstrated that clinical EEG is sensitive to dementia associated with Alzheimer's (AD) and Parkinson’s diseases (PD), and nonfluent/agrammatic Primary Progressive Aphasia (agPPA), but not Primary Progressive Apraxia of Speech (PPAOS). However, clinical EEG studies do not quantify interactions of multiple brain areas, or network activity. Graph theory (GT) simplifies analyzing and comparing complex brain networks. Studies have shown changes in EEG GT measures in AD and PD, but have not been studied in agPPA or PPAOS. The goal of this study was to use GT to characterize network‐level changes and associations with speech and language functioning in patients with agPPA and PPAOS.MethodsScalp EEGs of 14 agPPA and 7 PPAOS patients were collected during relaxed wakefulness (10‐20 positions, 256Hz sampling, 1–200Hz bandpass filter). Eight artifact‐free epochs were selected from non‐overlapping 1024‐point epochs. Via Brainwave software, GT weighted connectivity and minimum spanning tree (MST) measures were calculated for theta and alpha frequency bands. Differences in theta MST measures between agPPA and PPAOS were assessed with Wilcoxon rank‐sum tests. Spearman correlations were computed between behavioral and all network measures across all patients.ResultsTheta frequency MST diameter and eccentricity were significantly lower and leaf was significantly higher in agPPA compared to PPAOS patients; betweenness centrality did not differ. This indicates agPPA networks are more integrated (star‐like) than PPAOS. There were significant correlations between several network measures (e.g. kappa, lambda, PLI) and indices of speech‐language functioning.ConclusionsThe results provide EEG evidence of network alteration in agPPA and PPAOS patients. The GT measures and associations with behavioral measures provide support for reduced global efficiency, or network specificity, in these patients. The correlation of language measures with lambda (path length) in the theta frequency band suggests agPPA is associated with an inefficient path length and/or increased integration. The correlation between apraxia of speech (AOS) measures and MST eccentricity in the alpha frequency band suggests that more severe AOS is associated with reduced distance between two nodes. This study demonstrates potential for EEG GT measures to quantify network changes and distinguish network changes between related but different clinical syndromes.