Clinical Pathological Study of Cognitive Impairment in Essential Tremor

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DESCRIPTION (provided by applicant): Although the most recognizable clinical feature of essential tremor (ET) is tremor, there is emerging evidence that non-motor features (esp. cognitive dysfunction) are present. A growing number of studies show that ET patients have poorer cognitive performance than age-matched controls. In some ET patients, the cognitive problems are severe. Also, recent epidemiological studies have demonstrated that ET patients are more likely to have mild cognitive impairment (MCI) than age-matched controls, and an increased risk of dementia. While ET appears to be a risk factor for the development of cognitive impairment, the cause is not currently known. The cerebellar basis for ET could contribute to cognitive impairment, yet there is other evidence that ET is associated with an increased risk of developing tau-related disorders (Alzheimer's disease [AD] and progressive supranuclear palsy [PSP]). This absence of a mechanistic understanding results in a difficult clinical predicament - there is presently no way to deduce whether a given ET patient, based on his/her observed cognitive features, has early AD, early PSP, or merely the expected cognitive profile of ET. We have no predictive guidelines for patients. What are the next steps? It is important to conclusively characterize the cognitive impairment of ET and to disentangle its component causes. The overall goal of the proposed research is to refine our understanding of this clinical-pathological entity. We aim to perform longitudinal neuropsychological examinations on 350 ET cases and postmortem neuropathological examinations on 110 of these who die over 5 years, matching them to 220 autopsied non-ET cases. The novel concepts/new hypotheses we now put forward are as follows: i) for reasons that are as yet unclear, ET itself predisposes to tauopathic changes in the brain; thus, by extension, even if one were to match for level of cognitive impairment (normal cognition, MCI, or mild dementia), ET cases would still have more tau pathology than non-ET cases, ii) the nature/features of the tauopathy of ET is likely to differ from that of non-ET cases, iii) ET pathology alone, is likely to be the prime cause of cognitive deficits in a subgroup of ET cases, and iv) within the mix of ET cases, it should be possible to map certain cognitive profiles onto certain pathologies. Our 5-year proposal has two aims: AIM 1: To study the neuropathological basis of cognitive deficits in ET. AIM 2: To provide the first comprehensive characterization of cognition in ET and to demonstrate that the severity of certain cognitive deficits predicts non-ET pathology in ET. We expect that this research will elucidate the processes of dementia in ET and shape the counseling and treatment of ET patients with cognitive symptoms.