Clinical Pathological Study of Essential Tremor-Dementia - Essential tremor (ET) is a neurodegenerative disease whose defining clinical feature is action tremor. Aside from the disabling effects of tremor, we are learning that ET appears to be a risk factor for dementia among older adults (relative risks [RR] 1.64 – 1.89). In fact, recently completed studies indicate that the rate of conversion from normal cognition to dementia in older adults with ET is approximately three-times higher than in older adults without ET. Hence, we are witnessing an emerging recognition of a new association – ET with concomitant dementia (ET+D). As interesting as this is from a scientific perspective, given the extraordinarily high prevalence of ET (2.2% of the US population - 7 million people), the increased risk of dementia is concerning from clinical and public health perspectives. As with most new entities, our knowledge is limited. Preliminary data suggest that ET+D shares some, but not all, cognitive and neuropathologic features with established tauopathies (e.g., Alzheimer’s disease [AD] and Primary Age Related Tauopathy [PART]). However, there are fundamental gaps in knowledge about ET+D including its cognitive presentation, pathological and molecular underpinnings, and in vivo biomarkers. The PI (Dr. Louis) directs the Clinical Pathological Study of Cognitive Impairment in ET (COGNET, NINDS R01 NS086736, 2014 - 2025), a prospective, longitudinal cohort study of cognition in older ET subjects, with postmortem neuropathological analyses. It is the only ET-focused prospective, clinical-pathological cohort study. Building on the unique bank of ET brains with deep antemortem phenotyping in the COGNET study, we now seek to collect sufficient ET+D cases and ET+D brains to characterize ET+D as both a clinical and patho-mechanistic entity. To date, neither we nor others have characterized the cognitive features or the clinical predictors of ET+D (Aim 1). Further, the neuropathological features of ET+D are largely unknown, and matched comparisons with non-demented ET cases and individuals with other dementias (e.g., AD dementia) are needed (Aim 2). Reports have indicated increased tau pathology in ET, suggesting that ET+D is a form of tauopathy. However, classification of tauopathies is now advancing beyond conventional histology, through studies of tau fold structure. Toward that end, our recent pilot work indicates that ET+D cases exhibit tau fibril structures that are the same as that in AD and PART, although there seem to be some unique features as well (Aim 3). Finally, in vivo blood-based biomarkers (BBB), now acceptable as diagnostic tests for AD and reliable means of characterizing a range of neurodegenerative pathologies, have never been assessed as in vivo biomarkers for ET+D (Aim 4). At present, the field is at the point with ET that it was with Parkinson’s disease in the 1980s, when neurologists began to gain an inkling that cognitive symptoms were common and often severe in that disease. The proposed studies of ET+D aim to fill fundamental gaps in knowledge and drive our scientific understanding of this nascent clinical entity. We owe it to our patients to understand more.
