Essential tremor (ET) is among the most prevalent neurological diseases. Although it was long considered a purely motor disorder, ET is increasingly being regarded as more complex, with an emerging recognition of cognitive dysfunction. While cognitive deficits can be mild, other patients dement. Several epidemiological studies reveal a higher prevalence of mild cognitive impairment (MCI) and 1.5 to 2-fold increased risk of Alzheimer's disease (AD) in ET. Yet the study of cognition/dementia in ET is nascent. Our data are limited and patchy - the most basic ?whats? (i.e., clinical features, clinical course) and ?whys? (i.e., postmortem basis) are uncharted. In sum, there is a cognitive side to ET, and we know little about it. For the past 4 years, we have established and begun to follow an ET cohort to address several of these unknowns (Clinical-Pathological Study of Cognitive Impairment in ET, COGNET). COGNET is the largest (230 enrolled; 195 living), most comprehensive, and only active prospective cohort of ET patients. Key elements are detailed, motor-free, longitudinal cognitive testing, consensus cognitive diagnoses (normal cognition [NC], MCI, dementia), and autopsy data. The study called for a baseline and two follow-up assessments. Currently, mean follow-up from baseline is only 1.50 0.21 years (range = 0.31 - 2.29). Thirty-five died. The data have allowed us to begin to characterize the cognitive deficits in ET and study their pathological bases. Yet, there remain large, obvious gaps in knowledge. First, clinically, are the cognitive impairments in ET progressive? Do they progress at a faster rate than in the general population? What are the conversion rates to MCI and dementia? What are the clinical predictors of cognitive decline? Are cognitive deficits characteristic of AD predictive of worse clinical outcomes? It turns out that we know virtually nothing about the predictors, course and outcomes of cognitive impairments in ET, and such information cannot simply be taken from the general population. With a cohort now successfully assembled and longitudinal cognitive phenotyping ongoing, COGNET is poised to tackle important prognostic issues regarding the predictors and dynamics of cognitive deficits in ET (Aim 1). Second, pathologically, what is the basis for cognitive deficits in ET? Our studies point to heterogeneous deficits with heterogeneous bases, including AD pathologies. We only have 35 postmortems, and our nascent study of the pathological basis for cognitive deficits must grow and come to maturity (Aim 2). We now propose to continue this cohort, adding new measures to characterize the predictors and outcomes of cognitive impairments in ET. We propose enrolling 100 additional ET cases (proposed total n = 295).
AIM 1. To provide the first long-term prospective, longitudinal characterization of cognition in ET to address unanswered prognostic questions about cognitive impairment in ET (e.g., conversion rates to MCI and dementia).
AIM 2. To finalize our clinicopatho- logical study of ET by comparing the neuropathological features of 100 ET to 300 matched non-ET cases, and identifying the cognitive predictors of specific neuropathologies, particularly AD and other tauopathies.

Public Health Relevance

Essential tremor (ET), among the most common neurological illnesses, has traditionally been regarded as a purely motor disorder, but there is a growing body of evidence that cognitive dysfunction is also present and, of additional import, that ET itself seems to be a risk factor for the development of Alzheimer's disease (AD) and other tauopathies. This is an emerging and largely unexplored arena, and the goal of the proposed research is to lead the effort in determining the clinical and pathological characteristics of cognitive impairment in ET, and to identify those characteristics which indicate the presence of AD and other tauopathies. We expect that the proposed research will elucidate the origins of and processes of cognitive impairment in ET and, in due course, have an effect on prognostic counseling and treatment of ET patients with emerging cognitive features.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Adult Psychopathology and Disorders of Aging Study Section (APDA)
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Lungu, Codrin Ion
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University of Texas Sw Medical Center Dallas
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