Holly James Westervelt

Issues associated with repeated neuropsychological assessments

Distinguishing practice effects from other factors in repeated neuropsychological assessments are discussed in the context of research studies and clinical/forensic assessments. Potential methodological procedures for reducing the impact of practice effects in research settings are outlined. In contrast, the potential clinical utility and interpretation of practice effects in clinical assessments and forensic evaluations are highlighted.

Prediction of manifest Huntington's disease with clinical and imaging measures: a prospective observational study

BACKGROUND Although the association between cytosine-adenine-guanine (CAG) repeat length and age at onset of Huntingtons disease is well known, improved prediction of onset would be advantageous for clinical trial design and prognostic counselling. We compared various measures for tracking progression and predicting conversion to manifest Huntingtons disease. METHODS In this prospective observational study, we assessed the ability of 40 measures in five domains (motor, cognitive, psychiatric, functional, and imaging) to predict time to motor diagnosis of Huntingtons disease, accounting for CAG repeat length, age, and the interaction of CAG repeat length and age. Eligible participants were individuals from the PREDICT-HD study (from 33 centres in six countries [USA, Canada, Germany, Australia, Spain, UK]) with the gene mutation for Huntingtons disease but without a motor diagnosis (a rating below 4 on the diagnostic confidence level from the 15-item motor assessment of the Unified Huntingtons Disease Rating Scale). Participants were followed up between September, 2002, and July, 2014. We used joint modelling of longitudinal and survival data to examine the extent to which baseline and change of measures analysed separately was predictive of CAG-adjusted age at motor diagnosis. FINDINGS 1078 individuals with a CAG expansion were included in this analysis. Participants were followed up for a mean of 5·1 years (SD 3·3, range 0·0-12·0). 225 (21%) of these participants received a motor diagnosis of Huntingtons disease during the study. 37 of 40 cross-sectional and longitudinal clinical and imaging measures were significant predictors of motor diagnosis beyond CAG repeat length and age. The strongest predictors were in the motor, imaging, and cognitive domains: an increase of one SD in total motor score (motor domain) increased the risk of a motor diagnosis by 3·07 times (95% CI 2·26-4·16), a reduction of one SD in putamen volume (imaging domain) increased risk by 3·32 times (2·37-4·65), and a reduction of one SD in Stroop word score (cognitive domain) increased risk by 2·32 times (1·88-2·87). INTERPRETATION Prediction of diagnosis of Huntingtons disease can be improved beyond that obtained by CAG repeat length and age alone. Such knowledge about potential predictors of manifest Huntingtons disease should inform discussions about guidelines for diagnosis, prognosis, and counselling, and might be useful in guiding the selection of participants and outcome measures for clinical trials. FUNDING US National Institutes of Health, US National Institute of Neurological Disorders and Stroke, and CHDI Foundation.

Burden among spousal and child caregivers of patients with mild cognitive impairment.

Background/Aims: Patients with mild cognitive impairment (MCI) experience cognitive declines and often report significant emotional/behavioral changes. Despite this, few studies have examined the impact of MCI on caregiver burden. The purpose of this study was to confirm the presence of caregiver burden in MCI and examine the relationship between burden and patients’ neuropsychological, behavioral and emotional functioning. Methods: The current study included 51 individuals who had been diagnosed as having MCI using Petersen’s criteria. The patients underwent a thorough neuropsychological evaluation and completed the Beck Depression Inventory and Cognitive Difficulties Scale. The caregivers completed the Zarit Burden Interview and the Revised Memory and Behavior Checklist. Results: More than 30% of the caregivers reported clinically significant burden. Increased caregiver burden was associated with a longer course of cognitive symptoms, patient reports of worse depression and greater cognitive difficulties, and informant reports of patients having more behavior, mood and memory problems. Caregiver burden was not significantly associated with patients’ neuropsychological test performance. Conclusion: The results highlight the importance of addressing patients’ behavioral and emotional difficulties, as well as caregiver burden, as part of the clinical exam in MCI.

Odor identification deficits in diffuse lewy body disease

ObjectivesTo describe odor identification performance in patients with diffuse Lewy body disease and determine the clinical utility of odor identification tests in distinguishing diffuse Lewy body disease from Alzheimer disease. BackgroundThe presence of olfactory deficits, especially odor identification deficits, has been well established in both Alzheimer disease and Parkinson disease. The presence of olfactory deficits in diffuse Lewy body disease is also likely given the overlap of clinical symptoms and neuropathology with Alzheimer disease and Parkinson disease. However, odor identification abilities have not been described previously in diffuse Lewy body disease. MethodsNine patients from a clinic sample with diffuse Lewy body disease and nine carefully matched patients with Alzheimer disease were administered an odor identification task as part of their neuropsychologic evaluations. ResultsPatients with diffuse Lewy body disease performed significantly worse than patients with Alzheimer disease on the odor identification test. ConclusionsOdor identification deficits may be more prevalent and severe in people with diffuse Lewy body disease than in people with Alzheimer disease, and olfactory testing may be useful in antemortem differential diagnosis of the two disorders.

Odor identification in mild cognitive impairment subtypes.

The current study examined odor identification using the Brief Smell Identification Test (BSIT) in mild cognitive impairment (MCI) subtypes (17 “amnestic MCI”, 46 “amnestic-plus MCI”, and 25 “MCI other”). Performance in participants with MCI was compared to that of participants with Alzheimers disease (AD, n = 44) and healthy elderly (n = 21). MCI participants performed worse than controls, but better than those with AD. MCI subtypes did not differ. The magnitude of difference between MCI participants and controls was modest, raising some question of the clinical utility of the BSIT in early detection of MCI and early differential diagnosis.

Cognitive reserve and brain reserve in prodromal Huntington's disease

Huntington disease (HD) is associated with decline in cognition and progressive morphological changes in brain structures. Cognitive reserve may represent a mechanism by which disease-related decline may be delayed or slowed. The current study examined the relationship between cognitive reserve and longitudinal change in cognitive functioning and brain volumes among prodromal (gene expansion-positive) HD individuals. Participants were genetically confirmed individuals with prodromal HD enrolled in the PREDICT-HD study. Cognitive reserve was computed as the composite of performance on a lexical task estimating premorbid intellectual level, occupational status, and years of education. Linear mixed effects regression (LMER) was used to examine longitudinal changes on four cognitive measures and three brain volumes over approximately 6 years. Higher cognitive reserve was significantly associated with a slower rate of change on one cognitive measure (Trail Making Test, Part B) and slower rate of volume loss in two brain structures (caudate, putamen) for those estimated to be closest to motor disease onset. This relationship was not observed among those estimated to be further from motor disease onset. Our findings demonstrate a relationship between cognitive reserve and both a measure of executive functioning and integrity of certain brain structures in prodromal HD individuals.

Comparison of verbal memory impairment rates in mild cognitive impairment.

There are no accepted guidelines establishing the most sensitive neuropsychological methods to define memory impairment in mild cognitive impairment (MCI). We investigated whether similar impairment rates were observed between the Hopkins Verbal Learning Test–Revised (HVLT–R) and Logical Memory (LM) in 90 patients with amnestic or amnestic plus MCI. On HVLT–R delayed recall, 80% of participants performed in the MCI range compared to only 32.2% on LM II. The same pattern was seen for both amnestic and amnestic plus subtypes. Individuals impaired on HVLT–R delayed recall performed significantly worse on LM first recall and on delayed recall of LM Story A than those not impaired. MCI patients with executive dysfunction performed significantly worse than patients with no executive impairment on both LM I and HVLT–R Total Learning, but not for delayed recall of either measure. Future studies can address the longitudinal course of impairment on these measures.

Depressive symptom severity is related to poorer cognitive performance in prodromal Huntington disease

OBJECTIVE Depression is associated with more severe cognitive deficits in many neurological disorders, though the investigation of this relationship in Huntington disease (HD) has been limited. This study examined the relationship between depressive symptom severity and measures of executive functioning, learning/memory, and attention in prodromal HD. METHOD Participants (814 prodromal HD, 230 gene-negative) completed a neuropsychological test battery and the Beck Depression Inventory-II (BDI-II). Based on the BDI-II, there were 637 participants with minimal depression, 89 with mild depression, 61 with moderate depression, and 27 with severe depression in the prodromal HD group. RESULTS ANCOVA (controlling for age, sex, and education) revealed that performance on SDMT, Trails B, Hopkins Verbal Learning Test--Revised (HVLT-R) Immediate Recall, and Stroop interference was significantly different between the BDI-II severity groups, with the moderate and severe groups performing worse than the minimal and mild groups. There were no significant differences between the BDI-II severity groups for Trails A or HVLT-R Delayed Recall. Linear regression revealed that both gene status and depression severity were significant predictors of performance on all cognitive tests examined, with contributions of BDI-II and gene status comparable for Trails A, SDMT, and Stroop interference. Gene status had a higher contribution for HVLT-R Immediate and Delayed Recall and Trails B. CONCLUSIONS Our results suggest that depressive symptom severity is related to poorer cognitive performance in individuals with prodromal HD. Though there are currently no approved therapies for cognitive impairment in HD, our findings suggest that depression may be a treatable contributor to cognitive impairment in this population.

Patient and Family Perceptions of the Neuropsychological Evaluation: How Are We Doing?

To assess perceptions of the neuropsychological evaluation, 349 patients and 218 significant others presenting to an academic medical center neuropsychology service were surveyed over a two year period. Thirty-seven percent of the patient surveys (n = 129) and 37% of the significant other surveys (n = 80) were returned. Overall, both patients and significant others reported being satisfied with the interview, testing, and feedback sessions. Responders were generally receptive to the recommendations made, but were more inclined to have followed recommendations regarding patient safety (63.6%) than coping or support (31.8%). Some barriers to compliance with recommendations were identified.

Measuring executive dysfunction longitudinally and in relation to genetic burden, brain volumetrics, and depression in prodromal huntington disease

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.