Results of the citalopram to enhance cognition in Huntington disease trial.

BACKGROUND: The objective of this study was to evaluate citalopram for executive functioning in Huntington's disease (HD). METHODS: The study was randomized, double-blind, and placebo-controlled. Thirty-three adults with HD, cognitive complaints, and no depression (Hamilton Depression [HAM-D] rating scale ≤ 12) were administered citalopram 20 mg or placebo (7 visits, 20 weeks), with practice and placebo run-ins. The primary outcome was change in executive functioning. RESULTS: The intent to treat analysis was controlled for practice effects, comparing visits 1 and 2 to visits 5 and 6 for citalopram versus placebo. There were no significant benefits on the executive function composite (treatment-placebo mean difference -0.167; 95% confidence interval [CI], -0.361 to 0.028; P = .092). Citalopram participants showed improved clinician-rated depression symptoms on the HAM-D (t = -2.02; P = 0.05). There were no group differences on motor ratings, self-reported executive functions, psychiatric symptoms, or functional status. CONCLUSIONS: There was no evidence that short-term treatment with citalopram improved executive functions in HD. Despite excluding patients with active depression, participants on citalopram showed improved mood, raising the possibility of efficacy for subsyndromal depression in HD.

Preliminary study of the association of white-matter metabolite concentrations with disease severity in patients with Huntington's disease.

Proton magnetic resonance spectroscopy is used to measure several metabolites in cortical gray and white matter in patients with Huntington's disease. The preliminary results show that CAG-repeat length correlates with white-matter N-acetylaspartate concentrations, and disease severity correlates with several metabolites.

Cognitive features 10 or more years after successful breast cancer survival: comparisons across types of cancer interventions.

BACKGROUND: The present study examined the long-term cognitive implications of cancer treatment among breast cancer survivors aged 65 years and older to better understand the long term implications of cancer treatment. METHODS: Fifty-seven women survivors were compared with 30 healthy older female adult comparisons, matched in terms of age and education, with no history of cancer. Cancer survivors were also compared on the basis of treatment intervention, involving chemotherapy (n = 27) versus local therapy through surgery and radiation (n = 30). RESULTS: As a group, the breast cancer survivors scored lower on measures of general cognitive function, working memory, psychomotor speed, and executive function when compared with the normal comparisons. Among the cancer survivors, those who received local therapy scored lower than the other survivors and normal comparisons on measures of verbal learning, visual perception and construction, as well as visual attention and short-term retention. CONCLUSIONS: Our findings suggest that cognitive outcomes may involve greater age-related deficits among older cancer survivors compared with matched healthy subjects.

Clinical predictors of driving status in Huntington's disease.

The aim of this study was to identify the motor, cognitive, and behavioral determinants of driving status and risk factors for driving cessation in Huntington's disease (HD). Seventy-four patients with HD were evaluated for cognitive, motor, psychiatric, and functional status using a standardized battery (Unified Huntington's Disease Rating Scale [UHDRS] and supplemental neuropsychological testing) during a research clinic visit. Chart review was used to categorize patients into two driving status categories: (1) "currently driving" included those driving and driving but with clinician recommendation to restrict, and (2) "not driving" included those with clinician recommendation to cease driving and those not currently driving because of HD. Multi- and univariate logistic regression was used to identify significant clinical predictors of those driving versus not driving. Global cognitive performance and UHDRS Total Functional Capacity scores provided the best predictive model of driving cessation (Nagelkerke R(2) = 0.65; P < 0.0001). Measures of learning (P = 0.006) and psychomotor speed/attention (P = 0.003) accounted for the overall cognitive finding. In univariate analyses, numerous cognitive, motor, and daily functioning items were significantly associated with driving. Although driving status is associated with many aspects of the disease, results suggest that the strongest association is with cognitive performance. A detailed cognitive evaluation is an important component of multidisciplinary clinical assessment in patients with HD who are driving.

Risk factors for delirium in patients undergoing hematopoietic stem cell transplantation.

BACKGROUND: Delirium is common after hematopoietic stem cell transplantation (HSCT) and is associated with increased morbidity and mortality. Early recognition and treatment have been shown to improve long-term outcomes. We sought to investigate the relationship between potential risk factors and the development of delirium following HSCT. METHODS: Fifty-four inpatients admitted for HSCT were assessed prospectively for delirium every 2 to 3 days during their inpatient stay using standardized delirium and neuropsychological measures. Self reports of medical history, medical records, and neurocognitive and psychiatric assessments were used to identify risk factors. Both pre- and post-HSCT risk factors were examined. RESULTS: Delirium incidence was 35% and occurred with highest frequency in the 2 weeks following transplant. The only pre-transplantation risk factor was lower oxygen saturation (P = .003). Post-transplantation risk factors for delirium included higher creatinine (P < .0001), higher blood urea nitrogen levels (P = .005), lower creatinine clearance (P = .0006), lower oxygen saturation (P = .001), lower hemoglobin (P = .04), and lower albumin (P = .03). There was no observed association with level of cognitive performance, transplant type, disease severity, medical comorbidity index, age, or conditioning regimen. CONCLUSIONS: Routine laboratory values can assist in the identification of high-risk patients before delirium onset to improve early detection and treatment of delirium after HSCT.

Smaller intracranial volume in prodromal Huntington's disease: evidence for abnormal neurodevelopment.

Huntington's disease is an autosomal dominant brain disease. Although conceptualized as a neurodegenerative disease of the striatum, a growing number of studies challenge this classic concept of Huntington's disease aetiology. Intracranial volume is the tissue and fluid within the calvarium and is a representation of the maximal brain growth obtained during development. The current study reports intracranial volume obtained from an magnetic resonance imaging brain scan in a sample of subjects (n = 707) who have undergone presymptomatic gene testing. Participants who are gene-expanded but not yet manifesting the disease (prodromal Huntington's disease) are compared with subjects who are non-gene expanded. The prodromal males had significantly smaller intracranial volume measures with a mean volume that was 4% lower compared with controls. Although the prodromal females had smaller intracranial volume measures compared with their controls, this was not significant. The current findings suggest that mutant huntingtin can cause abnormal development, which may contribute to the pathogenesis of Huntington's disease.

Patterns of serotonergic antidepressant usage in prodromal Huntington disease.

Antidepressant usage in prodromal Huntington Disease (HD) remains uncharacterized, despite its relevance in designing experiments, studying outcomes of HD, and evaluating the efficacy of therapeutic interventions. We searched baseline medication logs of 787 prodromal HD and 215 healthy comparison (HC) participants for antidepressant use. Descriptive and mixed-effects logistic regression modeling characterized usage across participants. At baseline, approximately one in five prodromal HD participants took antidepressants. Of those, the vast majority took serotonergic antidepressants (selective serotonin reuptake inhibitor (SSRI) or serotonin/norepinephrine reuptake inhibitor (SNRI)). Significantly more prodromal HD participants used serotonergic antidepressants than their HC counterparts. Because of the prevalence of these medications, further analyses focused on this group alone. Mixed-effects logistic regression modeling revealed significant relationships of both closer proximity to diagnosis and female sex with greater likelihood to be prescribed a serotonergic antidepressant. More prodromal HD participants took antidepressants in general and specifically the subclass of serotonergic antidepressants than their at-risk counterparts, particularly when they were closer to predicted time of conversion to manifest HD. These propensities must be considered in studies of prodromal HD participants.

Practice effects predict cognitive outcome in amnestic mild cognitive impairment.

OBJECTIVE: Practice effects on cognitive tests have been shown to further characterize patients with amnestic mild cognitive impairment (aMCI) and may provide predictive information about cognitive change across time. We tested the hypothesis that a loss of practice effects would portend a worse prognosis in aMCI. DESIGN: Longitudinal, observational design following participants across 1 year. SETTING: Community-based cohort. PARTICIPANTS: Three groups of older adults: 1) cognitively intact (n = 57), 2) aMCI with large practice effects across 1 week (MCI + PE, n = 25), and 3) aMCI with minimal practice effects across 1 week (MCI - PE, n = 26). MEASUREMENTS: Neuropsychological tests. RESULTS: After controlling for age and baseline cognitive differences, the MCI - PE group performed significantly worse than the other groups after 1 year on measures of immediate memory, delayed memory, language, and overall cognition. CONCLUSIONS: Although these results need to be replicated in larger samples, the loss of short-term practice effects portends a worse prognosis in patients with aMCI.

Proton Magnetic Resonance Spectroscopy in adult cancer patients with delirium.

Delirium is associated with a host of negative outcomes, including increased risk of mortality, longer hospital stay, and poor long-term cognitive function. The pathophysiology of delirium is not well understood. Cancer patients undergoing a bone marrow transplant (BMT) are at high risk for developing delirium and Proton Magnetic Resonance Spectroscopy ((1)H MRS) could lead to better understanding of the delirium process. Fourteen BMT patients and 10 controls completed (1)H MRS, positioned above the corpus callosum, shortly after delirium onset or at study end if no delirium occurred. In the BMT-delirium group, statistically significantly elevated tCho/tCr was found in contrast to the BMT-no delirium group. The BMT-delirium group also showed statistically significantly lesser NAA/tCho compared with both controls and the BMT-no delirium group. Elevated choline and reduced NAA indicate inflammatory processes and white matter damage as well as neuronal metabolic impairment. Further research is needed to separate the choline peaks, as well as more detailed collection of medication regimens to determine whether a higher choline concentration is a function of the delirium process or cancer treatment effects.

The RBANS Effort Index: base rates in geriatric samples.

The Effort Index (EI) of the RBANS was developed to assist clinicians in discriminating patients who demonstrate good effort from those with poor effort. However, there are concerns that older adults might be unfairly penalized by this index, which uses uncorrected raw scores. Using five independent samples of geriatric patients with a broad range of cognitive functioning (e.g., cognitively intact, nursing home residents, probable Alzheimer's disease), base rates of failure on the EI were calculated. In cognitively intact and mildly impaired samples, few older individuals were classified as demonstrating poor effort (e.g., 3% in cognitively intact). However, in the more severely impaired geriatric patients, over one third had EI scores that fell above suggested cutoff scores (e.g., 37% in nursing home residents, 33% in probable Alzheimer's disease). In the cognitively intact sample, older and less educated patients were more likely to have scores suggestive of poor effort. Education effects were observed in three of the four clinical samples. Overall cognitive functioning was significantly correlated with EI scores, with poorer cognition being associated with greater suspicion of low effort. The current results suggest that age, education, and level of cognitive functioning should be taken into consideration when interpreting EI results and that significant caution is warranted when examining EI scores in elders suspected of having dementia.

Neuropsychological outcomes of older breast cancer survivors: cognitive features ten or more years after chemotherapy.

The authors examined the long-term cognitive implications of cancer treatment among breast cancer survivors over 65 years old who received treatment during midlife. Thirty women survivors were matched with 30 noncancer, healthy older adults in terms of age, education, and IQ. The cancer survivors scored significantly lower in the cognitive domains of executive functioning, working memory, and divided attention, reflecting potential dysfunction in frontal-subcortical brain regions. Our findings suggest that among breast cancer survivors who remain disease-free for more than a decade, the previous cancer treatment may further augment cognitive dysfunction associated with age-related brain changes.

"Frontal" behaviors before the diagnosis of Huntington's disease and their relationship to markers of disease progression: evidence of early lack of awareness.

Huntington's disease has been linked with fronto-subcortical neuropathology and behaviors consistent with this dysfunction. Little is known about these "frontal" behaviors in the earliest phase of the illness. Comparisons between participants in the Predict-HD study (745 "expansion-positive" and 163 "expansion-negative" control subjects) on the Frontal System Behavior Scale looked for evidence of frontal behaviors, including apathy, disinhibition, and executive dysfunction. The authors were also able to compare participant and companion reporting of these frontal behaviors as a possible indication of awareness of behaviors. Expansion-positive individuals reported significantly more of these frontal behaviors than expansion-negative peers. Self- and companion-reported frontal behaviors were related to other Huntington's disease markers. Expansion-positive participants closest to Huntington's disease diagnosis showed greater discrepancies with companions on ratings of frontal behaviors. Even though most are more than 10 years from Huntington's disease diagnosis, mild frontal behaviors were present in this prediagnosed sample, which might make these behaviors useful as markers for Huntington's disease onset. Participant/companion discrepancies, especially closest to Huntington's disease diagnosis, might suggest early lack of awareness in these individuals.

Earliest functional declines in Huntington disease.

We examined the gold standard for Huntington disease (HD) functional assessment, the Unified Huntington's Disease Rating Scale (UHDRS), in a group of at-risk participants not yet diagnosed but who later phenoconverted to manifest HD. We also sought to determine which skill domains first weaken and the clinical correlates of declines. Using the UHDRS Total Functional Capacity (TFC) and Functional Assessment Scale (FAS), we examined participants from Huntington Study Group clinics who were not diagnosed at their baseline visit but were diagnosed at a later visit (N=265). Occupational decline was the most common with 65.1% (TFC) and 55.6% (FAS) reporting some loss of ability to engage in their typical work. Inability to manage finances independently (TFC 49.2%, FAS 35.1%) and drive safely (FAS 33.5%) were also found. Functional decline was significantly predicted by motor, cognitive, and depressive symptoms. The UHDRS captured early functional losses in individuals with HD prior to formal diagnosis, however, fruitful areas for expanded assessment of early functional changes are performance at work, ability to manage finances, and driving. These are also important areas for clinical monitoring and treatment planning as up to 65% experienced loss in at least one area prior to diagnosis.

Comorbidities of obsessive and compulsive symptoms in Huntington's disease.

Although current reports document a high rate of obsessive and compulsive symptoms (O/Cs) in Huntington's disease (HD), there have been no studies published that have made an attempt to identify comorbidities of O/Cs in HD. We examined O/Cs in 1642 individuals with a diagnosis of HD. Of those endorsing significant O/Cs (27.2%), nearly one-quarter reported obtaining treatment for obsessive compulsive disorder. Individuals with HD and O/Cs were older, had poorer functioning, and a longer duration of illness than those without O/Cs. Individuals with HD and O/Cs endorsed significantly higher psychiatric comorbidities of depression, suicidal ideation, aggression, delusions, and hallucinations. Participants with the most severe O/Cs and worse performance on the Stroop task, a measure of executive function. Clinicians should be aware that patients with HD and O/Cs might have a somewhat different clinical picture from those without, and may require a specialized treatment plan.

Predictors of neuropsychological recovery in treatment for anorexia nervosa.

Previous research indicates that individuals with Anorexia Nervosa (AN) often experience some degree of neuropsychological dysfunction. Although most aspects of cognition improve with treatment, factors that predict neuropsychological improvement remain elusive. The present study investigated whether cognitive reserve, the estimated level of premorbid cognitive functioning, and AN subtype predicted neuropsychological improvement during inpatient treatment for AN. Neuropsychological functioning was assessed pre- and post-hospitalization in 28 women with AN (18 with restricting type and 10 with binge-eating/purging type), and cognitive reserve was estimated at admission using a word reading test. Level of cognitive reserve and AN subtype were both significant predictors of neuropsychological improvement in this sample. Cognitive reserve was significantly associated with improvements in verbal memory, semantic fluency, basic auditory attention and visuospatial construction. Participants with AN binge-eating/purging type demonstrated significantly greater neuropsychological improvement during treatment than did participants with AN restricting type. Information about cognitive reserve and AN subtype may provide clinicians with valuable prognostic information and help guide treatment.

Motor abnormalities in premanifest persons with Huntington's disease: the PREDICT-HD study.

The PREDICT-HD study seeks to identify clinical and biological markers of Huntington's disease in premanifest individuals who have undergone predictive genetic testing. We compared baseline motor data between gene-expansion carriers (cases) and nongene-expansion carriers (controls) using t-tests and Chi-square. Cases were categorized as near, mid, or far from diagnosis using a CAG-based formula. Striatal volumes were calculated using volumetric magnetic resonance imaging measurements. Multiple linear regression associated total motor score, motor domains, and individual motor items with estimated diagnosis and striatal volumes. Elevated total motor scores at baseline were associated with higher genetic probability of disease diagnosis in the near future (partial R(2) 0.14, P < 0.0001) and smaller striatal volumes (partial R(2) 0.15, P < 0.0001). Nearly all motor domain scores showed greater abnormality with increasing proximity to diagnosis, although bradykinesia and chorea were most highly associated with diagnostic immediacy. Among individual motor items, worse scores on finger tapping, tandem gait, Luria, saccade initiation, and chorea show unique association with diagnosis probability. Even in this premanifest population, subtle motor abnormalities were associated with a higher probability of disease diagnosis and smaller striatal volumes. Longitudinal assessment will help inform whether motor items will be useful measures in preventive clinical trials.

Randomized controlled trial of atomoxetine for cognitive dysfunction in early Huntington disease.

BACKGROUND: Cognitive symptoms are associated with functional disability in Huntington disease; yet, few controlled trials have examined cognitive treatments that could improve patient independence and quality of life. Atomoxetine is a norepinephrine reuptake inhibitor approved for treatment of attention-deficit/hyperactivity disorder. METHODS: Twenty participants with mild Huntington disease who complained of inattention were randomized to receive atomoxetine (80 mg/d) or placebo in a 10-week double-blind crossover study. Primary outcome measures were self-reported attention and attention and executive neuropsychological composite scores. Secondary outcomes were psychiatric and motor symptom scores. RESULTS: The rate of reported adverse effects while on atomoxetine was 56% (vs 35% on placebo), which most commonly included dry mouth (39%), loss of appetite (22%), insomnia (22%), and dizziness (17%). There were no serious adverse events related to atomoxetine. There were statistically significant, although mild, increases in heart rate and diastolic blood pressure on atomoxetine, consistent with other studies and not requiring medical referral. There were no significant improvements while on atomoxetine compared with placebo on primary outcomes. However, there was evidence of significant placebo effects on self-reported attention and psychiatric functions. There were no group differences on the Unified Huntington's Disease Rating total motor score. CONCLUSIONS: Atomoxetine demonstrated no advantages over placebo for primary or secondary outcomes. Although atomoxetine was not effective at improving attention at this dose, its safety and tolerability were similar to other studies.

Validation of the modified telephone interview for cognitive status in amnestic mild cognitive impairment and intact elders.

Although the modified Telephone Interview for Cognitive Status (mTICS) is frequently used as a screening measure of cognition in dementia and aging studies, it has not been validated in individuals with milder cognitive impairments. The current study compared 2 groups [amnestic Mild Cognitive Impairment (n=61) and cognitively intact elders (n=62)] on the mTICS and used regression models to predict baseline scores on standardized memory tests using baseline mTICS scores. Baseline mTICS scores were also used to predict 1-year follow-up scores on memory tests in a subsample (n=91). Large group differences (P<0.01) were found between the amnestic individuals and their healthy peers on the mTICS total score, 2-factor scores, and 3 of 14 individual items. Baseline mTICS scores predicted between 22% and 43% of baseline memory composite scores and 21% and 28% of 1-year memory composite scores. Overall, these results provide additional validation of the mTICS as a valuable screening instrument for cognition in individuals with milder cognitive impairments.

Emotional and motivational changes after bilateral lesions of the globus pallidus.

This study investigated motivational changes in a 44 year-old man (PJ) who developed considerable reduction in spontaneous activity and speech, flat affect, social withdrawal, loss of interest, inability to "feel," and lack of concern regarding his medical condition after bilateral, focal, anoxic lesions of the globus pallidus. PJ and 30 male controls performed a task designed to parse hedonic evaluation, or liking, from incentive motivation, or wanting. Affective stimuli were presented on a computer screen and subjects controlled viewing time by pressing keys. PJ's liking and wanting of unpleasant stimuli was similar to that of controls. In response to pleasant stimuli, PJ showed normal ratings of wanting and hedonic appreciation, but significantly reduced viewing time or made no responses. Active withdrawal from liked stimuli could constitute the basic mechanism underlying poor motivation and social withdrawal associated with globus pallidus damage.

Retention rates on RBANS memory subtests in elderly adults.

Identification of memory impairment is important for neuropsychological diagnostic and research applications, and retention rates on verbal and visual memory tests can provide useful information when characterizing a variety of neurological and psychiatric disorders. Although the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) is becoming a popular screening battery for cognitive functions, normative data on retention rates are not available. The retention rates of verbal and visual material were evaluated in a sample of clinical patients (n = 109) compared to a healthy control group (n = 718). Individual subtest retention rates were converted to age-corrected scaled scores based on the cumulative distribution of raw scores obtained by an elderly community-dwelling sample. Compared with the healthy normative sample, the percent retention found for the clinical group was significantly lower on all 3 RBANS memory subtests. These preliminary data suggest that retention rates of the RBANS memory subtests may add to the clinical utility of this test as a neuropsychological diagnostic and research tool.