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.

Serum Neurofilament Light-Chain Concentrations in Essential Tremor: a Case-Control Study.

Essential tremor (ET) is a common neurological disorder, with clinical and pathophysiological links to the cerebellum. Inquiries into the etiology, pathophysiology, and nosology of ET stand to benefit from the identification of disease biomarkers. Serum neurofilament light chain (NfL) has emerged as a novel signature of conditions in which neuronal injury reflects an outcome of the ongoing disease process. We sought to investigate the concentrations of NfL in ET patients and healthy controls. In this case-control study, our powered study population of 41 ET patients and 40 age-matched healthy controls underwent clinical assessments and measurement of serum NfL concentration using Simoa technology. Serum NfL was elevated in ET patients - mean log-transformed serum NfL concentration = 1.23 ± 0.19 (95% confidence interval [CI] = 1.17-1.29) vs. 1.08 ± 0.15 (95% CI = 1.03-1.13), p = 0.0002. This difference persisted after accounting for age, sex and Montreal Cognitive Assessment score in a multiple linear regression model (p = 0.002) and in an age-matched sample subset of 35 ET cases and 35 controls (p = 0.006). There was no association between tremor severity and serum NfL levels (p = 0.73). In this sample of ET patients and controls, serum NfL concentrations were significantly higher in ET. Studies in additional cohorts of ET cases would be of value in attempting to replicate these results and assessing diagnostic utility.

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.

A three wave assessment of a tobacco free campus policy within a minority serving institution.

OBJECTIVE: This study assessed changes (in relation to smoking status) in tobacco use, attitudes toward TFC policies, and tobacco use risk knowledge by applying a three Wave repeated cross-sectional assessment. PARTICIPANTS: Participants were students at Wave 1 (n = 2,169), Wave 2 (n = 2,576), and Wave 3 (n = 2,169) and faculty at Wave 1 (n = 256), Wave 2 (n = 204), and Wave 3 (n = 180). METHODS: Measures regarding sociodemographics, tobacco use, attitudes toward TFC policies, and tobacco use risk knowledge were completed. RESULTS: Compared with Wave 1, more students reported having quit smoking within the last six months at Waves 2 and 3. The negative attitudes toward TFC policies of those who reported quitting in the last six months aligned with those of nonsmokers. CONCLUSIONS: Study findings suggest smoking status as a relevant covariate to focus on to further strengthen and refine existing TFC policies.

Whole genome sequencing identifies candidate genes for familial essential tremor and reveals biological pathways implicated in essential tremor aetiology.

BACKGROUND: Essential tremor (ET), one of the most common neurological disorders, has a phenotypically heterogeneous presentation characterized by bilateral kinetic tremor of the arms and, in some patients, tremor involving other body regions (e.g., head, voice). Genetic studies suggest that ET is genetically heterogeneous. METHODS: We analyzed whole genome sequence data (WGS) generated on 104 multi-generational white families with European ancestry affected by ET. Genome-wide parametric linkage and association scans were analyzed using adjusted logistic regression models through the application of the Pseudomarker software. To investigate the additional contribution of rare variants in familial ET, we also performed an aggregate variant non-parametric linkage (NPL) analysis using the collapsed haplotype method implemented in CHP-NPL software. FINDINGS: Parametric linkage analysis of common variants identified several loci with significant evidence of linkage (HLOD ≥3.6). Among the gene regions within the strongest ET linkage peaks were BTC (4q13.3, HLOD=4.53), N6AMT1 (21q21.3, HLOD=4.31), PCDH9 (13q21.32, HLOD=4.21), EYA1 (8q13.3, HLOD=4.04), RBFOX1 (16p13.3, HLOD=4.02), MAPT (17q21.31, HLOD=3.99) and SCARB2 (4q21.1, HLOD=3.65). CHP-NPL analysis identified fifteen additional genes with evidence of significant linkage (LOD ≥3.8). These genes include TUBB2A, VPS33B, STEAP1B, SPINK5, ZRANB1, TBC1D3C, PDPR, NPY4R, ETS2, ZNF736, SPATA21, ARL17A, PZP, BLK and CCDC94. In one ET family contributing to the linkage peak on chromosome 16p13.3, we identified a likely pathogenic heterozygous canonical splice acceptor variant in exon 2 of RBFOX1 (ENST00000547372; c.4-2A>G), that co-segregated with the ET phenotype in the family. INTERPRETATION: Linkage and association analyses of WGS identified several novel ET candidate genes, which are implicated in four major pathways that include 1) the epidermal growth factor receptor-phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha-AKT serine/threonine kinase 1 (EGFR-PI3K-AKT) and Mitogen-activated protein Kinase 1 (ERK) pathways, 2) Reactive oxygen species (ROS) and DNA repair, 3) gamma-aminobutyric acid-ergic (GABAergic) system and 4) RNA binding and regulation of RNA processes. Our study provides evidence for a possible overlap in the genetic architecture of ET, neurological disease, cancer and aging. The genes and pathways identified can be prioritized in future genetic and functional studies. FUNDING: National Institutes of Health, NINDS, NS073872 (USA) and NIA AG058131(USA).

The Use of a SWOT Analysis to Evaluate a COVID-19 Mitigation Project in the Paso del Norte Region.

A SWOT (strengths, weaknesses, opportunities, and threats) analysis is a strategic planning and management technique used for project planning. It is sometimes called situational assessment or situational analysis. We applied this tool (with some adaptations) effectively in a health promotion/public health education intervention project in the Paso del Norte region. This region is composed of a predominantly Hispanic population and is marked by a dynamic flow of residents across the border. In this milieu, COVID-19 has disproportionately impacted communities of color and individuals who are economically and socially marginalized. The University of Texas at El Paso (UTEP) has partnered with the National COVID-19 Resilience Network (NCRN) to mitigate the impact of COVID-19 among farm and food production workers (i.e., farmworkers, dairy, and meat packing workers) in El Paso, Doña Ana, and Moore counties. Intervention strategies include: (1) providing culturally and linguistically appropriate COVID-19 information, (2) disseminating protective equipment, and (3) ensuring access to COVID-19 vaccines. After completing year 1 of the project, we conducted a multiple-level SWOT analysis to evaluate, gather insights, and develop actionable strategies that would allow better service delivery to our priority population. We provide this case study to illustrate how a SWOT analysis can be a useful tool for practitioners engaged in the practice of evaluating health promotion and disease prevention programs. Even when attention and energy is absorbed in the immediate course of action, a SWOT analysis can help to achieve positive and effective collaborations resulting in strong service levels.

Brain Donation Decisions as Disease Specific Behaviors: An Elucidation of the Donation Process in the Context of Essential Tremor.

Brain donation is a challenging process, comprising four sequential stages: (1) the brain donation decision, (2) pre-mortem arrangements and follow up, (3) specimen collection and (4) tissue processing. It is important to understand the factors that are pertinent to each stage. Currently, there is extensive information on factors that involve donor's personal and cultural backgrounds and how these could affect the process. However, little is known about disease-specific factors that influence the process. The Essential Tremor Centralized Brain Repository was established in 2003, and after nearly 20 years of collecting essential tremor (ET) brain tissue, we are well-positioned to discuss the brain donation process from a disease-specific standpoint. In the current manuscript, we discuss ET disease-specific factors that influence the first two stages of the brain donation process. We center our discussion around three points: (1) factors that influence the patient's decision to donate, (2) the involvement of next of kin in the donation, and (3) the rationale for enrolling patients prospectively and evaluating them longitudinally before the anatomical gift takes place. This discussion shares our understanding of the background from which our repository operates and may be of value for other brain banks that study similar neurodegenerative diseases.

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.

Lack of Familial Aggregation of the "Essential Tremor-Plus" Phenotype in Familial Essential Tremor.

BACKGROUND: Essential tremor (ET) is a highly prevalent neurological disease that frequently runs in families. A recent and controversial proposal is to separate ET patients into two distinct groups - ET versus ET-plus. If this were a valid construct, one would expect in familial aggregation studies to observe that ET-plus would cluster in some families yet be absent in others, rather than being randomly distributed across families. We examined whether there is evidence of familial aggregation of ET-plus. METHODS: Probands (n = 84 [56 ET-plus and 28 ET]) and their first- and second-degree relatives (n = 182 and 48) enrolled in a genetics study. χ2 and generalized estimating equations (GEE) tested associations between probands' ET-plus status and the ET-plus status of their relatives. RESULTS: χ2 analyses revealed that ET-plus was no more prevalent in relatives of probands diagnosed with ET-plus than in relatives of probands diagnosed with ET, p > 0.05. Restricting relatives to first-degree relatives similarly did not detect a significant association (p = 0.88). GEE yielded similar results (respective p's = 0.39 and 0.81). CONCLUSION: The data demonstrate that ET-plus does not seem to aggregate in families. As such, they do not lend support to the notion that ET-plus is a valid biological construct.

Distribución espacial de la morbimortalidad atribuible a la contaminación del aire por PM2.5 en Medellín (Colombia), 2010-2016

Objetivo: Esta investigación buscó establecer la distribución espacial de la morbimortalidad atribuible a la contaminación del aire ambiental por materia particulada (particulate matter 2.5) (PM2.5) en Medellín entre 2010 y 2016. Metodología: Se planteó un estudio ecológico. Se estandarizaron las direcciones de residencia de los pacientes atendidos y las defunciones por eventos de interés. Se emplearon mapas de calor, mediante el análisis de densidad de Kernel, por núcleos domiciliarios para áreas de 10 000 m2. Resultados: Se encontraron 45 487 y 2743 casos y defunciones, respectivamente, atribuibles a la contaminación del aire ambiental por PM2.5 con datos de localización geográfica. La zona suroccidental de la ciudad presentó las mayores densidades de eventos atribuibles por todas las causas estudiadas y por grupo de eventos, con algunas áreas pequeñas en otros lugares. Por su parte, la zona suroriental, con las mejores condiciones socioeconómicas, manifestó la menor concentración de eventos atribuibles. Conclusión: La información geocodificada de la morbimortalidad por núcleos domiciliarios posibilitó establecer la distribución de casos y muertes atribuibles a la contaminación ambiental del aire por PM2.5 en Medellín, con mayor concentración al suroccidente de la ciudad, lo que permite evidenciar la presencia de disparidades territoriales de este fenómeno.

Objective: This research aimed to establish the spatial distribution of morbidity and mortality attributable to particulate matter (pm2.5) air pollution in Medellín between 2010 and 2016. Methodology: An ecological study was proposed. Addresses of patients treated and deceased due to events of interest were standardized. Heat maps were used, through Kernel density analysis per residential units for areas of 10,000 m2. Results: 45,487 cases and 2,743 deaths attributable to pm2.5 air pollution with geographic location data were found. The southwestern area of the city presented the highest event densities attributable to all causes studied and by group of events, with some small areas in other places. On the other hand, the southeastern area, with the best socio-economic conditions, showed the lowest concentration of attributable events. Conclusion: Geocoded information of morbidity and mortality by residential units made it possible to establish the distribution of cases and deaths attributable to pm2.5 air pollution in Medellín, with a greater concentration in the southwestern part of the city, which makes the presence of territorial disparities in this phenomenon observable.

Objetivo: Esta pesquisa procurou estabelecer a distribuição espacial da morbimortalidade atribuível à poluição do ar ambiental por matéria particulada (particulate matter 2.5) (PM2.5) em Medellín entre 2010 e 2016. Metodologia: Propôs-se uma abordagem ecológica. Padronizaram-se os endereços de residência dos pacientes atendidos e as mortes por eventos de interesse. Empregaram-se mapas de calor, por meio da análise de densidade de Kernel, por núcleos domiciliários para áreas de 10000 m2. Resultados: Acharam-se 45487 e 2743 casos e mortes, respectivamente, atribuíveis à poluição do ar ambiental por PM2.5 com dados de localização geográfica. A zona do sudoeste da cidade apresentou as maiores densidades de eventos atribuíveis por todas as causas estudadas e por grupo de eventos, com algumas áreas pequenas em outros lugares. Por sua parte, a zona do sudeste, com as melhores condições socioeconômicas, manifestou a menor concentração de eventos atribuíveis. Conclusão: A informação geocodificada da morbimortalidade por núcleos domiciliários possibilitou estabelecer a distribuição de casos e mortes atribuíveis à poluição ambiental do ar por PM2.5 em Medellín, com maior concentração no sudoeste da cidade, o que permite evidenciar a presença de disparidades territoriais deste fenômeno

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.

The Progression of Essential Tremors: Illustrative Videos.

Background: Essential tremor (ET) is a progressive neurological disease whose natural history is one of progressive increase in tremor severity over time; surprisingly though, there are no published videotape diaries that visually and tangibly portray this progression over time. Phenomenology: Progressive, stepwise increase in limb tremor severity over a ten-to-fifteen-year period in three patients with ET. Educational value: We hope that this brief visual diary will serve as a useful teaching tool for students, primary care physicians, and neurologists to "see with their own eyes" the extent of change that can occur in the ETs.

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.

Brain donation in the era of COVID 19: challenges to the harvest in the face of a pandemic.

We have experienced numerous new challenges during the process of brain harvesting in the period of COVID-19. Although brain harvests have continued successfully during this time period, the numerous uncertainties and challenges described in this paper have nearly derailed the process several times. While the interface of the medical profession with patients in the context of a pandemic has been well-documented on several fronts, and particularly for those health care workers on the front lines, we are not aware of any documentary accounts of the challenges facing research and tissue donation programs. With this paper, we contribute an additional perspective and describe the lessons we have learned in addressing these novel issues.

Whole genome sequencing and rare variant analysis in essential tremor families.

Essential tremor (ET) is one of the most common movement disorders. The etiology of ET remains largely unexplained. Whole genome sequencing (WGS) is likely to be of value in understanding a large proportion of ET with Mendelian and complex disease inheritance patterns. In ET families with Mendelian inheritance patterns, WGS may lead to gene identification where WES analysis failed to identify the causative single nucleotide variant (SNV) or indel due to incomplete coverage of the entire coding region of the genome, in addition to accurate detection of larger structural variants (SVs) and copy number variants (CNVs). Alternatively, in ET families with complex disease inheritance patterns with gene x gene and gene x environment interactions enrichment of functional rare coding and non-coding variants may explain the heritability of ET. We performed WGS in eight ET families (n = 40 individuals) enrolled in the Family Study of Essential Tremor. The analysis included filtering WGS data based on allele frequency in population databases, rare SNV and indel classification and association testing using the Mixed-Model Kernel Based Adaptive Cluster (MM-KBAC) test. A separate analysis of rare SV and CNVs segregating within ET families was also performed. Prioritization of candidate genes identified within families was performed using phenolyzer. WGS analysis identified candidate genes for ET in 5/8 (62.5%) of the families analyzed. WES analysis in a subset of these families in our previously published study failed to identify candidate genes. In one family, we identified a deleterious and damaging variant (c.1367G>A, p.(Arg456Gln)) in the candidate gene, CACNA1G, which encodes the pore forming subunit of T-type Ca(2+) channels, CaV3.1, and is expressed in various motor pathways and has been previously implicated in neuronal autorhythmicity and ET. Other candidate genes identified include SLIT3 which encodes an axon guidance molecule and in three families, phenolyzer prioritized genes that are associated with hereditary neuropathies (family A, KARS, family B, KIF5A and family F, NTRK1). Functional studies of CACNA1G and SLIT3 suggest a role for these genes in ET disease pathogenesis.

Electronic cigarette use after the adoption of a tobacco-free campus policy.

Electronic (e)-cigarette use has increased markedly across groups in the past few years. For this reason, risk factors associated with e-cigarette use warrant further research. This study presents secondary data analyses on e-cigarette use from a large cross-sectional database assessing attitudes toward a tobacco-free campus (TFC) policy prior to policy implementation (n = 1188), one-month post policy (n = 1442), and one-year post policy(n = 1125). Students from a U.S. university located on the border with Mexico (Mage = 25.02 years, SD = 7.99; 59.2% female) were recruited via email to complete an online assessment of their tobacco use, attitudes toward TFC policies, perceived problematic tobacco use, and knowledge of tobacco use risk. The prevalence of any past-30-day e-cigarette use significantly increased from 4.4% to 26.6% between baseline and one-month post-policy, and reduced to 17.3% between one-month post-policy and one-year post policy. Weekly alcohol use was associated with e-cigarette use at each assessment point. There was some evidence of higher e-cigarette use among younger students and current smokers. Additional studies are needed to understand the influence of comprehensive TFC policies on both e-cigarette use and polysubstance use (i.e., alcohol and combustible cigarettes).

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.