Prevalence of and Annual Conversion Rates to Mild Cognitive Impairment and Dementia: Prospective, Longitudinal Study of an Essential Tremor Cohort.

OBJECTIVE: Despite recent attention to cognitive impairment in essential tremor, few studies examine rates of conversion to diagnoses of mild cognitive impairment and dementia. Development of dementia in essential tremor is associated with loss of functional ability and a doubling of mortality rate. This prospective, longitudinal study comprehensively reports the prevalence and incidence of, and the annual rates of conversion to, mild cognitive impairment and dementia in an essential tremor cohort. METHODS: Patients underwent detailed cognitive assessments and were assigned diagnoses of normal cognition, mild cognitive impairment, or dementia. There were 222 patients at baseline (mean age = 79.3 ± 9.7 years), and 177 patients participated in follow-up evaluations at 18, 36, 54, and 72 months (mean years of observation = 5.1 ± 1.7). Data were compared to those of historical controls and Parkinson disease patients. RESULTS: The cumulative prevalence of dementia and average annual conversion rate of mild cognitive impairment to dementia were 18.5% and 12.2%, nearly three times higher than rates in the general population, and approximately one half the magnitude of those reported for Parkinson disease patients. The cumulative prevalence of mild cognitive impairment (26.6%) was almost double that of the general population, but less than that in Parkinson disease populations. INTERPRETATION: We present the most complete exposition of the longitudinal trajectory of cognitive impairment in an essential tremor cohort yet presented. The prevalence of and conversion rates to dementia in essential tremor fall between those associated with the natural course of aging and the more pronounced rates observed in Parkinson disease. ANN NEUROL 2024;95:1193-1204.

Decreased Synaptic Vesicle Glycoprotein 2A Binding in the Human Postmortem Essential Tremor Cerebellum: Evidence of Reduction in Synaptic Density.

OBJECTIVE: Despite being one of the most prevalent neurological diseases, the pathophysiology of essential tremor (ET) is not fully understood. Neuropathological studies have identified numerous degenerative changes in the cerebellum of ET patients, however. These data align with considerable clinical and neurophysiological data linking ET to the cerebellum. While neuroimaging studies have variably shown mild atrophy in the cerebellum, marked atrophy is not a clear feature of the cerebellum in ET and a search for a more suitable neuroimaging signature of neurodegeneration is in order. Postmortem studies in ET have examined different neuropathological alterations in the cerebellum, but as of yet have not focused on measures of generalized synaptic markers. This pilot study focuses on synaptic vesicle glycoprotein 2A (SV2A), a protein expressed in practically all synapses in the brain, as a measure of synaptic density in postmortem ET cases. METHODS: The current study utilized autoradiography with the SV2A radioligand [18F]SDM-16 to assess synaptic density in the cerebellar cortex and dentate nucleus in three ET cases and three age-matched controls. RESULTS: Using [18F]SDM-16, SV2A was 53% and 46% lower in the cerebellar cortex and dentate nucleus, respectively, in ET cases compared to age-matched controls. CONCLUSION: In this pilot study, using in vitro SV2A autoradiography, we have observed significantly lower synaptic density in the cerebellar cortex and dentate nucleus of ET cases. Future research could expand on our sample size and focus on in vivo imaging in ET to explore whether SV2A imaging could serve as a much-needed disease biomarker.

Decreased Synaptic Vesicle Glycoprotein 2A Binding in the Human Postmortem Essential Tremor Cerebellum: Evidence of Reduction in Synaptic Density.

Objective Despite being one of the most prevalent neurological diseases, the pathophysiology of essential tremor (ET) is not fully understood. Neuropathological studies have identified numerous degenerative changes in the cerebellum of ET patients, however. These data align with considerable clinical and neurophysiological data linking ET to the cerebellum. While neuroimaging studies have variably shown mild atrophy in the cerebellum, marked atrophy is not a clear feature of the cerebellum in ET and that a search for a more suitable neuroimaging signature of neurodegeneration is in order. Postmortem studies in ET have examined different neuropathological alterations in the cerebellum, but as of yet have not focused on measures of generalized synaptic markers. This pilot study focuses on synaptic vesicle glycoprotein 2A (SV2A), a protein expressed in practically all synapses in the brain, as a measure of synaptic density in postmortem ET cases. Methods The current study utilized autoradiography with the SV2A radioligand [ 18 F]SDM-16 to assess synaptic density in the cerebellar cortex and dentate nucleus in three ET cases and three age-matched controls. Results Using [ 18 F]SDM-16, SV2A was 53% and 46% lower in the cerebellar cortex and dentate nucleus, respectively, in ET cases compared to age-matched controls. Conclusion For the first time, using in vitro SV2A autoradiography, we have observed significantly lower synaptic density in the cerebellar cortex and dentate nucleus of ET cases. Future research could focus on in vivo imaging in ET to explore whether SV2A imaging could serve as a much-needed disease biomarker.

Characterizing Lewy Pathology in 231 Essential Tremor Brains From the Essential Tremor Centralized Brain Repository.

The Essential Tremor Centralized Brain Repository is the largest repository of prospectively collected essential tremor (ET) brains (n = 231). Hence, we are uniquely poised to address several questions: What proportion of ET cases has Lewy pathology (LP)? What is the nature of that pathology and how does it relate to other comorbidities? Each brain had a complete neuropathological assessment, including α-synuclein immunostaining. We created a 10-category classification scheme to fully encapsulate the patterns of LP observed. Four metrics of cerebellar pathology were also quantified. Mean age at death = 89.0 ± 6.4 years. Fifty-eight (25.1%) had LP and 46 (19.9%) had early to late stages of Parkinson disease (PD). LP was very heterogeneous. Of 58 cases with LP, 14 (24.1%) clinically developed possible PD or PD after a latency of 5 or more years. There was a similar degree of cerebellar pathology in ET cases both with and without LP. In summary, 1 in 4 ET cases had LP-a proportion that seems higher than expected based on studies among control populations. Heterogeneous LP likely reflects clinical associations between ET and PD, and ET with Alzheimer disease-type neuropathology. These data further our understanding of ET and its relatedness to other degenerative diseases.

Through the Looking Glass: Remote Versus In-Person Videotaped Neurologic Assessment of Essential Tremor.

BACKGROUND: Remote assessment of essential tremor (ET) is unverified. OBJECTIVES: To compare assigned tremor scores from a remote videotaped research protocol with those from an in-person videotaped research protocol and assess the validity of remote and in-person videotape-based diagnoses when compared against the intake diagnosis (ET vs. control). METHODS: Participants with intake diagnoses of ET (11) or controls (15) completed a tremor examination that was filmed both remotely and in person. RESULTS: Agreement between the tremor ratings assigned during remote and in-person videos was substantial (composite κw, 0.67; mean Gwet's AC2 score, 0.92; mean percent agreement, 63.7%). In ET cases with less severe tremor, agreement was lower (p = 0.008). Diagnostic validity was high for both remote and in-person videos compared to the intake diagnosis. CONCLUSIONS: Remote video is a reasonable alternative to in-person video for the assessment of tremor severity and assignment of ET diagnoses. However, at low tremor amplitudes, agreement declines.

Mixed Motor Disorder: Essential Tremor Families With Heterogeneous Motor Phenomenology.

BACKGROUND AND OBJECTIVES: Essential tremor (ET) is one of the most prevalent movement disorders. Because ET is so common, individuals with other neurologic disorders may also have ET. There is evidence, however, that the cooccurrence of ET with Parkinson disease (PD) and/or dystonia is not merely a chance cooccurrence. We have observed combinations of these 3 movement disorders within individuals and across individuals within families containing multiple individuals with ET. This observation has a number of implications. Our objective is to present 4 ET families in whom motor phenomenology was heterogeneous and discuss the implications of this finding. METHODS: ET cases and their relatives were enrolled in the Family Study of Essential Tremor (2015-present). Phenotyping was performed by a senior movement disorders neurologist based on neurologic examination. RESULTS: We present 4 families, including 14 affected individuals, among whom assigned diagnoses were ET, PD, ET + PD, and ET + dystonia. In those with ET and another movement disorder, the predominant and earliest phenotype was ET. DISCUSSION: There are assortments of these 3 involuntary motor disorders, ET, dystonia, and PD, both within individuals and in different individuals within ET families. This observation has mechanistic implications. Furthermore, we believe that the concept of the mixed motor disorder should enter into and inform the clinical dialogue. In assigning diagnoses, clinicians are swayed by family history information, and they should be prepared to observe a mix of different motor disorders to manifest within particular families.

Banking brains: a pre-mortem "how to" guide to successful donation.

A review of the brain banking literature reveals a primary focus either on the factors that influence the decision to become a future donor or on the brain tissue processing that takes place after the individual has died (i.e., the front-end or back-end processes). What has not been sufficiently detailed, however, is the complex and involved process that takes place after this decision to become a future donor is made yet before post-mortem processing occurs (i.e., the large middle-ground). This generally represents a period of many years during which the brain bank is actively engaged with donors to ensure that valuable clinical information is prospectively collected and that their donation is eventually completed. For the past 15 years, the Essential Tremor Centralized Brain Repository has been actively involved in brain banking, and our experience has provided us valuable insights that may be useful for researchers interested in establishing their own brain banking efforts. In this piece, we fill a gap in the literature by detailing the processes of enrolling participants, creating individualized brain donation plans, collecting clinical information and regularly following-up with donors to update that information, and efficiently coordinating the brain harvest when death finally arrives.

Jaw Tremor Resulting in Broken Teeth: On the Essential Tremor Spectrum.

BACKGROUND: Jaw tremors in essential tremor (ET) rarely represent anything other than a cosmetic concern. PHENOMENOLOGY SHOWN: A case of an ET patient whose jaw tremor was severe enough to result in cracked teeth. EDUCATIONAL VALUE: It behooves treating clinicians to be aware of the full spectrum of this movement disorder.

Jaw tremor: prevalence and clinical correlates in three essential tremor case samples.

The spectrum of involuntary movements seen in essential tremor (ET) is limited. Jaw tremor is one such movement. The prevalence and clinical correlates of jaw tremor have not been studied in detail. The objective of this study was to estimate the prevalence and examine the clinical correlates of jaw tremor in ET using ET cases from three distinct settings (population, tertiary-referral center, brain repository). All ET cases underwent a videotaped tremor examination in which tremors (including limb, head, voice, and jaw) were assessed. The prevalence [95% confidence interval (CI)] of jaw tremor was lowest in the population sample (7.5%; 3.9%-14.2%), intermediate in the tertiary-referral center (10.1%; 6.8%-14.7%), and highest in the brain repository (18.0%; 12.3%-25.5%; P = 0.03). Jaw tremor was associated with older age (P < 0.001), more severe action tremor of the arms (P < 0.001), and presence of head and voice tremor (P < 0.001). Jaw tremor was present in 4/14 (28.6%) ET cases with consistent rest tremor vs. 15/193 (7.8%) cases without rest tremor (odds ratio = 4.8; 95% CI = 1.3-7.0; P = 0.009). The prevalence of jaw tremor was 7.5% to 18.0% and was dependent on the mode of ascertainment, being least prevalent in a population-based sample. ET cases with jaw tremor had a more clinically severe and more topographically widespread disorder. The association in our study between jaw tremor and rest tremor, along with the published observation that jaw tremor can occur in Parkinson's disease (PD), raises the question whether jaw tremor in ET is a marker for subsequent conversion to PD.