Search

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]

Background: 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.Methods: 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.Results: 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.Conclusion: 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. [ABSTRACT FROM AUTHOR]

The theory of "disinhibition" has been very influential in psychiatry and neurology for over a century. Disinhibition has been used to explain clinical findings in many neurological and psychiatric disorders including dementia, traumatic brain injury, attention deficit hyperactive disorder, substance abuse, impulsivity in personality disorders, and neurodevelopmental disorders. In addition, disinhibition has been used as a unifying theory to link clinical observations with cognitive findings, and even cellular findings. This review discusses the origins and history of the theory of disinhibition and its strengths and weaknesses in four domains: face validity, consistency with other brain mechanisms, consistency with evolutionary mechanisms, and empiric support. I assert that the vagueness of the theory, inconsistency with other brain mechanisms, and lack of empiric support limit the usefulness of this theory. Alternative approaches, based on findings in other motor, language, and cognitive functions, are discussed. [ABSTRACT FROM AUTHOR]

Increasing appreciation of the phenotypic and biological overlap between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, alongside evolving biomarker evidence for a pre-symptomatic stage of disease and observations that this stage of disease might not always be clinically silent, is challenging traditional views of these disorders. These advances have highlighted the need to adapt ingrained notions of these clinical syndromes to include both the full phenotypic continuum — from clinically silent, to prodromal, to clinically manifest — and the expanded phenotypic spectrum that includes ALS, frontotemporal dementia and some movement disorders. The updated clinical paradigms should also align with our understanding of the biology of these disorders, reflected in measurable biomarkers. The Miami Framework, emerging from discussions at the Second International Pre-Symptomatic ALS Workshop in Miami (February 2023; a full list of attendees and their affiliations appears in the Supplementary Information) proposes a classification system built on: first, three parallel phenotypic axes — motor neuron, frontotemporal and extrapyramidal — rather than the unitary approach of combining all phenotypic elements into a single clinical entity; and second, biomarkers that reflect different aspects of the underlying pathology and biology of neurodegeneration. This framework decouples clinical syndromes from biomarker evidence of disease and builds on experiences from other neurodegenerative diseases to offer a unified approach to specifying the pleiotropic clinical manifestations of disease and describing the trajectory of emergent biomarkers. In this Perspective, the authors propose a new classification system for amyotrophic lateral sclerosis and related neurodegenerative disorders that recognizes, in parallel, the clinical syndromes and the underlying biology of disease. The framework emerged from discussions at the Second International Pre-Symptomatic ALS Workshop in Miami (February 2023). Key points: Amyotrophic lateral sclerosis, frontotemporal dementia and a group of extrapyramidal movement disorders are related across a phenotypic spectrum and have shared biological substrates such as TDP43 or tau pathology. Disease evolves along a phenotypic continuum from clinically silent, to prodromal, to clinically manifest disease. Existing diagnostic criteria might require updates given new knowledge of prodromal and early manifest disease. Biomarkers reflecting the underlying biology of these diseases and the resulting neurodegenerative changes have begun to emerge, but the temporal relationship of the biomarkers to clinical phenotypes is unclear. The Miami Framework offers a unified approach to specifying both the pleotropic clinical manifestations of these diseases and, in parallel, the temporal course of emergent biomarkers. Informed by data and experience from multiple genetic forms of amyotrophic lateral sclerosis and frontotemporal dementia, the Miami Framework probably has relevance to all forms of these diseases. Communicating the emergence of prodromal disease to the affected individual is complex and requires great caution but can be informed by experience and insights from genetic and biomarker counselling. [ABSTRACT FROM AUTHOR]

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]

Background: Apathy is a common and problematic symptom of several neurodegenerative illnesses, but its neuroanatomical bases are not understood.Objective: To determine the regions associated with apathy in subjects with mild Alzheimer's disease (AD) using a method that accounts for the significant co-linearity of regional atrophy and neuropsychiatric symptoms.Methods: We identified 57 subjects with mild AD (CDR = 1) and neuropsychiatric symptoms in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. We performed a multivariate multiple regression with LASSO regularization on all symptom subscales of the Neuropsychiatric Inventory and the whole-brain ROI volumes calculated from their baseline MRIs with FreeSurfer. We compared our results to those from a previous study using the same method in patients with frontotemporal dementia (FTD) and corticobasal syndrome (CBS).Results: Of neuropsychiatric symptoms, apathy showed the most robust neuroanatomical associations in the AD subjects. Atrophy of the following regions were independently associated with apathy: the ventromedial prefrontal cortex; ventrolateral prefrontal cortex; posterior cingulate cortex and adjacent lateral cortex; and the bank of the superior temporal sulcus. These results replicate previous studies using FTD and CBS patients, mostly agree with the previous literature on apathy in AD, and correspond to the Medial and Orbital Prefrontal Cortex networks identified in non-human primates.Conclusion: The current study, previous studies from our laboratory, and the previous literature suggest that impairment of the same brain networks involved in arousal, threat response, and reward processing are associated with apathy in AD and FTD. [ABSTRACT FROM AUTHOR]

The prevalence of psychiatric disorders in primary lateral sclerosis (PLS) is currently unknown. In the present study, we compared the prevalence of psychiatric illness in patients with PLS and amyotrophic lateral sclerosis (ALS). We hypothesized that if the psychosocial stress of motor neuron disease predisposes patients to depressive disorders, patients with ALS (with a poorer prognosis and more disability than patients with PLS) should have a higher prevalence of depressive disorders than patients with PLS. We administered the gold standard of psychiatric assessment, the SCID, to 19 PLS and 13 ALS patients. We found a prevalence of current depressive disorders in PLS patients that was, by a non-significant trend, lower than that of ALS patients. The prevalence of current depressive disorders in the ALS patients was higher than previously reported and similar to that observed in non-neurological medical disorders. Other psychiatric disorders were rare. In conclusion, depressive disorders were the most commonly observed psychiatric disorders in both PLS and ALS. By a non-significant trend, the PLS patients had a lower current prevalence of depressive disorders than the ALS patients. These data are consistent with the hypothesis that the psychosocial stress of MND is a risk factor for depression. [ABSTRACT FROM AUTHOR]

The neuroanatomical correlates of depression remain unclear. Functional imaging data have associated depression with abnormal patterns of activity in prefrontal cortex (PFC), including the ventromedial (vmPFC) and dorsolateral (dlPFC) sectors. IfvmPFCand dlPFC are critical neural substrates for the pathogenesis of depression, then damage to either area should affect the expression of depressive symptoms. Using patients with brain lesions we show that, relative to nonfrontal lesions, bilateral vmPFC lesions are associated with markedly low levels of depression, whereas bilateral dorsal PFC lesions (involving dorsomedial and dorsolateral areas in both hemispheres) are associated with substantially higher levels of depression. These findings demonstrate that vmPFC and dorsal PFC are critically and causally involved in depression, although with very different roles: vmPFC damage confers resistance to depression, whereas dorsal PFC damage confers vulnerability. [ABSTRACT FROM AUTHOR]

Post-traumatic stress disorder (PTSD) is an often debilitating mental illness that is characterized by recurrent distressing memories of traumatic events. PTSD is associated with hypoactivity in the ventromedial prefrontal cortex (vmPFC), hyperactivity in the amygdala and reduced volume in the hippocampus, but it is unknown whether these neuroimaging findings reflect the underlying cause or a secondary effect of the disorder. To investigate the causal contribution of specific brain areas to PTSD symptoms, we studied a unique sample of Vietnam War veterans who suffered brain injury and emotionally traumatic events. We found a substantially reduced occurrence of PTSD among those individuals with damage to one of two regions of the brain: the vmPFC and an anterior temporal area that included the amygdala. These results suggest that the vmPFC and amygdala are critically involved in the pathogenesis of PTSD. [ABSTRACT FROM AUTHOR]

The prefrontal cortex (PFC) in humans has been studied for more than a century, but many crucial questions about its functions remain unanswered. This paper will highlight a few key differences between human and animal PFCs, and between the human PFC (HPFC) and other parts of the human brain. We then make a case that the HPFC is critically important for executing behaviors over time and integrating disparate information from throughout the brain. Finally, we will focus on our position in the current debate regarding how the HPFC performs its functions and discuss future directions for research. [ABSTRACT FROM AUTHOR]

Background: Cerebrospinal fluid (CSF) measures of β-amyloid1–42 and tau differ between patients with Alzheimer’s Disease (AD) and elderly normal controls. The effect of time and APOE genotype on these biomarkers continues to be elucidated. Methods: We assessed CSF β-amyloid1–42 and tau in 20 mild-to-moderate AD patients, 11 APOE ε4+ and 9 APOE ε4–, over a mean time of 3.8 years (range 1–11.1 years). Results: Over the period measured, CSF β-amyloid1–42 levels were lower in APOE ε4+ compared to APOE ε4– patients, and the levels decreased over time. Tau levels were stable over time and did not show an effect of APOE allele. Conclusions: While this is a limited clinical sample, the further decrease in CSF β-amyloid1–42 (i.e., more abnormal) combined with the CSF tau stability over a mean period of almost 4 years suggests that β-amyloid1–42 and tau maintain their potential usefulness as diagnostic biomarkers over time. These findings should be taken into account if CSF β-amyloid1–42 and tau are used as measures of treatment response. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

An introduction is presented in which the editor discusses various reports within the issue on topics including the reintroduction of psychiatry to frontotemporal dementia (FTD), the diagostic criteria in FTD, and neurobiological connections between FTD and schizophrenia.

Background: Apathy, defined as decreased goal-directed activity, has been observed in Parkinson's disease. A number of cognitive/psychiatric features have been documented in essential tremor, yet we are unaware of studies of apathy. Methods: Using the Apathy Evaluation Scale (range = 18-72 [more apathy]), we compared 79 essential tremor cases, 20 dystonia cases, and 39 Parkinson's disease cases with 80 normal controls. Results: The score of the Apathy Evaluation Scale was higher in essential tremor, dystonia, and Parkinson's disease cases than controls (all P ≤ .04). Parkinson's disease cases had the highest scores. Analyses stratified by presence/absence of depressive symptoms indicated the presence of a group of apathetic but nondepressed cases. Conclusions: Patients with Parkinson's disease, essential tremor, and dystonia had elevated apathy scores. Features of apathy seemed to occur in these conditions independent of depressive symptoms. The mechanistic basis for the apparent increased features of apathy in essential tremor and dystonia deserves further study. © 2011 Movement Disorder Society [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "The Miami Framework for ALS and related neurodegenerative disorders: an integrated view of phenotype and biology" published in Nature Reviews Neurology. The correction addresses a misspelling of Olga Uspenskaya's name, which has been amended in the HTML and PDF versions of the article. The document also includes a list of authors and their affiliations. [Extracted from the article]

Background: With the approval of disease-modifying treatments (DMTs) for early Alzheimer's disease (AD), there is an increased need for efficient and non-invasive detection methods for cerebral amyloid-β (Aβ) pathology. Current methods, including positron emission tomography (PET) and cerebrospinal fluid (CSF) analysis, are costly and invasive methods that may limit access to new treatments. Plasma tau phosphorylated at threonine-217 (P-tau217) presents a promising alternative, yet optimal cutoffs for treatment eligibility with DMTs like aducanumab require further investigation. This study evaluates the efficacy of one- and two-cutoff strategies for determining DMT eligibility at the Butler Hospital Memory & Aging Program (MAP). Methods: In this retrospective, cross-sectional diagnostic cohort study, we first developed P-tau217 cutoffs using site-specific and BioFINDER-2 training data, which were then tested in potential DMT candidates from Butler MAP (total n = 150). ROC analysis was used to calculate the area under the curve (AUC) and accuracy of P-tau217 interpretation strategies, using Aβ-PET/CSF testing as the standard of truth. Results: Potential DMT candidates at Butler MAP (n = 50), primarily diagnosed with mild cognitive impairment (n = 29 [58%]) or mild dementia (21 [42%]), were predominantly Aβ-positive (38 [76%]), and half (25 [50%]) were subsequently treated with aducanumab. Elevated P-tau217 predicted cerebral Aβ positivity in potential DMT candidates (AUC = 0.97 [0.92–1]), with diagnostic accuracy ranging from 0.88 (0.76–0.95, p = 0.028) to 0.96 (0.86–1, p <.001). When using site-specific cutoffs, a subset of DMT candidates (10%) exhibited borderline P-tau217 (between 0.273 and 0.399 pg/mL) that would have potentially required confirmatory testing. Conclusions: This study, which included participants treated with aducanumab, confirms the utility of one- and two-cutoff strategies for interpreting plasma P-tau217 in assessing DMT eligibility. Using P-tau217 could potentially replace more invasive diagnostic methods, and all aducanumab-treated participants would have been deemed eligible based on P-tau217. However, false positives remain a concern, particularly when applying externally derived cutoffs that exhibited lower specificity which could have led to inappropriate treatment of Aβ-negative participants. Future research should focus on prospective validation of P-tau217 cutoffs to enhance their generalizability and inform standardized treatment decision-making across diverse populations. [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

There is growing evidence that essential tremor (ET) patients are at high risk of cognitive impairment. Predictors of cognitive impairment have not been studied extensively. There is evidence from cross-sectional studies that sleep dysregulation is associated with cognitive dysfunction in ET, but longitudinal studies of the impact of sleep disruption on cognitive change have not been conducted. We investigated the extent to which sleep problems predict cognitive change in patients with ET. ET cases enrolled in a prospective, longitudinal study of cognitive performance. Sleep quality was assessed using the Pittsburg Sleep Quality Index (PSQI). Cognitive abilities across five domains (memory, executive function, attention, language, and visuospatial ability), and a global cognitive score (mean of the domains) were extracted from an extensive neuropsychological assessment. Generalized estimated equations were used to examine the association between baseline sleep problems and cognitive changes over three follow-up assessments each spaced 18 months apart. The 188 non-demented ET cases had a mean age of 77.7 ± 9.5 years. Longer sleep latency was associated with longitudinal decline in executive function (p = 0.038), and marginally with longitudinal decline in global cognitive performance (p = 0.075). After excluding 29 cases with mild cognitive impairment, results were similar. Cognitively healthy people with ET who have longer sleep latency had greater declines in executive function during prospective follow-up. Early detection of, and possibly intervention for, abnormal sleep latency may protect against certain aspects of cognitive decline in ET patients. • Sleep dysfunction is one of the major non-motor symptoms of ET. • Cognitive deficits seem to also appear significantly in patients with ET. • Longer sleep latency is associated with decline in executive function. • Results were significant in cognitively healthy older adults. [ABSTRACT FROM AUTHOR]

Introduction: Essential tremor (ET) patients may exhibit a variety of non-motor features, including cognitive decline and depressive symptoms. Studies of several neurodegenerative diseases link depression to cognitive decline, suggesting depression is an early marker of dementia. We examined whether baseline depressive symptoms predict incident dementia in elders with ET. Methods: Hundred and forty-one ET cases aged 70 years or older at baseline, enrolled in a prospective study of cognitive performance, took part in evaluations at baseline and at 18, 36, 54, and 72 months. Participants completed the Geriatric Depression Scale (GDS), a 30-item self-report measure of depressive symptoms, and a battery of neuropsychological tests and functional assessments, from which we derived cognitive diagnoses at each evaluation. Cox proportional hazards regression equations determined incident dementia risk based on participants' baseline depression scores. Results: Mean baseline age was 81.5 ± 6.7 years. Higher baseline GDS scores were associated with increased risk of dementia in an unadjusted model (hazards ratio [HR] = 1.11, 95% confidence interval [CI] = 1.02–1.20, p = 0.01) and after controlling for baseline age, education, number of medications, and tremor onset age (HR = 1.13, 95% CI = 1.02–1.25, p = 0.02). Conclusion: Baseline depression scores predicted incident dementia in elders with ET. With each one-point increase in baseline depression score, there was a 13% increase in incident dementia risk. Given the published data that reported depression may be twice as high in elders with ET compared to controls, this association is particularly worrisome in the ET population. [ABSTRACT FROM AUTHOR]

Changes in higher-order cognitive behaviors such as reward recognition, salience processing, novelty perception, decision-making, emotional contagion, motivation, and empathy may contribute to intimacy dysfunction. Network circuitry underlying these cognitive functions is often activated in sexually intimate behavior. We propose that sexual dysfunction in AD and bvFTD is more nuanced than is commonly believed, and propose how AD and bvFTD atrophy may correlate neuroanatomically to brain regions and networks that contribute to the higher-order cognitive aspects of intimacy. The characterization of sexual intimacy in dementias must be expanded to meet the needs of our dementia patients and their romantic partners. [ABSTRACT FROM AUTHOR]

Objective Given the association between essential tremor (ET) and higher rates of cognitive decline, assessing this decline is an important element of research and clinical care. The Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) are two broad, brief measures that are widely used to monitor cognitive impairment in various neurological disorders. We sought to determine the relative ability of the MoCA and the MMSE to detect cognitive decline in elderly patients with ET. Methods We administered a neuropsychological battery to an ET cohort every 18 months over 4.5 years. We defined the gold standard for change in cognition as the change in neuropsychological test scores over consecutive evaluations and applied the Reliable Change Method to detect meaningful increases/decreases in test scores. We performed receiver operating characteristics (ROC) analysis to quantify the area under the curve (AUC) and compare the ability of the MoCA and the MMSE to detect cognitive decline. Results The AUCs for the MoCA and the MMSE did not differ significantly at any interval or when all intervals were pooled for analysis. Across all intervals, the ability of the MoCA and the MMSE to detect cognitive decline was consistently fair or poor. Conclusions We found that the ability of the MoCA and the MMSE to detect cognitive decline in ET patients over 18-month intervals is inadequate. Unchanged scores on the MoCA and the MMSE in ET over time should be approached with caution. We propose that these screening tools should be supplemented with additional neuropsychological tests. [ABSTRACT FROM AUTHOR]

Symptoms of agitation, aggression, and psychosis frequently occur in patients with Alzheimer's disease (AD). These symptoms are distressing to patients and caregivers, often lead to institutionalization, are associated with increased mortality, and are very difficult to treat. Lithium is an established treatment for bipolar and other psychotic disorders in which agitation can occur. The Lit-AD study is the first randomized, double-blind, placebo-controlled trial to assess the efficacy of lithium treatment for symptoms of agitation or aggression, with or without psychosis, in older adults diagnosed with AD. Patients are randomly assigned to low dose (150–600 mg) lithium or placebo, targeting a blood level of 0.2–0.6 mmol/L, stratified by the presence/absence of psychotic symptoms. The study duration for each patient is 12 weeks. The primary study outcome is change in the agitation/aggression domain score on the Neuropsychiatric Inventory (NPI) over the study period. The secondary outcome is improvement in neuropsychiatric symptoms defined as a 30% decrease in a NPI core score that combines agitation/aggression and psychosis domain scores. The Treatment Emergent Symptom Scale (TESS) is used to assess somatic side effects. Other exploratory analyses examine the associations between improvement on lithium and indices shown to be associated with response to lithium in bipolar disorder: serum brain-derived neurotrophic factor (BDNF) levels, a SNP in intron 1 of the ACCN1 gene, and variation at the 7q11.2 gene locus. If lithium demonstrates efficacy in this Phase II pilot trial, a Phase III study will be developed to establish its clinical utility in these patients. Trial registration ClinicalTrials.gov Identifier NCT02129348 . [ABSTRACT FROM AUTHOR]

Introduction: This study aims to measure frequency and correlates of initial idiopathic psychiatric diagnosis in a cohort of 147 patients with Frontotemporal Dementia (FTD)-spectrum disorders. Methods: Participants were evaluated at the National Institutes of Health in Bethesda, Maryland. Initial participant diagnoses were determined by chart review and patient and informant interviews. Logistic regression was used to assess the relationships between diagnosis and age of symptom onset, gender, education, family history of psychiatric illness, and family history of dementia. Additional exploratory analyses investigated patients' first symptom type. Results: 25% (n=43) of all the patients reviewed were initially misdiagnosed with an idiopathic psychiatric illness, which is less than half the commonly cited 50% rate.3 Depression was the most common misdiagnosis (46.5%). Family history of dementia, family history of mental illness and an exploratory analysis of behavioral first symptoms suggested significant association with a greater likelihood of initial idiopathic psychiatric diagnosis in FTD patients. Discussion: This data confirms patterns of initial idiopathic psychiatric diagnosis in FTD and elucidates potential factors underlying misdiagnosis. Potential implications for patient outcomes, caregiver burden and healthcare costs are discussed. [ABSTRACT FROM AUTHOR]

Abstract: A hexanucleotide repeat expansion in C9ORF72 was recently found to cause some cases of frontotemporal lobar degeneration, frontotemporal dementia (FTD)-amyotrophic lateral sclerosis, and amyotrophic lateral sclerosis. Patients with frontotemporal lobar degeneration with the C9ORF72 repeat expansion are more likely than those without to present with psychosis. In this study, we screened DNA samples from 192 unrelated subjects with schizophrenia for the C9ORF72 repeat expansion. None of the subjects with schizophrenia had the pathogenic expansion. C9ORF72 repeat expansions either do not cause schizophrenia, or do so rarely (less than 1% of cases). [Copyright &y& Elsevier]

Abstract: This study aimed to evaluate genetic variability in the FUS and TDP-43 genes, known to be mainly associated with amyotrophic lateral sclerosis (ALS), in patients with the diagnoses of frontotemporal lobar degeneration (FTLD) and corticobasal syndrome (CBS). We screened the DNA of 228 patients for all the exons and flanking introns of FUS and TDP-43 genes. We identified 2 novel heterozygous missense mutations in FUS: P106L (g.22508384C>T) in a patient with behavioral variant frontotemporal dementia (bvFTD) and Q179H in several members of a family with behavioral variant FTD. We also identified the N267S mutation in TDP-43 in a CBS patient, previously only reported in 1 ALS family and 1 FTD patient. Additionally, we identified 2 previously reported heterozygous insertion and deletion mutations in Exon 5 of FUS; Gly174-Gly175 del GG (g. 4180-4185 delGAGGTG) in an FTD patient and Gly175-Gly176 ins GG (g. 4185-4186 insGAGGTG) in a patient with diagnosis of CBS. Not least, we have found a series of variants in FUS also in neurologically normal controls. In summary, we report that genetic variability in FUS and TDP-43 encompasses a wide range of phenotypes (including ALS, FTD, and CBS) and that there is substantial genetic variability in FUS gene in neurologically normal controls. [Copyright &y& Elsevier]

Psychiatric symptoms, including changes in emotional processing, are a common feature of many neurodegenerative disorders, such as Alzheimer's disease, dementia with Lewy Bodies, frontotemporal dementia, and Huntington's disease. However, the neuroanatomical basis of emotional symptoms is not well defined; this stands in contrast to the relatively well-understood neuroanatomical correlates of cognitive and motor symptoms in neurodegenerative disorders. Furthermore, psychiatric diagnostic categories, as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM) and International Statistical Classification of Diseases and Related Health Problems (ICD), may have limited applicability in patients with late-onset psychiatric symptoms in the context of neurodegenerative disorders. In this clinical review, we suggest that early-onset and late-onset psychiatric symptoms have distinct etiologies, and that late-onset changes in emotional processing are likely underpinned by neurodegenerative disease. Furthermore, we suggest that an improved understanding of the neuroanatomical correlates of emotional changes in neurodegenerative disease may facilitate diagnosis and future treatment development. Finally, we propose a novel clinical approach, in a preliminary attempt to incorporate late-onset emotional symptoms alongside cognitive and motor symptoms into a clinical "algorithm," with a focus on the neuroanatomy implicated when particular combinations of emotional, cognitive, and motor features are present. We anticipate that this clinical approach will assist with the diagnosis of neurodegenerative disorders, and our proposed schema represents a move towards integrating neurologic and psychiatric classification systems. [ABSTRACT FROM AUTHOR]

Compromises in compensatory neurobiologic mechanisms due to aging and/or genetic factors (i.e., APOE gene) may influence brain-derived neurotrophic factor (BDNF) val66met polymorphism effects on temporal lobe morphometry and memory performance. We studied 2 cohorts from Alzheimer's Disease Neuroimaging Initiative: 175 healthy subjects and 222 with prodromal and established Alzheimer's disease. Yearly structural magnetic resonance imaging and cognitive performance assessments were carried out over 3 years of follow-up. Both cohorts had similar BDNF Val/Val and Met allele carriers' (including both Val/Met and Met/Met individuals) distribution. In healthy subjects, a significant trend for thinner posterior cingulate and precuneus cortices was detected in Met carriers compared to Val homozygotes in APOE E4 carriers, with large and medium effect sizes, respectively. The mild cognitive impairment/Alzheimer's disease cohort showed a longitudinal decline in entorhinal thickness in BDNF Met carriers compared to Val/Val in APOE E4 carriers, with effect sizes ranging from medium to large. In addition, an effect of BDNF genotype was found in APOE E4 carriers for episodic memory (logical memory and ADAS-Cog) and semantic fluency measures, with Met carriers performing worse in all cases. These findings suggest a lack of compensatory mechanisms in BDNF Met carriers and APOE E4 carriers in healthy and pathological aging. [ABSTRACT FROM AUTHOR]

Objective: To further our understanding of the association between self-reported childhood learning disabilities (LDs) and atypical dementia phenotypes (Atypical Dementia), including logopenic primary progressive aphasia (L-PPA), Posterior Cortical Atrophy (PCA), and Dysexecutive-type Alzheimer’s Disease (AD). Methods: This retrospective case series analysis of 678 comprehensive neuropsychological assessments compared rates of self-reported LD between dementia patients diagnosed with Typical AD and those diagnosed with Atypical Dementia. 105 cases with neuroimaging or CSF data available and at least one neurology follow-up were identified as having been diagnosed by the neuropsychologist with any form of neurodegenerative dementia. These cases were subject to a consensus diagnostic process among three dementia experts using validated clinical criteria for AD and PPA. LD was considered Probable if two or more statements consistent with prior LD were documented within the Social & Developmental History of the initial neuropsychological evaluation. Results: 85 subjects (Typical AD n=68, Atypical AD n=17) were included in the final analysis. In logistic regression models adjusted for age, gender, handedness, education and symptom duration, patients with Probable LD, compared to patients without Probable LD, were significantly more likely to be diagnosed with Atypical Dementia vs. Typical AD (OR 13.1, 95% CI 1.3-128.4). All three of the L-PPA cases reporting a childhood LD endorsed childhood difficulty with language. By contrast, both PCA cases reporting Probable childhood LD endorsed difficulty with attention and/or math. Conclusions: In people who develop dementia, childhood LD may predispose to atypical phenotypes. Future studies are required to confirm whether atypical neurodevelopment predisposes to regional-specific neuropathology in AD and other dementias. [ABSTRACT FROM AUTHOR]

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]

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]

Brain-derived neurotrophic factor (BDNF), amemberof the neurotrophin family, promotes survival and synaptic plasticity in thehuman brain. The Val66Met polymorphism of the BDNF gene interferes with intracellular trafficking, packaging, and regulated secretion of this neurotrophin. The human prefrontal cortex (PFC) shows lifelong neuroplastic adaption implicating the Val66Met BDNF polymorphism in the recovery of higher-order executive functions after traumatic brain injury (TBI). In this study, we examined the effect of this BDNF polymorphism on the recovery of executive functioning after TBI. We genotyped a sample of male Vietnam combat veterans consisting of a frontal lobe lesion group with focal penetrating head injuries and a non-head-injured control group for the Val66Met BDNF polymorphism. The Delis-Kaplan Executive Function System as a standardized psychometric battery was administrated to examine key domains of executive functions. The results revealed that the Met allele but not the hypothesized Val allele promotes recovery of executive functioning. Overall, the Met66 carriers in the lesion group performed as well as the Met66 carriers in the control group. The Met66 allele accounted for 6.2% of variance for executive functioning independently of other significant predictors including preinjury intelligence, left hemisphere volume loss, and dorsolateral PFC volume loss. The findings point to different mechanisms of the Val66Met BDNF gene in complex phenotypes under normal and pathological conditions. A better understanding of these mechanisms could be instrumental in the development and application of effective therapeutic strategies to facilitate recovery from TBI. [ABSTRACT FROM AUTHOR]

Objectives: To understand the differential neuroanatomical substrates underlying apathy and depression in Frontotemporal dementia (FTD). Methods: T1-MRIs and clinical data of patients with behavioral and aphasic variants of FTD were obtained from an open database. Cortical thickness was derived, its association with apathy severity and difference between the depressed and not depressed were examined with appropriate covariates. Results: Apathy severity was significantly associated with cortical thinning of the lateral parts of the right sided frontal, temporal and parietal lobes. The right sided orbitofrontal, parsorbitalis and rostral anterior cingulate cortex were thicker in depressed compared to patients not depressed. Conclusions: Greater thickness of right sided ventromedial and inferior frontal cortex in depression compared to patients without depression suggests a possible requisite of gray matter in this particular area for the manifestation of depression in FTD. This study demonstrates a method for deriving neuroanatomical patterns across non-harmonized neuroimaging data in a neurodegenerative disease. [ABSTRACT FROM AUTHOR]

Objective: Historically, psychiatric conditions and neurodegenerative diseases have been considered differential diagnoses in older adults with cognitive impairment. However, recent evidence has shown that neuropsychiatric symptoms may be prodromal for neurodegenerative disease. Subjective Cognitive Decline (SCD) is a potential marker for pre-clinical Alzheimer's Disease (AD) that is frequently related to mood disturbances. Delineating the relationship between neuropsychiatric symptoms, SCD, and cognitive impairment will help to define both the independent and combined utility of SCD and neuropsychiatric symptoms as markers of preclinical AD. This abstract uses the DSM-5 Cross-Cutting Measure (DSM-5 CC), a novel comprehensive screening tool for psychiatric symptoms, to examine the relationship between objective and subjective measures of cognition as they relate to neuropsychiatric symptoms. Participants and Methods: 27 community dwelling, cognitively diverse older adults (78% female, mean age 71.9 ± 7) were enrolled in the Concerns about Memory Problems (CAMP) study. Inclusion criteria included the expressed concern about memory functioning by participants on a 5-item screener, while exclusion criteria were defined as previous diagnosis of neurodegenerative diseases and/or major stroke. All participants completed neuropsychological testing and study surveys including the DSM-5 CC. Participants completed Level 1 and all Level 2 (L2) forms of the DSM-5 CC. Spearman two-tailed non-parametric correlations and independent samples t-tests were conducted to examine the relationship between the DSM-5 CC and the 5-item subjective cognition screener, as well as the DSM-5 CC and objective cognition results. Results: Subjective measures of cognition, as measured by answers to the 5-item screening measure, were significantly associated with DSM-5 CC measures. Question 1 on the SCD screener which asks, "Compared to others your age, do you have difficulty with memory or thinking abilities?" was associated with anger (p=.033) and depression (p=.018) L2 forms. Question 3, "Do any difficulties with memory or thinking abilities make it difficult for you to do things in daily life?)" was associated with the L2 forms for somatic symptoms (p=.016) and repetitive thoughts and behaviors (p<.001). Objective measures of cognition from neuropsychological testing also correlated with DSM-5 CC sub-scores. Digits Backwards Length (DBL) correlated with DSM-5 CC Level 1 Sum (r= -.57, p=.002). DBL (r=-.59 p=.001) and Digits Backwards Total Correct (DBTC) (r=-.47, p=.013) associated with somatic symptoms L2 and sleep L2 (DBL: r=,-.45 p=.019; DBTC: r=-.39, p=.044). Category Naming (animals) was also associated with anxiety L2 (r=-.42, p=.030). Conclusions: Subjective and objective measures of cognition were each related to sub-scores of the DSM-5 CC. Interestingly, the associations were largely non-overlapping. These results highlight the importance of considering a wide range of neuropsychiatric symptoms in the assessment of SCD and cognitive impairment. Findings contribute to the growing body of literature suggesting that neuropsychiatric symptoms should be studied in conjunction with cognitive symptoms among older adults as co-occurring phenomena. Future directions will need to include longitudinal studies that can examine the prodromal nature of SCD and neuropsychiatric symptoms for Alzheimer's and other neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Primary lateral sclerosis is a distinct entity that has recently been classified as a “restricted phenotype” of ALS. It is characterized by a pattern of isolated upper motor neuron involvement that often begins in the legs and spreads diffusely. Distinction from other conditions requires careful consideration of clinical presentation and time course of disease. Mills’ Syndrome is a rare unilateral variant of primary lateral sclerosis. Cognitive and behavioral involvement may occur. [ABSTRACT FROM AUTHOR]

Background: Changes in sexual behaviors in frontotemporal dementia (FTD) are common and multifaceted, but not well characterized.Objective: To characterize changes in sexual behaviors and intimacy in FTD compared to corticobasal syndrome (CBS) and normal controls (NC), and to evaluate the neuroanatomical associations of these changes.Methods: Spouses of 30 FTD patients, 20 CBS patients, and 35 NC completed the Sexual Symptoms in Neurological Illness and Injury Questionnaire (SNIQ), which captures changes in sexual interest, inappropriate sexual behaviors, and prosocial sexual behaviors. 25 patients with FTD and 14 patients with CBS also received 18-flouorodeoxyglucose positron-emission topography (18FDG-PET) scans to determine the metabolic changes associated with these symptoms.Results: FTD patients showed a greater increase in inappropriate sexual behaviors than CBS patients [p = 0.009] and NC [p < 0.001] and a greater decrease in prosocial sexual behaviors than CBS patients [p = 0.026] and NC [p < 0.001]. Groups did not differ in change in sexual interest. Among both patient groups, the most common change was decreased prosocial sexual behaviors p < 0.01. Hypometabolism in Brodmann's Area 10 (BA10), within the right frontal pole, correlated with decreased prosocial sexual behaviors [p(FWE-corr) <0.05, k = 44]. No anatomical associations were found with other sexual changes.Conclusion: Decreased prosocial sexual behavior was associated with hypometabolism in BA 10, an area tied to social knowledge and theory of mind, supporting the idea that changes reflect social-cognitive deficits due to frontal dysfunction. [ABSTRACT FROM AUTHOR]

Background: There are currently no disease-targeted treatments for cognitive or behavioral symptoms in patients with behavioral variant frontotemporal dementia (bvFTD).Objective: To determine the effect of tolcapone, a specific inhibitor of Catechol-O-Methyltransferase (COMT), in patients with bvFTD.Methods: In this randomized, double-blind, placebo-controlled, cross-over study at two study sites, we examined the effect of tolcapone on 28 adult outpatients with bvFTD. The primary outcome was reaction time on the N-back cognitive test. As an imaging outcome, we examined differences in the resting blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) signal intensity between subjects on placebo versus tolcapone performing the N-back test. Secondary outcomes included measures of cognitive performance and behavioral disturbance using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Neuropsychiatric Inventory-Questionnaire (NPI-Q), and Clinical Global Impressions scale (CGI).Results: Tolcapone was well tolerated and no patients dropped out. The most frequent treatment-related adverse event during tolcapone treatment was elevated liver enzymes (21%). There were no significant differences between tolcapone treatment and placebo in the primary or imaging outcomes. However, there were significant differences between RBANS total scores (p < 0.01), NPI-Q total scores (p = 0.04), and CGI total scores (p = 0.035) between treatment conditions which were driven by differences between baseline and tolcapone conditions. Further, there was a trend toward significance between tolcapone and placebo on the CGI (p = 0.078).Conclusions: Further study of COMT inhibition and related approaches with longer duration of treatment and larger sample sizes in frontotemporal lobar degeneration-spectrum disorders may be warranted. [ABSTRACT FROM AUTHOR]

Background: Anticholinergic challenge can induce odor identification impairment that indicates Alzheimer's disease (AD) pathology, and short-term change in odor identification impairment with cholinesterase inhibitor (CheI) treatment may predict longer term cognitive outcomes.Objective: In patients with mild cognitive impairment (MCI) treated prospectively with donepezil, a CheI, for 52 weeks, to determine if 1) acute decline in odor identification ability with anticholinergic challenge can predict cognitive improvement, and 2) change in odor identification over 8 weeks can predict cognitive improvement.Methods: MCI was diagnosed clinically without AD biomarkers. At baseline, the University of Pennsylvania Smell identification Test (UPSIT) was administered before and after an anticholinergic atropine nasal spray challenge. Donepezil was started at 5 mg daily, increased to 10 mg daily if tolerated, and this dose was maintained for 52 weeks. Main outcomes were ADAS-Cog total score and Selective Reminding Test (SRT) total immediate recall score measured at baseline, 26 and 52 weeks.Results: In 100 study participants, mean age 70.14 (SD 9.35) years, atropine-induced decrease in UPSIT score at baseline was not associated with change in ADAS-Cog or SRT scores over 52 weeks. Change in UPSIT score from 0 to 8 weeks did not show a significant association with change in the ADAS-Cog or SRT measures over 52 weeks.Conclusion: These negative findings in a relatively large sample of patients with MCI did not replicate results in much smaller samples. Change in odor identification with anticholinergic challenge, and over 8 weeks, may not be useful predictors of cognitive improvement with CheI in patients with MCI. [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]

Objectives: Patients with essential tremor exhibit heterogeneous cognitive functioning. Although the majority of patients fall under the broad classification of cognitively "normal," essential tremor is associated with increased risk for mild cognitive impairment and dementia. It is possible that patterns of cognitive performance within the wide range of normal functioning have predictive utility for mild cognitive impairment or dementia. These cross-sectional analyses sought to determine whether cognitive patterns, or "clusters," could be identified among individuals with essential tremor diagnosed as cognitively normal. We also determined whether such clusters, if identified, were associated with demographic or clinical characteristics of patients. Methods: Elderly subjects with essential tremor (age >55 years) underwent comprehensive neuropsychological testing. Domain means (memory, executive function, attention, visuospatial abilities, and language) from 148 individuals diagnosed as cognitively normal were partitioned using k -means cluster analysis. Individuals in each cluster were compared according to cognitive functioning (domain means and test scores), demographic factors, and clinical variables. Results: There were three clusters. Cluster 1 (n = 64) was characterized by comparatively low memory scores (p <.001), Cluster 2 (n = 39) had relatively low attention and visuospatial scores (p <.001), and Cluster 3 (n = 45) exhibited consistently high performance across all domains. Cluster 1 had lower Montreal Cognitive Assessment scores and reported more prescription medication use and lower balance confidence. Conclusions: Three patterns of cognitive functioning within the normal range were evident and tracked with certain clinical features. Future work will examine the extent to which such patterns predict conversion to mild cognitive impairment and/or dementia. [ABSTRACT FROM AUTHOR]

Objective: To develop a validated, caregiver-based measurement scale to assess sexual changes across several domains in a sample of 86 patients with penetrating traumatic brain injury (TBI) and 65 patients with neurodegeneration due to frontotemporal dementia and corticobasal syndrome. Methods: A new measure, the Sexual Symptoms in Neurological Illness and Injury Questionnaire (SNIQ), was constructed. Dimensionality, monotonicity, item discrimination power, and scalability were evaluated using nonparametric Mokken item response theory (IRT) methodology. Results: Three primary domains were established. The domains presented with sufficient reliability (rho.70 to.80), while meeting the Mokken IRT criteria of medium scalability. The domains were labeled ‘Prosocial sexual behaviour’ (H = .42), ‘Sexual interest’ (H = .50), and ‘Inappropriate sexual behaviour’ (H = .41). A fourth dimension emerged, ‘Detachment’ (H = .47), but with very few items. Conclusions: Construct validity was established for groups of items pertaining to three unique aspects of sexuality. These findings support further use of the SNIQ in assessing and researching sexual behaviours in patients with dementia and brain injury. [ABSTRACT FROM AUTHOR]

Objectives: Essential tremor (ET) confers an increased risk for developing both amnestic and non-amnestic mild cognitive impairment (MCI). Yet, the optimal measures for detecting mild cognitive changes in individuals with this movement disorder have not been established. We sought to identify the cognitive domains and specific motor-free neuropsychological tests that are most sensitive to mild deficits in cognition as defined by a Clinical Dementia Rating (CDR) of 0.5, which is generally associated with a clinical diagnosis of MCI. Methods: A total of 196 ET subjects enrolled in a prospective, longitudinal, clinical-pathological study underwent an extensive motor-free neuropsychological test battery and were assigned a CDR score. Logistic regression analyses were performed to identify the neuropsychological tests which best identified individuals with CDR of 0.5 (mild deficits in cognition) versus 0 (normal cognition). Results: In regression models, we identified five tests in the domains of Memory and Executive Function which best discriminated subjects with CDR of 0.5 versus 0 (86.9% model classification accuracy). These tests were the California Verbal Learning Test II Total Recall, Logical Memory II, Verbal-Paired Associates I, Category Switching Fluency, and Color-Word Inhibition. Conclusions: Mild cognitive difficulty among ET subjects is best predicted by combined performance on five measures of memory and executive function. These results inform the nature of cognitive dysfunction in ET and the creation of a brief cognitive battery to assess patients with ET for cognitively driven dysfunction in life that could indicate the presence of MCI. (JINS , 2018, 24 , 1084–1098) [ABSTRACT FROM AUTHOR]

Essential tremor (ET) is a progressive neurological disease associated with functional disability, diminished quality of life and, in some individuals, poorer balance, cognitive impairment, depression and sleep dysregulation. Individuals with ET may rely on family members and friends to act as informal caregivers to assist with daily activities and provide emotional support. There is a high prevalence of embarrassment among individuals with ET, which may be a result of the outwardly visible nature of tremor. Studies in populations with outwardly visible disability have shown that perception by caregivers of a care-recipient's social distress can contribute to caregiver burden. We hypothesize that in ET, perception by caregivers of ET participant embarrassment is a predictor for caregiver burden. Data were collected from 57 ET participants and their caregivers. We measured ET participant embarrassment using the Essential Tremor Embarrassment Assessment (ETEA), and measured perception by caregivers of ET participant embarrassment using a modified version of the ETEA. The Zarit Burden Interview was used to measure caregiver burden . Perceived embarrassment was associated with ET participant embarrassment. In linear regression models, perceived embarrassment was a stronger predictor for caregiver burden than measures of ET participant cognitive and physical impairment. The results indicate that perception of ET participant embarrassment can be burdensome for caregivers. Clinicians may wish to address patient embarrassment and perceived embarrassment to better support caregivers and ET patients. [ABSTRACT FROM AUTHOR]

Background: Anticholinergic challenge can induce odor identification impairment that indicates Alzheimer's disease pathology.Objective: To determine if decline in odor identification ability with anticholinergic challenge can predict improvement with donepezil, a cholinesterase inhibitor (ChEI), in patients with mild cognitive impairment (MCI).Methods: At baseline, the University of Pennsylvania Smell identification Test (UPSIT) was administered before and after an anticholinergic atropine nasal spray challenge. Donepezil was started at 5 mg daily, increased to 10 mg daily if tolerated, and then the dose was kept constant for 52 weeks. Main outcomes were change in Selective Reminding Test (SRT) total immediate recall and ADAS-Cog total score from baseline to 26 and 52 weeks.Results: In 37 participants, mean age 70.4 (SD 9.8) y, greater atropine-induced decrease in UPSIT score at baseline was associated with greater improvement in SRT total recall score from baseline to 26 and 52 weeks (p < 0.03). This effect remained after adjusting for time, age, education, gender, APOE ɛ4 status, and baseline cognitive score (p < 0.05). Decrease in UPSIT score was associated with global improvement (CIBIC-plus) over 52 weeks (p < 0.02). After excluding patients with congential anosmia, increase in UPSIT score from 0 to 8 weeks showed a trend-level association with improvement on the ADAS-Cog (p = 0.07).Conclusions: Anticholinergic challenge-induced odor identification decline was associated with cognitive improvement, and short-term improvement in odor identification tended to predict longer term cognitive improvement. These simple inexpensive strategies have the potential to improve selection of patients with MCI for ChEI treatment. [ABSTRACT FROM AUTHOR]

ObjectivesIndividuals with essential tremor (ET) exhibit a range of cognitive deficits generally conceptualized as “dysexecutive” or “fronto-subcortical,” and thought to reflect disrupted cortico-cerebellar networks. In light of emerging evidence that ET increases risk for Alzheimer’s disease (AD), it is critical to more closely examine the nature of specific cognitive deficits in ET, with particular attention to amnestic deficits that may signal early AD.MethodsWe performed a cross-sectional analysis of baseline data from 128 ET cases (age 80.4±9.5 years) enrolled in a longitudinal, clinical-pathological study. Cases underwent a comprehensive battery of motor-free neuropsychological tests and a functional assessment to inform clinical diagnoses of normal cognition (ET-NC), mild cognitive impairment (MCI) (ET-MCI), or dementia (ET-D). ET-MCI was subdivided into subtypes including: amnestic single-domain (a-MCI), amnestic multi-domain (a-MCI+), non-amnestic single-domain (na-MCI), or non-amnestic multi-domain (na-MCI+).ResultsNinety-one (71.1%) cases were ET-NC, 24 (18.8%) were ET-MCI, and 13 (10.2%) were ET-D. Within MCI, the a-MCI+ subtype was the most common (13/24; 54.2%) followed by a-MCI (4/24; 16.7%), na-MCI+ (4/24; 16.7%), and na-MCI (3/24; 12.5%). Cases with amnestic MCI demonstrated lower recognition memory Z-scores (−2.4±1.7) than non-amnestic groups (−0.9±1.2) (p=.042).ConclusionsAmnestic MCI, defined by impaired memory recall but associated with lower memory storage scores, was the most frequent MCI subtype in our study. Such impairment has not been explicitly discussed in the context of ET and may be an early hallmark of AD. Results have implications for the prognosis of specific cognitive deficits in ET. (JINS, 2017, 23, 390–399) [ABSTRACT FROM PUBLISHER]

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]

Frontotemporal lobar degeneration comprises a group of disorders characterized by behavioural, executive, language impairment and sometimes features of parkinsonism and motor neuron disease. In 1994 we described an Irish-American family with frontotemporal dementia linked to chromosome 17 associated with extensive tau pathology. We named this disinhibition-dementia-parkinsonism-amyotrophy complex. We subsequently identified mutations in the MAPT gene. Eleven MAPT gene splice site stem loop mutations were identified over time except for 5' splice site of exon 10. We recently identified another Irish family with autosomal dominant early amnesia and behavioural change or parkinsonism associated with the 'missing' +15 mutation at the intronic boundary of exon 10. We performed a clinical, neuropsychological and neuroimaging study on the proband and four siblings, including two affected siblings. We sequenced MAPT and performed segregation analysis. We looked for a biological effect of the tau variant by performing real-time polymerase chain reaction analysis of RNA extracted from human embryonic kidney cells transfected with exon trapping constructs. We found a c.915+15A>C exon 10/intron 10 stem loop mutation in all affected subjects but not in the unaffected. The c.915+15A>C variant caused a shift in tau splicing pattern to a predominantly exon 10+ pattern presumably resulting in predominant 4 repeat tau and little 3 repeat tau. This strongly suggests that the c.915+15A>C variant is a mutation and that it causes frontotemporal dementia linked to chromosome 17 in this pedigree by shifting tau transcription and translation to +4 repeat tau. Tau (MAPT) screening should be considered in families where amnesia or atypical parkinsonism coexists with behavioural disturbance early in the disease process. We describe the final missing stem loop tau mutation predicted 15 years ago. Mutations have now been identified at all predicted sites within the 'stem' when the stem-loop model was first proposed and no mutations have been found within the 'loop' region as expected. Therefore we 'close the tau loop' having 'opened the loop' 21 years ago. [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]

Background and Aims: Caregiver stress is often a serious problem when caring for a patient with frontal lobe dysfunction. Methods: A total of 102 caregivers of both patients with frontotemporal degeneration and corticobasal syndrome completed the Frontal Systems Behavior Scale (FrSBe) and the Zarit Burden Interview (ZBI). To analyze the association between apathy or disinhibition (or both) and caregiver burden, the effects of the total FrSBe and the apathy and disinhibition subscales of the FrSBE on the total ZBI score were assessed with logistic regressions and t tests. Results: Total FrSBE score and the apathy FrSBE subscore predicted caregiver burden. Apathy occurred without disinhibition, and the two occurred together, but disinhibition without apathy was very rare. Conclusions: Disinhibition without apathy occurred very rarely. Apathy was more associated with caregiver burden than disinhibition. © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]