Practice Effects and Stability of Neuropsychological and UHDRS Tests Over Short Retest Intervals in Huntington Disease.

BACKGROUND: In Huntington disease (HD), cognitive changes due to disease-progression or treatment are potentially confounded by "practice effects" (PE)--performance improvement from prior exposure to test materials. OBJECTIVE: A practice run-in ("dual baseline") was used in an HD cognitive trial to determine if PE could be minimized and evaluate performance trajectories over multiple visits. METHODS: Non-depressed adults (N = 36) with mild to moderate HD-related cognitive deficits participated in a clinical trial to examine the efficacy of citalopram to enhance cognition. Cognitive tests were administered at three visits (2 weeks separating each visit), before active treatment randomization. Some tests were also administered at screening. Therefore 3-4 pre-treatment repetitions were available. We examined test improvement using repeated-measures ANOVAs with planned pairwise comparisons. RESULTS: Despite the practice run-in and use of alternate test forms, results indicated ongoing improvements over at least three test sessions on all three UHDRS cognitive tests. Trails A and B showed improvements between the third and fourth session, which suggests that one pre-baseline visit may not be effective in reducing practice on this important and commonly used test. CONCLUSIONS: Overall, 7 out of 13 variables showed some degree of short-term PE, even after multiple sessions and alternate forms. Tests assessing processing speed and memory may be particularly confounded by ongoing PE across at least 2-3 sessions. Practice run-in periods and alternate forms may help minimize the impact of such effects in HD clinical trials but awareness of which tests are most susceptible to PE is important in clinical trial design.

Does interval between screening and baseline matter in HD cognitive clinical trials?

BACKGROUND: "Practice effects" (PE), or performance improvements due to prior exposure to testing, are known to confound cognitive test results, particularly when short intervals occur between two test sessions. OBJECTIVE: We examined two subsamples with short or long re-test intervals from a recent clinical trial. METHODS: Thirty-four non-depressed adults with mild Huntington Disease (HD) participated. Three cognitive tests were administered at screening and again at baseline, before active treatment randomization. Half the sample had a 24-hour retest interval while the other half was >6-days. RESULTS: The two groups differed on demographic/clinical factors (age, Total Motor Score and Total Functional Capacity). After controlling for age and motor score, PE differences were found on three of the five UHDRS cognitive tests: the longer interval group showed larger PE on Symbol-Digit Modalities and Stroop color, while the rapid interval group had larger PE on Stroop interference. Controlling for screening cognitive performance yielded similar results. CONCLUSIONS: Length of interval between screening and baseline visits and level of disease severity may influence stability of UHDRS cognitive test results in clinical trials 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.

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.

Characterization of depression in prodromal Huntington disease in the neurobiological predictors of HD (PREDICT-HD) study.

Depression causes significant morbidity and mortality, and this also occurs in Huntington Disease (HD), an inherited neurodegenerative illness with motor, cognitive, and psychiatric symptoms. The presentation of depression in this population remains poorly understood, particularly in the prodromal period before development of significant motor symptoms. In this study, we assessed depressive symptoms in a sample of 803 individuals with the HD mutation in the prodromal stage and 223 mutation-negative participants at the time of entry in the Neurobiological Predictors of HD (PREDICT-HD) study. Clinical and biological HD variables potentially related to severity of depression were analyzed. A factor analysis was conducted to characterize the symptom domains of depression in a subset (n=168) with clinically significant depressive symptoms. Depressive symptoms were found to be more prevalent in HD mutation carriers but did not increase with proximity to HD diagnosis and were not associated with length of the HD mutation. Increased depressive symptoms were significantly associated with female gender, self-report of past history of depression, and a slight decrease in functioning, but not with time since genetic testing. The factor analysis identified symptom domains similar to prior studies in other populations. These results show that individuals with the HD mutation are at increased risk to develop depressive symptoms at any time during the HD prodrome. The clinical presentation appears to be similar to other populations. Severity and progression are not related to the HD mutation.

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.

Symptom validity test performance in the Huntington Disease Clinic.

Symptom validity tests (SVTs) are often used in neuropsychological assessment; however, recent studies indicate that cognitive impairment/dementia may contribute to failing scores on some effort tests. The purpose of this study was to characterize how individuals with Huntington disease (HD) perform on three SVTs and to examine the relationship between SVT performance and demographic and clinical variables. Results indicate that while the majority of HD patients passed the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Effort Index (EI; 82% of n = 121) and the Test of Memory Malingering (92% of n = 36), failure of these SVTs was associated with poorer cognitive and adaptive functioning, and greater motor impairment. Results showed that less than one-third passed the RBANS Effort Scale (ES; 30% of n = 43) and few clinical and demographic variables were correlated with this SVT performance. Although some SVTs may be better suited to HD, cognitive ability should be considered when evaluating effort in HD.

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.

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.

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.

Substance abuse may be a risk factor for earlier onset of Huntington disease.

Environmental factors may contribute as much as one-third of the variance in Huntington disease (HD) age of onset. Substance abuse is a risk factor for other neurodegenerative disorders; however, whether substance abuse influences HD age of onset is not well established. This study investigated the relationships between alcohol, drug, and tobacco abuse and HD age of onset in 136 participants with symptomatic HD. CAG repeat length was used as a covariate in all analyses, as it represents the most significant determinant of HD age of onset. The relationship between substance abuse, HD age of onset, and sex was also examined, as women may experience greater medical harm from substance abuse. Lifetime alcohol abuse and lifetime drug abuse were associated with earlier age of HD onset; a similar trend was seen for current tobacco abuse. For women, lifetime alcohol abuse was associated with earlier onset of HD, with a similar trend for lifetime drug abuse. However, alcohol, drug, and tobacco abuse were not significantly associated with age of onset in men. Further work is needed to determine whether substance abuse is a causative risk factor for earlier onset of HD, and why the environmental factors associated with age of onset vary by sex.

Perceived stress in prodromal Huntington disease.

This study examines perceived stress and its relationship to depressive symptoms, life changes and functional capacity in a large sample of individuals who are positive for the Huntington disease (HD) gene expansion but not yet diagnosed. Participants were classified by estimated proximity to HD diagnosis (far, mid, near) and compared with a non-gene-expanded comparison group. Persons in the mid group had the highest stress scores. A significant interaction between age and time since HD genetic testing was also found. Secondary analyses using data from a different data collection point and including a diagnosed group showed the highest stress scores in the diagnosed group. Possible explanations and implications are discussed.

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.

Estimating premorbid IQ in the prodromal phase of a neurodegenerative disease.

Estimates of premorbid intellect are often used in neuropsychological assessment to make inferences about cognitive decline. To optimize the method of controlling for premorbid intellect in assessments of prodromal neurodegenerative disease, we examined performance on the American National Adult Reading Test (ANART; administered during Years 1 and 3) and the two-subtest version of the Wechsler Abbreviated Scale of Intelligence (WASI; administered in Years 2 and 4) in an ongoing prospective longitudinal study of 371 participants with prodromal Huntington disease and 51 participants with normal CAG repeats. Although both measures performed similarly, the ANART demonstrated slightly lower variability in performance over a 2-year period and had slightly higher test-retest reliability than the WASI.

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.

The Trail Making Test in prodromal Huntington disease: contributions of disease progression to test performance.

We examined the Trail Making Test (TMT) in a sample of 767 participants with prodromal Huntington disease (prodromal HD) and 217 healthy comparisons to determine the contributions of motor, psychiatric, and cognitive changes to TMT scores. Eight traditional and derived TMT scores were also evaluated for their ability to differentiate prodromal participants closer to estimated age of diagnosis from those farther away and prodromal individuals from healthy comparisons. Results indicate that motor signs only mildly affected Part A, and psychiatric symptoms did not affect either part. Tests of perceptual processing, visual scanning, and attention were primarily associated with Part A, and executive functioning (response inhibition, set-shifting), processing speed, and working memory were associated with Part B. Additionally, TMT scores differentiated between healthy comparisons and prodromal HD individuals as far as 9-15 years before estimated diagnosis. In participants manifesting prodromal motor signs and psychiatric symptoms, the TMT primarily measures cognition and is able to discriminate between groups based on health status and estimated time to diagnosis.

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.

Estimating premorbid functioning in huntington's disease: the relationship between disease progression and the wide range achievement test reading subtest.

The estimation of premorbid abilities is an essential part of a neuropsychological evaluation, especially in neurodegenerative conditions. Although word pronunciation tests are one standard method for estimating the premorbid level, research suggests that these tests may not be valid in neurodegenerative diseases. Therefore, the current study sought to examine two estimates of premorbid intellect, the Wide Range Achievement Test (WRAT) Reading subtest and the Barona formula, in 93 patients with mild to moderate Huntington's disease (HD) to determine their utility and to investigate how these measures relate to signs and symptoms of disease progression. In 89% of participants, WRAT estimates were below the Barona estimates. WRAT estimates were related to worsening memory and motor functioning, whereas the Barona estimates had weaker relationships. Neither estimate was related to depression or functional capacity. Irregular word reading tests appear to decline with HD progression, whereas estimation methods based on demographic factors may be more robust but overestimate premorbid functioning.

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.

Neurocognitive signs in prodromal Huntington disease.

OBJECTIVE: PREDICT-HD is a large-scale international study of people with the Huntington disease (HD) CAG-repeat expansion who are not yet diagnosed with HD. The objective of this study was to determine the stage in the HD prodrome at which cognitive differences from CAG-normal controls can be reliably detected. METHOD: For each of 738 HD CAG-expanded participants, we computed estimated years to clinical diagnosis and probability of diagnosis in 5 years based on age and CAG-repeat expansion number (Langbehn, Brinkman, Falush, Paulsen, & Hayden, 2004). We then stratified the sample into groups: NEAR, estimated to be ≤9 years; MID, between 9 and 15 years; and FAR, ≥15 years. The control sample included 168 CAG-normal participants. Nineteen cognitive tasks were used to assess attention, working memory, psychomotor functions, episodic memory, language, recognition of facial emotion, sensory-perceptual functions, and executive functions. RESULTS: Compared with the controls, the NEAR group showed significantly poorer performance on nearly all of the cognitive tests and the MID group on about half of the cognitive tests (p = .05, Cohen's d NEAR as large as -1.17, MID as large as -0.61). One test even revealed significantly poorer performance in the FAR group (Cohen's d = -0.26). Individual tasks accounted for 0.2% to 9.7% of the variance in estimated proximity to diagnosis. Overall, the cognitive battery accounted for 34% of the variance; in comparison, the Unified Huntington's Disease Rating Scale motor score accounted for 11.7%. CONCLUSIONS: Neurocognitive tests are robust clinical indicators of the disease process prior to reaching criteria for motor diagnosis of HD.