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Background: Depressive symptoms are associated with essential tremor (ET). However, the relationship between cognitive, functional, and motor measures with depressive symptoms in ET is not yet understood.Methods: The following measures were cross-sectionally assessed in a group of 223 subjects with ET: the Montreal Cognitive Assessment (MoCA) Scale, the Lawton Independent Activities of Daily Living (IADL) Scale, a neurologist assessment of tremor severity, and the Geriatric Depression Scale (GDS).Results: 20% (44) of the subjects met GDS criteria for depression (GDS ≥ 10). 43% (94) of the subjects showed at least some cognitive impairment (≤24 on the MoCA), and 15.3% (34) reported significant functional impairment (IADL score < 7). There was no significant association between GDS score and tremor scale score. The total GDS was negatively associated with the total MoCA score (Spearman's r = -0.15, p = 0.03). The total GDS was also negatively associated with the IADL score (Spearman's r = -0.19, p = 0.02), (logistic model odds ratio, OR = 4.91, p < 0.01). Over 60% of subjects who were depressed, per GDS cut-off score (≥10), were not receiving medical treatment for depression.Conclusions: There was a high point prevalence of depressive symptoms in subjects with ET. Self-report depressive symptoms are dissociated from tremor severity. Hence, these data do not support the hypothesis that depression in ET represents a psychological reaction to the tremor. There appears to be a clustering of cognitive, functional, and depressive symptoms in ET. Screening of depression in ET can improve our understanding and treatment of this disorder. [ABSTRACT FROM AUTHOR]

Objective: To investigate the relationship between awareness of memory loss and psychological well-being in a nonclinically depressed sample of participants with mild to moderate Alzheimer disease (AD).Methods: Study participants (N = 104) enrolled through Columbia University Medical Center and the University of Pennsylvania completed clinical and cognitive assessments. Participants were rated with regard to their degree of awareness of memory deficits and completed questionnaires relating to their psychological well-being, including mood and quality of life (QOL). Mediating models were used to establish the relationship between awareness, depression, and QOL and to examine potential mediators of awareness and depression, including psychological distress, objective memory deficits, and negative self-ratings.Results: There was a direct association between awareness of memory deficits and depressed mood but not awareness and QOL. However, there was an indirect association between awareness and QOL through depression. Neither psychological distress, memory deficits, nor negative self-ratings mediated the relationship between awareness and depression.Conclusion: Awareness is associated with depressed mood in nonclinically depressed participants with mild to moderate AD. However, depressed mood does not appear to reflect the direct psychological reaction to awareness of memory loss. Moreover, awareness has only an indirect association with QOL via depressed mood. These results suggest that preserved awareness does not have a direct negative impact on overall psychological well-being in AD. [ABSTRACT FROM AUTHOR]

Unawareness of memory loss is a challenging characteristic of Alzheimer’s disease (AD) and other age-related neurodegenerative conditions at their earliest stages, adversely affecting important outcomes such as patient decision making and safety. The basis of this metacognitive disturbance has been elusive; however it is almost certainly determined in part by compromise to brain regions critical for self-assessment. The subjectivity of traditional measurements of self-awareness in dementia has likely limited the rigor with which its neuroanatomic correlates can be established. Here we objectively measure memory awareness (metamemory) using a Feeling of Knowing (FOK) task in a group of cognitively diverse older adults, including 14 with mild AD and 20 cognitively healthy older adults. Performance on the metamemory task was examined in relation to the structural integrity of 14 bilateral neuroanatomic regions hypothesized to support self-awareness. Less accurate metamemory was associated only with reduced right insular volume ( r =.41, p =.019). Implications of the current findings for models of metacognitive aging are discussed, with attention to the role of the insula in the conscious detection of errors. [ABSTRACT FROM AUTHOR]

The article reports on research which investigated the relationship between the progresion of Alzheimer's disease, psychosis, depressed mood and agitation or aggression in patients from four U.S. memory clinics. Researchers evaluated 517 patients. They found that psychosis and depressed mood were associated with cognitive decline and that there was poor prognosis associated with psychosis and depression in patients with Alzheimer's disease.

Abstract: Research to understand variability at the highest end of the cognitive performance distribution has been scarce. Our aim was to define a cognitive endophenotype based on exceptional episodic memory (EM) performance and to investigate familial aggregation of EM in families from the Long Life Family Study (LLFS). Using a sample of 1911 nondemented offspring of long-lived probands, we created a quantitative phenotype, EM (memory z ≥ 1.5), and classified LLFS families as EM and non-EM families based on the number of EM offspring. We then assessed differences in memory performance between LLFS relatives in the parental generation of EM families and those in non-EM families using multivariate analysis adjusted for APOE Apolipoprotein E genotype. LLFS relatives in the proband generation from EM families showed better EM performance than those from non-EM families (β = 0.74, standard error = 0.19, p = 1.4 × 10−4). We demonstrated that there is a familial correlation of the EM endophenotype, suggesting that genetic variants might influence memory performance in long-lived families. [Copyright &y& Elsevier]

Objectives: To examine the association between physical activity (PA) and Alzheimer disease (AD) course. Background: PA has been related to lower risk for AD. Whether PA is associated with subsequent AD course has not been investigated. Methods: In a population-based study of individuals aged 65 years and older in New York who were prospectively followed up with standard neurologic and neuropsychological evaluations (every ~1.5 years), 357 participants i) were nondemented at baseline and ii) were diagnosed with AD during follow-up (incident AD). PA (sum of participation in a variety of physical activities, weighted by the type of activity [light, moderate, and severe]) obtained 2.4 (standard deviation [SD], 1.9) years before incidence was the main predictor of mortality in Cox models and of cognitive decline in generalized estimating equation models that were adjusted for age, gender, ethnicity, education, comorbidities, and duration between PA evaluation and dementia onset. Results: One hundred fifty incident AD cases (54%) died during the course of 5.2 (SD, 4.4) years of follow-up. When compared with incident AD cases who were physically inactive, those with some PA had lower mortality risk, whereas incident AD participants with much PA had an even lower risk. Additional adjustments for apolipoprotein genotype, smoking, comorbidity index, and cognitive performance did not change the associations. PA did not affect rates of cognitive or functional decline. Conclusion: Exercise may affect not only risk for AD but also subsequent disease duration: more PA is associated with prolonged survival in AD. [ABSTRACT FROM AUTHOR]

Essential tremor (ET) is characterized by considerable clinical heterogeneity. In 2018, the term "ET plus" was introduced to mark a potential stratification point for dividing ET into subtypes – ET vs ET plus (i.e., ET cases with neurological features other than action tremor). However, as ET progresses, patients often develop increasingly severe tremor, spread of tremor, tremor under different activation conditions, and other features. Given this situation, ET plus may represent a disease stage rather than a disease classification or subtype. In theory, if the defining characteristics of a disease subtype fluctuate with age or disease duration, it raises the distinct possibility the "subtype" is a disease stage. A cohort of 241 prospectively enrolled ET cases underwent a detailed motor and cognitive assessment in which the features of ET plus including cerebellar signs (intention tremor, tandem gait difficulty), rest tremor, dystonia, and cognitive performance were evaluated. We determined whether these features of ET plus correlated with action tremor duration and age. We demonstrated that numerous ET plus features were significantly correlated with both age and action tremor duration (numerous p values < 0.05). The same relationships were observed in a series of sensitivity analyses. We observed that the component parts of ET plus are highly age- and stage-dependent. These features are yearly-changing features conditional on a demographic and disease stage variable. These data support the notion that ET plus may represent a disease stage rather than a distinct disease subtype or disease classification. • Essential tremor (ET) is characterized by considerable clinical heterogeneity. • The term "ET plus" was introduced as an ET subtype. • Numerous ET plus features significantly correlate with tremor duration and age. • ET plus may be a disease stage rather than a disease subtype. [ABSTRACT FROM AUTHOR]

Introduction: Although the hallmark feature of essential tremor (ET) is tremor, there is growing appreciation that cognitive impairment also occurs, including increased prevalence of mild cognitive impairment (MCI) and increased prevalence and incidence of dementia. With emerging knowledge of ET-cognitive impairment, come fundamental questions regarding its course, bases, predictors and clinical outcomes. Studies in the general population and in Parkinson's disease (PD), a related movement disorder, offer a starting point from which to begin filling these clinically important knowledge gaps.Methods: A PubMed search (June 2018) identified articles for this review.Results: Much of our knowledge of cognitive impairment in ET is of the static condition (e.g., prevalence of cognitive impairment in ET), with nearly no information on its bases, predictors and dynamics (i.e., course, and clinical outcomes). In PD, where such data have been published, rates of cognitive decline and conversion to MCI/dementia are higher than in the general population. Predictors of cognitive change in PD and the general population have also been identified, yet they only partially overlap one another.Conclusion: The predictors and dynamics of cognitive impairment have been investigated fairly extensively in the general population, to a somewhat lesser extent in PD, and are emerging only now in ET. We suggest that longitudinal studies specific to ET are needed, and we outline variables to be considered in these investigations. Increased knowledge of ET-cognitive impairment will facilitate meaningful counseling of patients and their families. [ABSTRACT FROM AUTHOR]

• Identifying factors that help people maintain good cognitive functions as they age is important. • We conducted a genome-wide association study of processing speed in members of families enriched for extreme human longevity. • We discovered rare variants that are associated with maintaining excellent processing speed at very old age. • These variants may help identify therapeutic targets for the preservation of cognitive function. We conducted a genome-wide association study of Digit Symbol Substitution Test scores administered in 4207 family members of the Long Life Family Study (LLFS). Genotype data were imputed to the HRC panel of 64,940 haplotypes resulting in ∼15M genetic variants with a quality score > 0.7. The results were replicated using genetic data imputed to the 1000 Genomes phase 3 reference panel from 2 Danish twin cohorts: the study of Middle Aged Danish Twins and the Longitudinal Study of Aging Danish Twins. The genome-wide association study in LLFS discovered 18 rare genetic variants (minor allele frequency (MAF) < 1.0%) that reached genome-wide significance (p -value < 5 × 10−8). Among these, 17 rare variants in chromosome 3 had large protective effects on the processing speed, including rs7623455, rs9821776, rs9821587, rs78704059, which were replicated in the combined Danish twin cohort. These SNPs are located in/near 2 genes, THRB and RARB , that belonged to the thyroid hormone receptors family that may influence the speed of metabolism and cognitive aging. The gene-level tests in LLFS confirmed that these 2 genes are associated with processing speed. [ABSTRACT FROM AUTHOR]

Abstract: The authors investigated whether cognitive function may be used as an endophenotype for longevity by assessing the cognitive performance of a family-based cohort consisting of 1380 individuals from 283 families recruited for exceptional survival in field centers in Boston, New York, Pittsburgh, and Denmark. Cognitive performance was assessed in the combined offspring of the Long Life Family Study (LLFS) probands and their LLFS siblings as compared with their spouses'' cognitive performance. Our results indicate that the combined offspring of the LLFS probands and their siblings achieve significantly higher scores on both digit forward and backward tasks (p = 5 10-5 and p = 8 10-4 respectively) as well as on a verbal fluency task (p = 0.008) when compared with their spouse controls. No differences between groups were found for the other cognitive tests assessed. We conclude that LLFS family members in the offspring generation demonstrate significantly better performance on multiple tasks requiring attention, working memory, and semantic processing when compared with individuals without a family history of exceptional survival, suggesting that cognitive performance may serve as an important endophenotype for longevity. [Copyright &y& Elsevier]

Introduction: Essential tremor (ET), a common movement disorder, is characterized by motor, cognitive and psychiatric symptoms. Depressed mood, a symptom of ET, has historically been viewed as a psychological response to disability. However, depressive symptoms are emerging as a predictor of cognitive decline across several clinical populations. We examined if depressive symptoms predict decline in global cognition, memory, and executive functioning among older adults with ET.Methods: 125 cognitively normal participants with ET completed three in-person assessments of cognition, mood, and motor symptoms at baseline, 18 months, and 36 months; baseline data were collected from July 2014-July 2016. Depressive symptoms were measured with the Geriatric Depression Scale. Cognitive functioning was measured via a 3-4 hour neuropsychological evaluation. Generalized linear regression models examined depressive symptoms as a predictor of decline in global cognition, executive functioning (EF), and memory.Results: Participants were grouped according to a median split (GDS <5 versus ≥ 5) due to the bimodal distribution of the data. In unadjusted models, depressive symptoms did not predict change in global cognition (b = -0.002, p = .502) or EF (b = 0.000, p = .931), however individuals with GDS ≥ 5 demonstrated faster memory decline in unadjusted (b = -0.008, p = .039) and adjusted models (b = -0.009, p = .019).Conclusion: The presence of 5 or more depressive symptoms predicted mildly faster memory decline in cognitively normal older adults with ET over 36 months. We discuss potential mechanisms and clinical implications. [ABSTRACT FROM AUTHOR]

Background: Essential tremor (ET), among the most common neurological diseases, is associated with cognitive dysfunction. Yet, nearly all knowledge of ET-related cognitive impairment is static and cross-sectional (e.g., prevalence), with virtually no dynamic information (i.e., course and progression, conversion rates, and clinical outcomes).Objectives: To quantify the rate of progression from mild cognitive impairment (MCI) to dementia in a cohort of elderly ET cases.Methods: 167 ET cases, enrolled in a prospective, longitudinal, clinical-pathological study, underwent an extensive neuropsychological testing battery at baseline (T1), 1.5 years (T2), and 3 years (T3). Results of these assessments informed clinical diagnoses of normal cognition (ET-NC), MCI (ET-MCI), and dementia (ET-D).Results: At baseline, 26 cases (82.7 ± 7.7 years) were diagnosed with ET-MCI and were available for follow-up at T2. At T2, three of 26 (11.5%) had converted to ET-D. At the start of T2, 23 cases (83.6 ± 7.7 years) were diagnosed with ET-MCI and were available for follow-up at T3. At T3, six of 23 (26.1%) converted to ET-D. The average annual conversion rate from ET-MCI to ET-D was 12.5%.Conclusions: The study of cognitive impairment in ET is a nascent field, with limited data. We show that the conversion rate from ET-MCI to ET-dementia was 12.5%. Available studies on historical controls have reported conversion rates of 2.6-6.3%. Data such as these systematically fill gaps in knowledge, creating a scientifically-derived knowledge base to guide physicians and patients in clinical settings. [ABSTRACT FROM AUTHOR]

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 ± 8.3 vs. 60.9 ± 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. [ABSTRACT FROM AUTHOR]

Objective The extent to which individuals with ET who have clinically significant cognitive impairment are aware of their cognitive changes is unclear. Reduced awareness has important implications for everyday function and decision-making. Methods 150 individuals with ET (109 Normal Cognition (ET-NC group), and 30 with MCI and 11 dementia (ET-CI group)) completed self-ratings and objective assessments of memory, language, and executive functioning. Discrepancy scores were calculated to assess awareness of cognitive functioning. One sample t -tests evaluated whether mean discrepancy scores in each group were comparable to zero (i.e., accurate). Analyses of covariance (ANCOVA) compared discrepancy scores across two groups controlling for age and education. Results In the ET-NC group, discrepancy scores for language ( M = − 0.08, SD = 1.10) and executive functioning ( M = − 0.01, SD = 0.99) were comparable to zero. Memory discrepancy scores ( M = 0.32, SD = 1.22) were greater than zero. In the ET-CI group, memory, ( M = 0.78, SD = 1.01), language, ( M = 0.46, SD = 0.95), and executive ( M = 0.39, SD = 1.14) discrepancy scores were all greater than zero. Discrepancy scores were larger in ET-CI group than in ET-NC group for memory: F (1,148) = 4.02, p = 0.047, language: F (1,148) = 6.16, p = 0.014, and executive: F (1,148) = 4.51, p = 0.035. Conclusions Individuals with ET and normal cognition accurately assessed their language and executive abilities, demonstrating mild overconfidence in memory function. Individuals with ET and cognitive impairment overestimated their performance in all domains of functioning. Since ET is linked to increased risk for cognitive impairment, and such impairment may not be accurately perceived, cognitive functioning should be proactively and regularly screened in ET. [ABSTRACT FROM AUTHOR]

There is increasing evidence that essential tremor (ET) is a complex and heterogeneous disorder with nonmotor features including cognitive deficits and sleep problems. We are unaware of a study that has examined sleep deficits in ET across the full spectrum of cognitive presentations. Cross-sectional (baseline) data on self-reported nighttime sleep dysfunction and excessive daytime sleepiness were collected using the Pittsburgh Sleep Quality Index (PSQI) and the Epworth Sleepiness Scale (ESS) in 96 ET cases enrolled in a prospective study. Cases underwent a comprehensive neuropsychological assessment, and were classified as ET with normal cognition (ET-NC), ET with mild cognitive impairment (ET-MCI), and ET with dementia (ET-D). PSQI scores did not significantly differ across the three ET cognitive groups (p = 0.22). ESS scores were highest (more daytime sleepiness) in the ET-MCI group, followed by the ET-D and ET-NC groups, respectively (p = 0.016). We examined sleep dysfunction across the cognitive spectrum in ET. We demonstrate for the first time that excessive daytime sleepiness is greater in ET-MCI than ET-NC. Unpredicted low ESS scores in the dementia group raises two possibilities: a self-report bias related to cognitive impairment and/or the possibility that currently undefined pathological heterogeneity in ET may map onto multiple presentations of non-motor deficits. [ABSTRACT FROM AUTHOR]

Background Physical inactivity may be the result of medical comorbidities. Inactivity itself may also lead to important health consequences, especially in older patients. Essential tremor (ET) patients may have a variety of physical and cognitive problems that could detrimentally impact on level of physical activity. Yet, to our knowledge, there have been no studies of physical activity in these patients. Methods Self-reported physical activity was assessed using the Physical Activity Scale for the Elderly (PASE) in 100 ET cases (mean age 80.5 years) enrolled in a clinical study. Additional clinical measures were the total tremor score, Montreal Cognitive Assessment (MOCA) score and number of steps taken off of the straight line during tandem gait (a measure of balance). Results Lower PASE score was associated with older age, more tandem gait difficulty, higher total tremor score and lower MOCA score (all p < 0.05). In a linear regression model that included total tremor score, MOCA score, number of steps off of the straight line during tandem gait, and age, higher total tremor score (p = 0.046) and more steps off of the straight line during tandem gait (p = 0.014) were independently associated with reductions in physical activity. Conclusions Several of the motor features of ET (tremor and imbalance) are independently associated with reductions in level of physical activity. [ABSTRACT FROM AUTHOR]

Mild cognitive impairment (MCI) was present in 26/167 (15.6%) of our essential tremor (ET) cases, which is more than double the proportion they report (7%). The relevant analysis comparing older onset ET to controls was not conducted; however, given the above results, the risk of incident dementia in older onset ET cases would almost certainly have been significantly elevated when compared with controls. As a result, the reported prevalence of ET was three times higher than expected, indicating that as many as two-thirds of the individuals labelled as ET had normal tremor [2]. [Extracted from the article]

Abstract: In the present study we aimed to determine the prevalence of C9ORF72 GGGGCC hexanucleotide expansion in our cohort of 53 frontotemporal lobar degeneration (FTLD) patients and 174 neurologically normal controls. We identified the hexanucleotide repeat, in the pathogenic range, in 4 (2 bv-frontotemporal dementia (FTD) and 2 FTD-amyotrophic lateral sclerosis [ALS]) out of 53 patients and 1 neurologically normal control. Interestingly, 2 of the C9ORF72 expansion carriers also carried 2 novel missense mutations in GRN (Y294C) and in PSEN-2(I146V). Further, 1 of the C9ORF72 expansion carriers, for whom pathology was available, showed amyloid plaques and tangles in addition to TAR (trans-activation response) DNA-binding protein (TDP)-43 pathology. In summary, our findings suggest that the hexanucleotide expansion is probably associated with ALS, FTD, or FTD-ALS and occasional comorbid conditions such as Alzheimer''s disease. These findings are novel and need to be cautiously interpreted and most importantly replicated in larger numbers of samples. [Copyright &y& Elsevier]