Kylie Ternes

Multimodal evaluation demonstrates in vivo 18 F-AV-1451 uptake in autopsy-confirmed corticobasal degeneration

in vivo evaluations of F-AV-1451 in patients with pathological confirmation. We report a multimodal evaluation of a 58-year-old male with autopsy-confirmed CBD. He participated in in vivo baseline (15 months pre-death) clinical, F-AV-1451 PET, F-florbetapir PET, MRI, and DTI and longitudinal (5 months pre-death) F-AV-1451 PET research studies (Online Resource 1). When enrolled in research, the patient met clinical criteria for progressive supranuclear palsy (Online Resource 2). Baseline F-AV-1451 (Fig. 1a) revealed the highest retention in deep grey matter areas commonly associated with CBD pathology [1], including bilateral substantia nigra, globus pallidus, and midbrain. Follow-up F-AV1451 revealed more visible retention in bilateral frontal and posterior temporal cortical regions along with midbrain and pons (Fig. 1b). A direct assessment of annualized change revealed a 1–9 % increase in F-AV-1451 retention, which was highest in the pons, medulla, and midbrain along with bilateral frontal and right temporo-parietal cortices (Fig. 1c). Baseline MRI (Fig. 2a) revealed predominantly reduced cortical grey matter in bilateral frontal cortex and right angular gyrus along with deep grey structures, including the midbrain, putamen, right globus pallidus, right caudate, and left hippocampus. White matter revealed increased mean diffusivity (a measure of white matter integrity) in the corpus callosum, bilateral tapetum, pontine crossing fibres, and right lateralized corticospinal tract, and posterior corona radiata. These observations are consistent with previously reported distributions of disease in CBD [6]. Spearman correlations revealed inverse associations between baseline F-AV-1451 and grey matter volume (rs = −0.209; p = 0.016; Fig. 2b) and mean diffusivity (rs = −0.329; p = 0.032; Fig. 2c). Furthermore, we Corticobasal degeneration (CBD) is characterized by 4-repeat misfolded tau (4Rtau) including astrocytic plaques, threads, and neuronal tangles [1]. F-AV-1451 is a PET radioligand that achieves in vivo binding in Alzheimer’s disease (AD) [8] and autoradiographic evidence of binding to paired helical filaments (PHFs) composed of 3-repeat misfolded tau (3Rtau) and 4Rtau characteristic of AD histopathology [4, 5, 7]. However, autoradiographic studies of F-AV-1451 on CBD postmortem tissue failed to demonstrate binding in cortical regions [5, 7], though there was minimal pathology in one study (<1.1 % tau-load) [7]. Another study suggests minimal, but present, autoradiographic binding of F-AV-1451 for 4Rtau [4]. Given mixed autoradiographic evidence in CBD, there is a need for

18F-Flortaucipir PET/MRI Correlations in Nonamnestic and Amnestic Variants of Alzheimer Disease

Nonamnestic Alzheimer disease (AD) variants, including posterior cortical atrophy and the logopenic variant of primary progressive aphasia, differ from amnestic AD in distributions of tau aggregates and neurodegeneration. We evaluated whether 18F-flortaucipir (also called 18F-AV-1451) PET, targeting tau aggregates, detects these differences, and we compared the results with MRI measures of gray matter (GM) atrophy. Methods: Five subjects with posterior cortical atrophy, 4 subjects with the logopenic variant of primary progressive aphasia, 6 age-matched patients with AD, and 6 control subjects underwent 18F-flortaucipir PET and MRI. SUV ratios and GM volumes were compared using regional and voxel-based methods. Results: The subgroups showed the expected 18F-flortaucipir–binding patterns. Group effect sizes were generally stronger with 18F-flortaucipir PET than with MRI volumes. There were moderate-to-high correlations between regional GM atrophy and 18F-flortaucipir uptake. 18F-flortaucipir binding and GM atrophy correlated similarly to cognitive test performance. Conclusion: 18F-flortaucipir binding corresponds to the expected neurodegeneration patterns in nonamnestic AD, with potential for earlier detection of pathology than is possible with MRI atrophy measures.

Estimating frontal and parietal involvement in cognitive estimation: a study of focal neurodegenerative diseases.

We often estimate an unknown value based on available relevant information, a process known as cognitive estimation. In this study, we assess the cognitive and neuroanatomic basis for quantitative estimation by examining deficits in patients with focal neurodegenerative disease in frontal and parietal cortex. Executive function and number knowledge are key components in cognitive estimation. Prefrontal cortex has been implicated in multilevel reasoning and planning processes, and parietal cortex has been associated with number knowledge required for such estimations. We administered the Biber cognitive estimation test (BCET) to assess cognitive estimation in 22 patients with prefrontal disease due to behavioral variant frontotemporal dementia (bvFTD), to 17 patients with parietal disease due to corticobasal syndrome (CBS) or posterior cortical atrophy (PCA) and 11 patients with mild cognitive impairment (MCI). Both bvFTD and CBS/PCA patients had significantly more difficulty with cognitive estimation than controls. MCI were not impaired on BCET relative to controls. Regression analyses related BCET performance to gray matter atrophy in right lateral prefrontal and orbital frontal cortices in bvFTD, and to atrophy in right inferior parietal cortex, right insula, and fusiform cortices in CBS/PCA. These results are consistent with the hypothesis that a frontal-parietal network plays a crucial role in cognitive estimation.

Cognitive reserve in frontotemporal degeneration Neuroanatomic and neuropsychological evidence

Objective: To evaluate if cognitive reserve (CR) contributes to interindividual differences in frontal gray matter density (GMD) and executive impairment that underlie heterogeneity in the disease course of confirmed frontotemporal lobar degeneration (FTLD) pathology. Methods: Fifty-five patients with autopsy confirmation or a pathogenic mutation consistent with underlying tau (FTLD-tau) or TDP-43 (FTLD-TDP) pathology and 90 demographically comparable healthy controls were assessed with T1 MRI and neuropsychological measures (Mini-Mental State Examination, letter fluency, forward digit span, Rey complex figure, and Boston Naming Test). CR was indexed using a composite measure of education and occupation. We used t tests to identify reduced GMD in patients with FTLD relative to controls, regression analyses to relate reduced GMD to CR index, and correlations to relate regions of GMD associated with CR to performance on neuropsychological measures. Results: Patients with FTLD demonstrated impairment on neuropsychological measures. Patients with FTLD exhibited reduced bilateral frontotemporal GMD relative to controls, consistent with the known anatomic distribution of FTLD pathology. Higher CR index was associated with superior letter fluency and with GMD in right dorsolateral prefrontal cortex, orbitofrontal cortex, rostral frontal cortex, and inferior frontal gyrus. Furthermore, we found that higher GMD in frontal regions associated with CR was associated with superior letter fluency. Conclusions: Executive control and verbal ability assessed by letter fluency in FTLD is mediated in part by CR and frontal GMD. The identification of factors influencing cognitive and anatomic heterogeneity in FTLD suggests that CR should be considered in symptom detection, prognosis, and treatment.Objective: To evaluate if cognitive reserve (CR) contributes to interindividual differences in frontal gray matter density (GMD) and executive impairment that underlie heterogeneity in the disease course of confirmed frontotemporal lobar degeneration (FTLD) pathology. Methods: Fifty-five patients with autopsy confirmation or a pathogenic mutation consistent with underlying tau (FTLD-tau) or TDP-43 (FTLD-TDP) pathology and 90 demographically comparable healthy controls were assessed with T1 MRI and neuropsychological measures (Mini-Mental State Examination, letter fluency, forward digit span, Rey complex figure, and Boston Naming Test). CR was indexed using a composite measure of education and occupation. We used t tests to identify reduced GMD in patients with FTLD relative to controls, regression analyses to relate reduced GMD to CR index, and correlations to relate regions of GMD associated with CR to performance on neuropsychological measures. Results: Patients with FTLD demonstrated impairment on neuropsychological measures. Patients with FTLD exhibited reduced bilateral frontotemporal GMD relative to controls, consistent with the known anatomic distribution of FTLD pathology. Higher CR index was associated with superior letter fluency and with GMD in right dorsolateral prefrontal cortex, orbitofrontal cortex, rostral frontal cortex, and inferior frontal gyrus. Furthermore, we found that higher GMD in frontal regions associated with CR was associated with superior letter fluency. Conclusions: Executive control and verbal ability assessed by letter fluency in FTLD is mediated in part by CR and frontal GMD. The identification of factors influencing cognitive and anatomic heterogeneity in FTLD suggests that CR should be considered in symptom detection, prognosis, and treatment.

Dissociation of quantifiers and object nouns in speech in focal neurodegenerative disease.

Quantifiers such as many and some are thought to depend in part on the conceptual representation of number knowledge, while object nouns such as cookie and boy appear to depend in part on visual feature knowledge associated with object concepts. Further, number knowledge is associated with a frontal-parietal network while object knowledge is related in part to anterior and ventral portions of the temporal lobe. We examined the cognitive and anatomic basis for the spontaneous speech production of quantifiers and object nouns in non-aphasic patients with focal neurodegenerative disease associated with corticobasal syndrome (CBS, n=33), behavioral variant frontotemporal degeneration (bvFTD, n=54), and semantic variant primary progressive aphasia (svPPA, n=19). We recorded a semi-structured speech sample elicited from patients and healthy seniors (n=27) during description of the Cookie Theft scene. We observed a dissociation: CBS and bvFTD were significantly impaired in the production of quantifiers but not object nouns, while svPPA were significantly impaired in the production of object nouns but not quantifiers. MRI analysis revealed that quantifier production deficits in CBS and bvFTD were associated with disease in a frontal-parietal network important for number knowledge, while impaired production of object nouns in all patient groups was related to disease in inferior temporal regions important for representations of visual feature knowledge of objects. These findings imply that partially dissociable representations in semantic memory may underlie different segments of the lexicon.

TAU BINDING MEASURED USING PET IN MEDIAL TEMPORAL LOBE CORRELATES WITH SUBREGIONAL ATROPHY AND EPISODIC MEMORY PERFORMANCE IN ALZHEIMER'S DISEASE

TEMPORAL LOBE CORRELATES WITH SUBREGIONAL ATROPHY AND EPISODIC MEMORY PERFORMANCE IN ALZHEIMER’S DISEASE Sandhitsu Das, Jeffrey Phillips, Laura E. M. Wisse, Grace Stockbower, Kylie Ternes, Corey T. McMillan, Paul A. Yushkevich, Murray Grossman, Ilya Nasrallah, David Wolk, University of Pennsylvania, Philadelphia, PA, USA; University of Pennsylvania, Philadelphia, PA, USA. Contact e-mail: sudas@seas.upenn.edu