Distinct spatiotemporal atrophy patterns in corticobasal syndrome are associated with different underlying pathologies.

Objective: To identify imaging subtypes of the cortico-basal syndrome (CBS) based solely on a data-driven assessment of MRI atrophy patterns, and investigate whether these subtypes provide information on the underlying pathology. Methods: We applied Subtype and Stage Inference (SuStaIn), a machine learning algorithm that identifies groups of individuals with distinct biomarker progression patterns, to a large cohort of 135 CBS cases (52 had a pathological or biomarker defined diagnosis) and 252 controls. The model was fit using volumetric features extracted from baseline T1-weighted MRI scans and validated using follow-up MRI. We compared the clinical phenotypes of each subtype and investigated whether there were differences in associated pathology between the subtypes. Results: SuStaIn identified two subtypes with distinct sequences of atrophy progression; four-repeat-tauopathy confirmed cases were most commonly assigned to the Subcortical subtype (83% of CBS-PSP and 75% of CBS-CBD), while CBS-AD was most commonly assigned to the Fronto-parieto-occipital subtype (81% of CBS-AD). Subtype assignment was stable at follow-up (98% of cases), and individuals consistently progressed to higher stages (100% stayed at the same stage or progressed), supporting the model's ability to stage progression. Interpretation: By jointly modelling disease stage and subtype, we provide data-driven evidence for at least two distinct and longitudinally stable spatiotemporal subtypes of atrophy in CBS that are associated with different underlying pathologies. In the absence of sensitive and specific biomarkers, accurately subtyping and staging individuals with CBS at baseline has important implications for screening on entry into clinical trials, as well as for tracking disease progression.

Active lifestyles moderate clinical outcomes in autosomal dominant frontotemporal degeneration.

INTRODUCTION: Leisure activities impact brain aging and may be prevention targets. We characterized how physical and cognitive activities relate to brain health for the first time in autosomal dominant frontotemporal lobar degeneration (FTLD). METHODS: A total of 105 mutation carriers (C9orf72/MAPT/GRN) and 69 non-carriers reported current physical and cognitive activities at baseline, and completed longitudinal neurobehavioral assessments and brain magnetic resonance imaging (MRI) scans. RESULTS: Greater physical and cognitive activities were each associated with an estimated >55% slower clinical decline per year among dominant gene carriers. There was also an interaction between leisure activities and frontotemporal atrophy on cognition in mutation carriers. High-activity carriers with frontotemporal atrophy (-1 standard deviation/year) demonstrated >two-fold better cognitive performances per year compared to their less active peers with comparable atrophy rates. DISCUSSION: Active lifestyles were associated with less functional decline and moderated brain-to-behavior relationships longitudinally. More active carriers "outperformed" brain volume, commensurate with a cognitive reserve hypothesis. Lifestyle may confer clinical resilience, even in autosomal dominant FTLD.

Multicenter validation of a bedside antisaccade task as a measure of executive function.

OBJECTIVE: To create and validate a simple, standardized version of the antisaccade (AS) task that requires no specialized equipment for use as a measure of executive function in multicenter clinical studies. METHODS: The bedside AS (BAS) task consisted of 40 pseudorandomized AS trials presented on a laptop computer. BAS performance was compared with AS performance measured using an infrared eye tracker in normal elders (NE) and individuals with mild cognitive impairment (MCI) or dementia (n = 33). The neuropsychological domain specificity of the BAS was then determined in a cohort of NE, MCI, and dementia (n = 103) at UCSF, and the BAS was validated as a measure of executive function in a 6-center cohort (n = 397) of normal adults and patients with a variety of brain diseases. RESULTS: Performance on the BAS and laboratory AS task was strongly correlated and BAS performance was most strongly associated with neuropsychological measures of executive function. Even after controlling for disease severity and processing speed, BAS performance was associated with multiple assessments of executive function, most strongly the informant-based Frontal Systems Behavior Scale. CONCLUSIONS: The BAS is a simple, valid measure of executive function in aging and neurologic disease.

Spatial summation in the receptive fields of MT neurons.

Receptive fields (RFs) of cells in the middle temporal area (MT or V5) of monkeys will often encompass multiple objects under normal image viewing. We therefore have studied how multiple moving stimuli interact when presented within and near the RF of single MT cells. We used moving Gabor function stimuli, <1 degrees in spatial extent and approximately 100 msec in duration, presented on a grid of possible locations over the RF of the cell. Responses to these stimuli were typically robust, and their small spatial and temporal extent allowed detailed mapping of RFs and of interactions between stimuli. The responses to pairs of such stimuli were compared against the responses to the same stimuli presented singly. The responses were substantially less than the sum of the responses to the component stimuli and were well described by a power-law summation model with divisive inhibition. Such divisive inhibition is a key component of recently proposed "normalization" models of cortical physiology and is presumed to arise from lateral interconnections within a region. One open question is whether the normalization occurs only once in primary visual cortex or multiple times in different cortical areas. We addressed this question by exploring the spatial extent over which one stimulus would divide the response to another and found effective normalization from stimuli quite far removed from the RF center. This supports models under which normalization occurs both in MT and in earlier stages.