Prenatal exposure to metals and autism spectrum disorder: Current status and future directions.

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder with genetic and environmental contributors to etiology. Many metals have the potential to be neurotoxic and their exposures are widespread. The field of metals exposure and ASD research is emerging, and in this review article we assess the current state of the literature, with emphasis on the previous two years. Epidemiology studies are discussed with respect to exposure timing, exposure matrix, and outcome assessment. Toxicology studies are described for exposure dosing and timing, as well as behavioral and molecular outcomes. Further epidemiological and toxicological investigations can identify the timing and importance of metals as ASD risk factors and uncover biological mechanisms for risk mitigation and therapeutic strategies.

Subtle Cerebellar Features in Relatives of Essential Tremor Cases.

Background: Essential tremor (ET) cases often exhibit a range of mild cerebellar signs. Their unaffected relatives have been shown in prior studies to exhibit subtle (i.e., preclinical) disease features. Objective: To quantify subtle cerebellar signs in unaffected first-degree relatives of ET cases stratified based on their tremor severity. Methods: Two hundred sixty-nine first-degree relatives of ET cases, none of whom reported tremor or a diagnosis of ET, or were diagnosed with ET based on detailed neurological examination, were stratified based on total tremor score (TTS) into two groups (lower TTS vs. higher TTS) and quartiles. Changes in gait, balance, and intention tremor were quantified on neurological examination. Results: Higher TTS performed worse on the tandem stance task (p = 0.011). When stratified into TTS quartiles, higher quartile was associated with worse performance in tandem stance (p = 0.011) and stance with feet together (p = 0.028). Similarly, intention tremor in the arms (p = 0.0002) and legs (p = 0.047) were higher in the groups with more tremor. Discussion: The links between ET and the cerebellum are multiple. These data provide intriguing evidence that subtle cerebellar signs (i.e., changes in balance and intention tremor) are more prevalent among first-degree relatives of ET cases with more tremor (i.e., those who may be themselves on the pathway to developing ET). These data contribute to a better characterization of what may be an early subclinical stage of the disease.

Heavy Metals Exposure and Alzheimer's Disease and Related Dementias.

Alzheimer's disease and related dementias lack effective treatment or cures and are major public health challenges. Risk for Alzheimer's disease and related dementias is partially attributable to environmental factors. The heavy metals lead, cadmium, and manganese are widespread and persistent in our environments. Once persons are exposed to these metals, they are adept at entering cells and reaching the brain. Lead and cadmium are associated with numerous health outcomes even at low levels of exposure. Although manganese is an essential metal, deficiency or environmental exposure or high levels of the metal can be toxic. In cell and animal model systems, lead, cadmium, and manganese are well documented neurotoxicants that contribute to canonical Alzheimer's disease pathologies. Adult human epidemiologic studies have consistently shown lead, cadmium, and manganese are associated with impaired cognitive function and cognitive decline. No longitudinal human epidemiology study has assessed lead or manganese exposure on Alzheimer's disease specifically though two studies have reported a link between cadmium and Alzheimer's disease mortality. More longitudinal epidemiologic studies with high-quality time course exposure data and incident cases of Alzheimer's disease and related dementias are warranted to confirm and estimate the proportion of risk attributable to these exposures. Given the widespread and global exposure to lead, cadmium, and manganese, even small increases in the risks of Alzheimer's disease and related dementias would have a major population impact on the burden on disease. This article reviews the experimental and epidemiologic literature of the associations between lead, cadmium, and manganese on Alzheimer's disease and related dementias and makes recommendations of critical areas of future investment.

The "Caring Giver": Emotional Caregiving in the Setting of Essential Tremor.

INTRODUCTION: Essential tremor (ET) is a common neurological disorder associated with functional impairment. Emerging evidence shows that some ET caregivers experience burden, but the unique interpersonal aspects of caregiving in the context of ET have not been fully examined. RESEARCH DESIGN: Open-ended questions were administered to 98 ET care-recipient-caregiver dyads. Responses were analyzed using conventional content analysis. RESULTS: The unique visibility of disability and feelings of embarrassment that occur with ET prompts caregivers to be highly attuned to care-recipient emotions. Providing companionship, promoting independence, and reducing embarrassment are three themes we found that describe the ET caregiving experience. DISCUSSION: Caregiving in ET often goes beyond aiding with activities of daily living; it has a significant emotional component especially in relation to independence and embarrassment. Future studies on caregiving in ET and conditions in which disability is visible should consider using a definition of caregiving that includes emotional caregiving.

Enfeeblement in Elders with Essential Tremor: Characterizing the Phenomenon and Its Role in Caregiver Burden.

Background: Individuals with essential tremor (ET), a common movement disorder, experience functional impairment, which contributes to burden experienced by their loved ones and caregivers. Some burdened caregivers report their loved ones as seeming debilitated or prematurely old, a concept that we have called enfeeblement. Using the Essential Tremor Enfeeblement Survey (ETES), we seek to characterize enfeeblement in elders with ET and assess its contribution to caregiver burden. Methods: We administered the ETES (range = 8-40, higher scores indicating more enfeeblement) and other scales to 98 caregivers of individuals with ET. Individuals with ET were also queried regarding tremors, cognitive abilities, and overall health. We then identified demographic and clinical correlates of ETES and modeled the contribution of ETES to caregiver burden (assessed using the Zarit 12-item Burden Interview [ZBI-12]). Results: Mean ETES score was 14.2 ± 6.2 (median = 12.0, range = 8.0-32.0); 26.5% of respondents endorsed at least one of the eight ETES items. Older age, greater tremor severity and disability, more functional and gait disability, more cognitive difficulty, and more depressive symptoms were associated with higher ETES scores. ETES was the strongest contributor to caregiver burden (ZBI-12) and substantially increased the variance explained in models of caregiver burden. Discussion: Enfeeblement seems to describe a previously unexplained component of caregiver burden in elders with ET. The presence of enfeeblement may contribute to greater burden and should be factored into assessments of patient and caregiver needs.

Enfeeblement in Essential Tremor: Development and Validation of a New Psychometric Measure.

INTRODUCTION: Despite a growing body of knowledge regarding essential tremor (ET), past studies have fallen short in capturing the full impact of ET on patients and caregivers. We propose enfeeblement (i.e., having the qualities of being prematurely old, helpless, or debilitated) as a novel clinical outcome measure in ET. Due to the lack of enfeeblement scales for ET in the literature, we developed and validated an enfeeblement scale for ET. METHODS: The Essential Tremor Enfeeblement Survey (ETES) consists of eight 5-point Likert-type scale questions and is designed to be a caregiver-reported outcome. RESULTS: Enfeeblement scores showed a floor effect of 15.3%, no ceiling effects, and demonstrated good overall test-retest reliability (intraclass correlation coefficient = 0.73), favorable internal consistency (Cronbach α coefficient = 0.92) and good convergent validity. CONCLUSION: The ETES has robust properties. Aside from future studies of enfeeblement in ET, enfeeblement should be explored more broadly as a psychometric measure across other neurological disorders.

More unaffected first-degree relatives of essential tremor cases have mild cognitive deficits than age-matched controls.

BACKGROUND: In numerous case-control studies, essential tremor (ET) has been associated with cognitive impairment. ET is often familial. However, cognitive impairment has not been studied in family members of ET cases. Endophenotypes are measurable clinical characteristics that may be present in individuals with increased risk for disease; as such, they may be present before disease onset. We administered a global cognitive screen to first-degree relatives of ET cases (FD-ET) and age-matched controls (Co). METHODS: We administered the Montreal Cognitive Assessment (MoCA) to 156 FD-ET and 73 Co, none of whom were diagnosed with ET or reported tremor. MoCA <26 was considered suggestive of cognitive impairment. RESULTS: FD-ET and Co were similar with respect to age (60.1 ±â€¯8.3 vs. 60.9 ±â€¯7.4 years) and numerous demographic factors. FD-ET and Co also had similar MoCA scores; however, 34 of 156 (21.8%) FD-ET had a MoCA score <26 vs only 5 (6.9%) of 73 Co (p = 0.004). In a univariate logistic regression model, FD-ET were 3.79 times more likely to have a low (<26) MoCA than were Co (odds ratio = 3.79, p = 0.008). In a multivariate logistic regression model, adjusting for age and other covariates, FD-ET were 4.83 times more likely to have a low MoCA than were Co (odds ratio = 4.83, p = 0.003). CONCLUSION: More FD-ET had low MoCA scores when compared with Co. These data provide additional support for the scientific notions that (1) cognitive difficulties are a disease-associated feature of ET and (2) there may be a pre-tremor phase of illness in ET.

Unaffected first-degree relatives of essential tremor cases have more imbalance than age-matched control subjects.

BACKGROUND: Endophenotypes are measurable clinical characteristics that may be present in individuals with increased risk for disease (e.g., unaffected family members). Endophenotypes are useful; they may clarify diagnosis in genetic studies and foster the development of animal models. In recent years, problems with balance and mild gait ataxia have been associated with essential tremor (ET). We compared gait and balance of first-degree relatives of ET cases (FD-ET) to that of age-matched controls (Co). METHODS: One-hundred-ninety FD-ET and 68 Co, none of whom reported tremor or were diagnosed with ET, underwent a standardized assessment of gait and balance. RESULTS: FD-ET reported more near-falls in the past year (p = 0.015) and lower balance confidence according to the Activities of Balance Confidence (ABC-6) Scale (p = 0.03). The specific ABC-6 items for which FD-ET reported lower balance confidence than Co were being bumped into by people while walking (p = 0.006) and walking outside on icy sidewalks (p = 0.007). On videotaped neurological examination, FD-ET were able to stand in the tandem position for fewer seconds than were Co (p = 0.048). The differences between FD-ET and Co, although statistically significant, were clinically mild. CONCLUSION: FD-ET reported more near-falls in the past year and a reduction in balance confidence; additionally, ability to maintain tandem stance was impaired compared to Co. These data suggest a more pervasive abnormality of cerebellar dysfunction than previously conceived, extending beyond ET cases themselves and manifesting in mild form in their unaffected family members.

Comparative Burden of Subclinical Tremor in a Cohort of Normal Individuals Stratified by Familial Risk for Essential Tremor.

BACKGROUND: The burden of mild (i.e., subclinical) tremor within essential tremor (ET) families is not fully understood. We assessed the burden of mild tremor in a cohort of 287 adults, none of whom reported tremor or were diagnosed with ET. METHODS: We recruited adults in 2 groups based on the familial risk for ET: 244 high-risk individuals (i.e., reporting one or more first-degree relative with ET) and 43 low-risk individuals (i.e., reporting no relatives with ET). Tremor was objectively assessed on 4 hand-drawn spirals (total spiral score = 0-12). Mild tremor was defined using 3 different cut points. RESULTS: The prevalence rates of mild tremor among high-risk individuals ranged from 41.4 to 98.4% and were highly dependent on the cut point. Above a certain threshold (i.e., a total spiral score ≥5), 1-in-5 (i.e., 19.7%) high-risk individuals exhibited mild tremor, whereas no low-risk individuals did. High-risk individuals were 3.09-4.50 times more likely than low-risk individuals to exhibit mild tremor. CONCLUSION: The burden of ET extends beyond the boundaries of the clinically defined disease, and partially expressed forms of ET are abundant in ET families. This fact greatly complicates gene-finding studies and epidemiological studies whose goal is to detect disease-linked associations.