Whitwell, Jennifer L.

Objective: Progressive apraxia of speech (PAOS) is a neurodegenerative syndrome characterized by impaired motor speech planning and programming, whereas behavioral variant frontotemporal dementia (bvFTD) is characterized by deviant behavioral (e.g., personality and social) features. Clinical and anatomic characteristics of bvFTD in the context of PAOS are understudied. Methods: We identified 12 participants with PAOS and features that were consistent with bvFTD at baseline or follow-up. Eleven completed a head MRI scan. We compared clinical features and anatomical patterns of atrophy in these 11 PAOS-bvFTD participants to 11 matched PAOS participants without bvFTD and 22 age- and sex-matched healthy controls. Statistical Parametric Mapping (SPM) was applied to visualize gray matter volume across both groups compared to controls and each other. Medians and 25th and 75th percentiles were assessed in patients and across groups; Fisher’s Exact Test and Mann–Whitney U tests were applied using BlueSky software, version 10.3.1-Pro. Results: As expected, PAOS-bvFTD participants performed worse on the Frontal Behavioral Inventory (median: 33/72 vs. 10/72), 20-item behavioral assessment scale (4.5/20 vs. 1.0/20), and the Neuropsychiatry inventory (4/36 vs. 1.5/36) compared to the PAOS group (p < 0.01 for all), with no differences in other demographic, neurological, or language tests. Seven of the eleven PAOS-bvFTD participants had bvFTD features develop within three years of symptom onset. The PAOS-bvFTD and PAOS groups showed volume loss in frontal lobe regions compared to controls, with PAOS-bvFTD participants having more prefrontal volume loss than PAOS participants. Conclusions: Behavioral features consistent with bvFTD can co-occur in patients with PAOS and are related to greater atrophy of the prefrontal cortex.

Abstract Objective: We investigated differences in cognition between variants of progressive supranuclear palsy (PSP) including PSP-Richardson (PSP-RS) and subcortical and cortical variants using updated diagnostic criteria and comprehensive neuropsychological assessment. Method: We recruited 140 participants with PSP (age = 71.3 ± 6.9 years; education = 15.0 ± 2.8 years; 49.3% female) who completed neurological and neuropsychological assessment. Participants received diagnoses of PSP clinical variants at their evaluation (or retrospectively if evaluated before 2017) according to the Movement Disorder Society PSP criteria. We grouped variants as PSP-RS (62 participants), PSP-Cortical (25 with PSP-speech/language and 9 with PSP-corticobasal syndrome), and PSP-Subcortical (27 with PSP-parkinsonism, 11 with PSP-progressive gait freezing, and 6 with PSP-postural instability). Analysis of covariance adjusted for age assessed for differences in neuropsychological performance between variants across cognitive domains. Results: PSP-Cortical participants performed worst on measures of visual attention/working memory (Spatial Span Forward/Backward/Total), executive function (Frontal Assessment Battery), and language (Letter Fluency). PSP-RS participants performed worst on verbal memory (Camden Words). There were no significant group differences for the MoCA or indices of visuospatial function. There were no sex or education differences between PSP groups; however, there were differences in age at visit and disease duration. Conclusions: In a large sample of participants with PSP, there were differences in cognition across PSP-RS, PSP-Subcortical, and PSP-Cortical variants, with PSP-Cortical and, to a lesser extent, PSP-RS, performing worse on tests of attention and executive function. These findings suggest cognitive distinctions among PSP clinical variants and highlight the value of neuropsychological assessment in differential diagnosis of PSP subtypes for more accurate and timely clinical classification.

AbstractBackgroundProgressive supranuclear palsy (PSP) can present with different clinical variants which show distinct, but partially overlapping, patterns of neurodegeneration and tau deposition in a PSP network of regions, including cerebellar dentate, superior cerebellar peduncle, midbrain, thalamus, basal ganglia, and frontal lobe. We sought to determine whether disruptions in functional connectivity within this PSP network measured using resting‐state functional MRI (rs‐fMRI) differed between PSP‐Richardson’s syndrome and the cortical and subcortical variants of PSP.MethodStructural MRI and rs‐fMRI scans were collected for 40 PSP‐RS, 24 PSP‐cortical (12 speech and language; 10 corticobasal syndrome; 2 frontal) and 36 PSP‐subcortical (18 parkinsonism; 11 progressive gait freezing; 6 postural instability; 1 oculomotor) participants who met the Movement Disorder Society PSP clinical criteria (Table 1). Ninety‐six participants underwent flortaucipir‐PET scans. MRIs were processed using CONN Toolbox. Functional connectivity between seeds placed throughout the PSP network was compared between each PSP group and 83 healthy controls, and between the PSP groups, covarying for age and sex.ResultsConnectivity was reduced throughout the network in PSP‐RS compared to controls (Figure 1A), involving cerebellar dentate, midbrain nuclei, subthalamic nuclei, basal ganglia, thalamus, and frontal regions. Frontal regions showed reduced connectivity to other regions in the network in PSP‐cortical, including substantia nigra and superior cerebellar peduncle. Disruptions in connectivity in PSP‐subcortical were less pronounced, with the strongest disruption between the pallidum and putamen. When PSP groups were compared to each other (Figure 1B), PSP‐RS had lower connectivity from the thalamus and cerebellar dentate to the cortex compared to PSP‐subcortical and from the thalamus to substantia nigra than PSP‐cortical. PSP‐subcortical had lower connectivity from the subthalamic nucleus to caudate than PSP‐RS and from the subthalamic nucleus to substantia nigra than PSP‐cortical and higher connectivity from the thalamus to the prefrontal cortex than both the other variants. Voxel‐based analyses replicated these patterns. There was moderate evidence that tau uptake in the PSP network regions influenced connectivity between these regions in PSP.ConclusionsPatterns of disrupted functional connectivity revealed both variant‐specific and shared disease pathways among PSP variants, providing insight into the disease heterogeneity beyond patterns of atrophy.

AbstractBackgroundPosterior Cortical Atrophy (PCA) is one of the atypical Alzheimer’s Disease (AD) variants, characterized by predominant visuospatial and visuoperceptual deficits, with dorsal and ventral subtypes recognized clinically and radiographically. A third primary occipital (caudal) variant has been suggested. The objective of this study was to determine its demographics, clinical manifestations, and biomarker findings.MethodFifty‐two PCA patients with positive amyloid PET scans were investigated. Patients underwent neuropsychological assessment, 3T MRI imaging and FDG‐, amyloid‐ and tau‐PET scans. Regional FDG‐PET values were normalized to the pons and 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 (i.e., more abnormal) than the z scores in all other brain regions. Global amyloid‐PET, temporoparietal FDG‐PET and temporal tau‐PET regions‐of‐interest (ROI) were calculated. Student’s T test and Fisher’s exact analyses were used to investigate differences in demographics, clinical findings, and imaging biomarkers across the two groups.ResultNine patients were classified as primary occipital; primary occipital patients were older (64.8±6.9 versus 59.3±6.8, p=0.034) and had more years of education (17.7±1.7 versus 15.1±2.6, p=0.007) compared to the other PCA patients. Clinical evaluation revealed worse performance for the primary occipital group on the Ishihara test for color perception (p<0.001), while the other PCA patients performed worse on the Western Aphasia Battery (WAB) praxis scale (p=0.005). Overall neuropsychiatric symptom burden as defined by the NPI‐Q was lower in the primary occipital group (p<0.001). The FDG‐PET meta‐ROI (weighted median uptake in angular gyrus, posterior cingulate, and inferior temporal ROIs, normalized to the pons and vermis) was higher in the primary occipital subtype (p=0.006), but no differences were observed in amyloid and tau‐PET.ConclusionClinical and biomarker findings suggest primary occipital PCA is characterized by an older age at onset, more color perception dysfunction, less severe ideomotor apraxia and less hypometabolism in temporal‐parietal meta‐ROI compared to more established phenotypes.

AbstractBackgroundWhite matter hyperintensities (WMH) are markers of cerebral small vessel disease and have been associated with higher risk of typical amnestic Alzheimer’s disease (AD), however, little is known about the role of WMHs in atypical variants of AD. This study aimed to determine the frequency and distribution of WMH in two atypical variants of AD: logopenic progressive aphasia (LPA) and posterior cortical atrophy (PCA), and determine whether WMH are associated with demographic and clinical outcomes in these cohorts.MethodSeventy‐five LPA and 39 PCA patients were recruited by the Neurodegenerative Research Group and underwent two‐ dimensional fluid‐attenuated inversion recovery (FLAIR) MRI and Pittsburgh Compound B (PiB) PET. All patients were PiB‐positive. All FLAIR images were segmented using an in‐house software, then were manually edited by a trained imaging analyst. WMH volume was scaled by total intracranial volume to correct for differences in head size. Adjusted WMH burdens were compared between LPA and PCA, and associations were assessed between WMH burden and age, global PiB standard uptake value ratios (SUVRs), and clinical metrics, including tests of general cognitive impairment, executive function, naming, repetition, visuospatial and visuoperceptual function, and parkinsonism. Associations between WMHs and clinical scores were adjusted for age and brain volume to correct for atrophy.ResultTotal WMH burden was similar in PCA and LPA, however, regional differences were identified with PCA having greater subcortical WMH burden in right occipital, parietal, and temporal lobes compared to LPA, and LPA having greater WMH burden in left deep grey and white matter and greater subcortical burden in left parietal lobe compared to PCA. Total WMH burden was greater with older age in both groups but was not related to global PiB SUVR either globally or locally. Greater total WMH was associated with visuoperceptual performance in both cohorts after correcting for atrophy. When assessed regionally, visuoperceptual performance was associated with right subcortical occipital WMH across the cohort.ConclusionRegional distribution of WMHs differ across clinical variants of atypical AD and WMHs may impact clinical outcomes, although further work is needed to determine whether they reflect cerebrovascular disease or regionally specific neurodegenerative changes.

AbstractBackgroundQuantitative susceptibility mapping (QSM) can detect iron distribution in the brain by estimating the local tissue magnetic susceptibility of every voxel. Dysregulation of neuronal iron has been correlated with typical Alzheimer’s disease (tAD), but little is known about iron distribution in atypical clinical presentations of AD such as logopenic progressive aphasia (LPA) and posterior cortical atrophy (PCA).MethodEleven PCA patients and eight LPA patients were recruited by the Neurodegenerative Research Group at Mayo Clinic, Rochester, MN, and underwent MRI that included a five‐echo gradient echo sequence for calculation of QSM. Mean QSM signal was extracted from gray and white matter for regions‐of‐interest across the brain using the Mayo Clinic Adult Lifespan Template. Hierarchical models were fit per‐region and per‐hemisphere to compare PCA and LPA to each other, to 20 healthy controls, and to 20 patients with tAD recruited by the Alzheimer’s Disease Research Center.ResultStrong evidence (posterior probability>0.99) was observed for greater susceptibility in the left middle occipital gyrus and amygdala in both LPA and PCA, and in the right precuneus and inferior temporal gyrus in PCA compared to controls. Moderate evidence for greater susceptibility (posterior probability>0.90) was also observed in the left insula, inferior occipital gyrus, entorhinal cortex, and right inferior parietal gyrus and amygdala in both LPA and PCA, along with right angular gyrus and middle occipital gyrus in PCA and right insula and caudate in LPA, when compared to controls. Comparing between phenotypes, LPA showed moderate evidence for greater susceptibility in the caudate, hippocampus, substantia nigra, left supramarginal gyrus and posterior cingulate compared to PCA, while PCA showed greater susceptibility in the right precuneus compared to LPA. Both LPA and PCA showed moderate‐strong evidence for greater susceptibility than tAD, particularly in medial and lateral parietal regions.ConclusionUnique iron profiles were identified in LPA and PCA within cortical and subcortical structures. These changes are in line with disease‐related neurodegenerative changes in the clinical phenotypes, suggesting that QSM could be an informative marker to study iron deposition in these patients.

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.

Abstract Background In 2017, the International Parkinson and Movement Disorder Society put forward new clinical criteria for the diagnosis of PSP, recognizing diverse PSP phenotypes. In this study, we compared the sensitivity and specificity of the new criteria with the National Institutes of Neurological Disease and Society for Progressive Supranuclear Palsy criteria at different times. Methods Patients with clinical parkinsonism, clinical and/or neuropathological diagnosis of PSP, were identified from the Society for Progressive Supranuclear Palsy brain bank. All patients had neuropathologic diagnoses and detailed clinical examination performed by a neurologist at 1 of the 3 Mayo Clinic sites, in Florida, Arizona, and Minnesota. Clinical symptoms and signs were abstracted retrospectively in a blinded fashion and used to determine whether patients met either diagnostic criterion. Patients were divided into early and late disease stage groups using a 3‐year cutoff. Results A total of 129 patients were included, of whom 66 had PSP pathology (51%). The remainder had other neurodegenerative diseases. The overall sensitivity of the International Parkinson and Movement Disorder Society criteria was 87.9%, compared with 45.5% for the National Institutes of Neurological Disease and Society for Progressive Supranuclear Palsy criteria, whereas the specificity of the International Parkinson and Movement Disorder Society probable PSP criteria was 85.7%, compared with 90.5% for the National Institutes of Neurological Disease and Society for Progressive Supranuclear Palsy. Individual patients were noted to have features of multiple PSP phenotypes. Conclusion The International Parkinson and Movement Disorder Society criteria recognize several phenotypes of progressive supranuclear palsy and hence have higher sensitivity than the previous criteria. © 2019 International Parkinson and Movement Disorder Society