Progressive supranuclear palsy (PSP) is a rare neurodegenerative disorder in which, classically, patients present with postural instability and falls, parkinsonism, and slowing of vertical saccades. PSP patients typically have deficits in cognitive functioning, difficulties with most daily activities, and present with notable behavioral disturbances—particularly apathy, impulsivity, and irritability. Using data from 154 patients meeting criteria for clinically probable PSP, domain and total scores of the Neuropsychiatric Inventory were examined and compared to demographics, disease severity, cognition, and motor features. Behavioral abnormalities were common in this cohort of PSP patients, with more than half experiencing apathy, depression, and sleeping problems, and approximately one third displaying agitation, irritability, disinhibition, and eating problems. Few clinical correlates of neuropsychiatric symptoms were observed in this cohort. Given the prevalence of neuropsychiatric symptoms in PSP, these patients are expected to be frequently seen by psychiatrists and other mental health professionals for symptom management and increased quality of life. Clinical trials are clearly needed to address the neuropsychiatric morbidity in these patients.
Parkinsonism; Parkinsonian; Neuropsychiatric inventory; Neuropsychiatric functioning; Apathy; depression
Although amyloid deposition remains a marker of the development of Alzheimer's disease, results linking amyloid and cognition have been equivocal. Twenty-five community-dwelling non-demented older adults were examined with 18F-flutemetamol, an amyloid imaging agent, and a cognitive battery, including an estimate of premorbid intellect and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). In the first model, 18F-flutemetamol uptake significantly correlated with the Delayed Memory Index of the RBANS (r = −.51, p = .02) and premorbid intellect (r = .43, p = .03). In the second model, the relationship between 18F-flutemetamol and cognition was notably stronger when controlling for premorbid intellect (e.g., three of the five RBANS Indexes and its Total score significantly correlated with 18F-flutemetamol, r's = −.41 to −.58). Associations were found between amyloid-binding 18F-flutemetamol and cognitive functioning in non-demented older adults. These associations were greatest with delayed memory and stronger when premorbid intellect was considered, suggesting that cognitive reserve partly compensates for the symptomatic expression of amyloid pathology in community-dwelling elderly.
Amyloid; Neuroimaging; Neuropsychology; Alzheimer's disease; Premorbid intellect
Despite the growing use of the modified Telephone Interview for Cognitive Status (mTICS) as a cognitive screening instrument, it does not yet have demographic corrections. Demographic data, mTICS, and a neuropsychological battery were collected from 274 community dwelling older adults with intact cognition or mild cognitive impairments. Age, education, premorbid intellect, and depression were correlated with mTICS scores. Using regression equations, age and education significantly predicted mTICS total score, and depression and premorbid intellect further enhanced this prediction. These results were comparable when only examining the 153 cognitively intact subjects. By using these corrections, clinicians and researchers can more accurately predict an individual’s cognitive status with this telephone screening measure.
Cognitive difficulties appear to be a more prevalent clinical feature in progressive supranuclear palsy (PSP) than previously thought, and significant cognitive impairment is prevalent in a majority of patients PSP patients not considered clinically demented. The neurocognitive performance of 200 patients with PSP across multiple sites was examined with a variety of commonly used neuropsychological tests. Results indicate primary executive dysfunction (e.g., 74% impaired on the Frontal Assessment Battery, 55% impaired on Initiation/Perseveration subscale of the Dementia Rating Scale), with milder difficulties in memory, construction, and naming. These results have important clinical implications for providers following patients with PSP.
Progressive supranuclear palsy; Frontal-executive; Parkinsonism; Dementia; Memory
Executive dysfunction (ED) is a characteristic of Huntington disease (HD), but its severity and progression is less understood in the prodromal phase, e.g., before gross motor abnormalities. We examined planning and problem-solving abilities using the Towers Task in HD mutation-positive individuals without motor symptoms (n = 781) and controls (n = 212). Participants with greater disease progression (determined using mutation size and current age) performed more slowly and with less accuracy on the Towers Task. Performance accuracy was negatively related to striatal volume while both accuracy and working memory were negatively related to frontal white matter volume. Disease progression at baseline was not associated with longitudinal performance over 4 years. Whereas the baseline findings indicate that ED becomes more prevalent with greater disease progression in prodromal HD and can be quantified using the Towers task, the absence of notable longitudinal findings indicates that the Towers Task exhibits limited sensitivity to cognitive decline in this population.
Huntington's disease; Genetic disorders; Executive functions; Neuroimaging (structural); Norms/normative studies; Practice effects/reliable change; longitudinal change
The current study sought to describe the functional profiles of patients with early-stage progressive supranuclear palsy (PSP) in a large prospective, multisite study.
Using data from 202 individuals meeting criteria for clinically definite or probable PSP, 3 functional scales were examined. Functional scores were then compared to measures of motor, cognition, and psychiatric symptoms.
Functional disability was high in early-stage PSP, with 100% of patients having less than perfect scores on all functional scales. Whereas functional scores tended not to be related to cognition or psychiatric symptoms, they were strongly related to motoric ratings.
Both clinically and in research settings, the definition of functional intactness/impairment has important implications. Future studies should examine if functional impairment is this high in PSP or if new scales of functional abilities need to be developed for this condition.
Huntington disease (HD) is a neurodegenerative disease associated with cognitive, motor, and psychiatric deterioration over time. Although there is currently no cure for HD, there has been a surge of clinical trials available to patients with HD over the past 5 years. However, cognitive measures have generally been lacking from these trials. A brief, repeatable neuropsychological battery is needed to assess cognitive endpoints. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) may be useful for assessing change in interventional studies or for clinical monitoring. A total of 38 patients with HD were assessed using the RBANS, other cognitive tests, and the standardized HD battery (Unified Huntington's Disease Rating Scale, UHDRS) at two clinic visits approximately 16 months apart. The RBANS Attention Index, as well as individual subtest scores on Coding, Digit Span, List Recognition, Figure Copy, and Figure Recall all declined significantly over this interval. Performance on the UHDRS cognitive tests (Symbol Digit Modalities; Stroop Color, and Stroop Word) also declined, as did functional capacity. Results suggest that cognitive changes were detected both on established cognitive tasks used in HD research and on the RBANS in patients with measurable functional decline. The RBANS provided additional information about other cognitive domains affected (e.g., memory) and may be a useful measure for tracking longitudinal change.
Huntington Disease; Neuropsychological assessment; Memory; Dementia; Executive functions
Huntington’s disease (HD) is a progressive, neuropsychiatric disorder, and limited reports indicate that risperidone might improve motor and psychiatric functioning for these patients.
In an open label, retrospective study to evaluate the effectiveness of risperidone on motor, psychiatric, and cognitive functioning in HD, 17 patients taking risperidone and 12 patients not taking any antipsychotic medication were compared across a year.
Patients taking risperidone demonstrated significantly improved psychiatric functioning and motor stabilization, whereas patients not taking risperidone were stable psychiatrically and worsened motorically.
Although controlled clinical trials are clearly needed, these preliminary results support the use of risperidone in patients with HD in treating their psychiatric and possibly motor symptoms.
Huntington’s disease; Risperidone; Treatment; Psychiatric symptoms; Motor; Cognition
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.
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.
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.
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.
Huntington disease; randomized controlled trial; neuropsychological assessment; clinical trials
Practice effects have been widely reported in healthy older adults, but these improvements due to repeat exposure to test materials have been more equivocal in individuals with mild cognitive impairment (MCI).
The current study examined short-term practice effects in MCI by repeating a brief battery of cognitive tests across one week in 59 older adults with amnestic MCI and 62 intact older adults.
Participants with amnestic MCI showed significantly greater improvements on two delayed recall measures (p < 0.01) compared to intact peers. All other practice effects were comparable between these two groups. Practice effects significantly improved scores in the MCI group so that 49% of them were reclassified as “intact” after one week, whereas the other 51% remained “stable” as MCI. Secondary analyses indicated the MCI-Intact group demonstrated larger practice effects on two memory measures than their peers (p < 0.01).
These results continue to inform us about the nature of memory deficits in MCI, and could have implications for the diagnosis and possible treatment of this amnestic condition.
mild cognitive impairment; practice effects; repeat testing
In primary care 50–95% of patients with depression present with vegetative symptoms (VS). Based on the extant literature, older adults showing VS (but no dysphoria) may show functional impairment but this hypothesis has not been empirically tested. The goal of this study was to examine neurocognitive and daily functioning of elderly patients showing exclusively VS in comparison with patients presenting with VS and dysphoria.
Seven hundred and eighty-seven primary care patients received measures of neurocognition and daily functioning. Neurocognition was measured with the repeatable battery for the assessment of neuropsychological status (RBANS). Three groups were compared: (1) patients with two or more VS of depression without dysphoria (VS − D), (2) patients with at least one VS and dysphoria (VS + D), and (3) comparison patients without multiple VS or dysphoria.
Nearly one third of the sample (31%) fell into the VS − D group, whereas 15% fell into the VS + D group. Both VS groups showed poorer neurocognition and activities of daily living than comparisons. Only one subtest of the RBANS (i.e., picture naming) showed a significant difference between VS + D and VS − D, and there was no significant difference on daily functioning. VS − D patients reported less frequent past history of depression and endorsed less anxiety compared to VS + D.
Elderly patients presenting with clusters of VS with or without dysphoria show poorer neurocognitive and functional performance. Relative poorer cognition and daily functioning in VS − D are potential harbingers of further decline and consistent with under-reporting of sadness in older age.
vegetative symptoms; primary care; late-life depression; nondysphoric depression; neurocognition; right hemisphere functions; subthreshold depression
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.
Psychiatric; Antidepressant; Neuroprotection; Clinical trials; SSRI
Practice effects are improvements in cognitive test performance associated with repeated administrations of same or similar measures and are traditionally seen as error variance. However, there is growing evidence that practice effects provide clinically useful information.
Within session practice effects (WISPE) across 2 hours were collected on sixty-one non-consecutive patients referred for suspected dementia and compared to the Mini Mental Status Examination (MMSE), a screening measure of dementia severity.
In all patients, WISPE on two cognitive measures were significantly correlated with MMSE, even after controlling for baseline cognitive scores (partial r=0.47, p<0.001; partial r=0.26, p=0.046). In patients diagnosed with probable Alzheimer’s disease, the trend was even stronger (partial r=0.72, p<0.01; partial r=0.58, p=0.046). In both groups, lower WISPE were associated with lower MMSE scores (i.e., greater dementia severity), even after controlling for initial cognitive scores.
If future research validates these findings with longitudinal studies, then WISPE may have important clinical applications in dementia evaluations.
practice effects; dementia; cognition; assessment
Obsessive and compulsive symptoms (OCS) are more prevalent in patients with diagnosed Huntington’s disease (HD) than in the general population. Although psychiatric symptoms have been reported in individuals with the HD gene expansion prior to clinical diagnosis (pre-HD), little is known about OCS in this phase of disease.
The goal of this study was to assess OCS in 300 pre-HD individuals and 108 non–gene-expanded controls from the Neurobiological Predictors of Huntington’s Disease (PREDICTHD)study (enrolled between November 2002 and April 2007) using a multidimensional, self-report measure of OCS, the Schedule of Compulsions, Obsessions, and Pathologic Impulses (SCOPI). Additionally, pre-HD individuals were classified into 3 prognostic groups on the basis of age and CAG repeat length as “near-to-onset” (< 9 estimated years to onset), “mid-to-onset” (9–15 years to onset), and “far-to-onset” (> 15 years to onset). We compared the 3 pre-HD groups to the controls on SCOPI total score and 5 subscales (checking, cleanliness, compulsive rituals, hoarding, and pathologic impulses), controlling for age and gender.
All models showed a significant (p < .05) group effect except for hoarding, with an inverted-U pattern of increasing symptoms: controls < far-to-onset < mid-to-onset, with the near-to-onset group being similar to controls. Although the mid-to-onset group showed the most pathology, mean scores were below those of patients with diagnosed obsessive-compulsive disorder. SCOPI items that separated pre-HD individuals from controls were focused on perceived cognitive errors and obsessive worrying.
Subclinical OCS were present in pre-HD participants compared to controls. The OCS phenotype in pre-HD may present with obsessive worrying and checking related to cognitive errors and may be a useful target for clinical screening as it could contribute to functional status.
Repeated assessments are a relatively common occurrence in clinical neuropsychology. The current paper will review some of the relevant concepts (e.g., reliability, practice effects, alternate forms) and methods (e.g., reliable change index, standardized based regression) that are used in repeated neuropsychological evaluations. The focus will be on the understanding and application of these concepts and methods in the evaluation of the individual patient through examples. Finally, some future directions for assessing change will be described.
Reliable change; Practice effects; Assessment
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.
Neuropsychological assessment; Depression; Daily functioning; Occupation; ADLs (activities of daily living)
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.
Huntington disease; perceived stress; depression
The Effort Index (EI) of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was developed to identify inadequate effort. Although researchers have examined its validity, the reliability of the EI has not been evaluated. The current study examined the temporal stability of the EI across 1 year in two independent samples of older adults. One sample consisted of 445 cognitively intact older adults (mean age = 72.89; 59% having 12–15 years of education) and the second sample consisted of 51 individuals diagnosed with amnestic Mild Cognitive Impairment (mean age = 82.41; 41% having 12–15 years of education). For both samples, the EI was found to have low stability (Spearman's ρ = .32–.36). When participants were divided into those whose EI stayed stable or improved versus those whose EI worsened (i.e., declining effort) on retesting, it was observed that individuals with lower baseline RBANS Total scores tended to worsen on the EI across time. Overall, the findings suggest low temporal stability of the EI in two geriatric samples. In particular, individuals with poorer cognition at baseline could present with poorer effort across time. These findings also suggest the need to further examine the temporal stability of other effort measures.
Malingering/symptom validity testing; Elderly/geriatrics/aging; Mild cognitive impairment
Formulae to estimate premorbid memory functioning in a sample of cognitively intact older adults have been developed. These formulae were validated in a small sample of patients with amnestic Mild Cognitive Impairment. However, further validation is clearly needed. The current study applied these formulae to a sample of 1,059 patients referred to a dementia clinic and compared the premorbid estimates of memory functioning with current memory abilities. Large and statistically significant differences were observed in the current sample, with premorbid memory scores exceeding current memory scores. Although some cautions should be observed when using these estimates clinically, growing support for these estimates of premorbid memory abilities may aid clinicians in determining change across time in older patients.
Predicting cognition; Learning and memory; Assessment
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.
Longitudinal, observational design following participants across one year.
Three groups of older adults: 1. cognitively intact (n=57), 2. aMCI with large practice effects across one week (MCI+PE, n=25), and 3. aMCI with minimal practice effects across one week (MCI−PE, n=26).
After controlling for age and baseline cognitive differences, the MCI−PE group performed significantly worse than the other groups after one year on measures of immediate memory, delayed memory, language, and overall cognition.
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.
Mild Cognitive Impairment; practice effects; dementia
This study evaluated brain volumes in healthy older subjects without dementia who presented with memory complaints. The objective was to examine cortical volumes in relation to cognitive performance among patients who do not have dementia, but who do have mild cognitive deficits.
Fifteen participants were evaluated (mean age = 71.8 ± 6.2). Brain structure was measured via high-resolution magnetic resonance imaging to quantify gray and white matter volumes. Volumetric measures were assessed relative to cognitive function in separate regression models controlling for total cerebral volume. Reported here are measures of global cognitive performance using the Mattis Dementia Rating Scale (DRS) in relation to volumetric measures.
Baseline MMSE scores ranged from 27 to 30 (mean = 29.3; SD = 0.9). After controlling for total cerebral volume, we observed that lower white matter volume in the temporal lobe [F(1,14) = 5.72, p = 0.03] was associated with lower performance on the Mattis Dementia Rating Scale (DRS).
Structural imaging may help provide useful clinical information in the context of mild cognitive decline. Currently, the diagnosis of dementia relies on longitudinal measures of cognition. Future studies will help determine whether the addition of brain imaging may enhance diagnostic certainty as well as predict long-term outcome.
Cognition; Imaging; Aging; Memory
Although delirium is a common medical comorbidity with altered cognition as its defining feature, few publications have addressed the neuropsychological prodrome, profile, and recovery of patients tested during delirium. We characterize neuropsychological performance in 54 hemapoietic stem cell/bone marrow transplantation (BMT) patients shortly before, during, and after delirium and in BMT patients without delirium and 10 healthy adults. Patients were assessed prospectively before and after transplantation using a brief battery. BMT patients with delirium performed more poorly than comparisons and those without delirium on cross-sectional and trend analyses. Deficits were in expected areas of attention and memory, but also in psychomotor speed and learning. The patients with delirium did not return to normative “average” on any test during observation. Most tests showed a mild decline in the visit before delirium, a sharp decline with delirium onset, and variable performance in the following days. This study adds to the few investigations of neuropsychological performance surrounding delirium and provides targets for monitoring and early detection; Trails A and B, RBANS Coding, and List Recall may be useful for delirium assessment.
Bone marrow transplantation; Cognition; Cancer; Attention; Delirium
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.
Huntington's disease; movement disorders; basal ganglia; assessment; dementia
PREDICT-HD is a large-scale international study of people with the Huntington Disease CAG-repeat expansion who are not yet diagnosed with HD. The objective of this study was to determine at what stage in the HD prodrome cognitive differences from CAG-normal controls can be reliably detected.
For each of 738 HD CAG-expanded participants, we computed estimated years to clinical diagnosis and probability of diagnosis in five 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.
Compared to the controls, the NEAR group showed significantly poorer performance on nearly all, and the MID group on about half of the cognitive tests (p = 0.05, 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 UHDRS Motor Score accounted for 11.7%.
Neurocognitive tests are robust clinical indicators of the disease process prior to reaching criteria for motor diagnosis of HD.
cognitive assessment; presymptomatic; neuropsychology; psychomotor; prediagnosis