Kevin Duff

Detection of Huntington’s disease decades before diagnosis: the Predict-HD study

Objective: The objective of the Predict-HD study is to use genetic, neurobiological and refined clinical markers to understand the early progression of Huntington’s disease (HD), prior to the point of traditional diagnosis, in persons with a known gene mutation. Here we estimate the approximate onset and initial course of various measurable aspects of HD relative to the time of eventual diagnosis. Methods: We studied 438 participants who were positive for the HD gene mutation, but did not yet meet the diagnostic criteria for HD and had no functional decline. Predictability of baseline cognitive, motor, psychiatric and imaging measures was modelled non-linearly using estimated time until diagnosis (based on CAG repeat length and current age) as the predictor. Results: Estimated time to diagnosis was related to most clinical and neuroimaging markers. The patterns of association suggested the commencement of detectable changes one to two decades prior to the predicted time of clinical diagnosis. The patterns were highly robust and consistent, despite the varied types of markers and diverse measurement methodologies. Conclusions: These findings from the Predict-HD study suggest the approximate time scale of measurable disease development, and suggest candidate disease markers for use in preventive HD trials.

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, Cohens d NEAR as large as -1.17, MID as large as -0.61). One test even revealed significantly poorer performance in the FAR group (Cohens 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 Huntingtons 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.

Utility of the RBANS in detecting cognitive impairment associated with Alzheimer's disease : Sensitivity, specificity, and positive and negative predictive powers

Although initially developed as a brief dementia battery, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) has not yet demonstrated its sensitivity, specificity, and positive and negative predictive powers in detecting cognitive impairment in patients with Alzheimers disease (AD). Therefore, the current study examined the clinical utility of the RBANS by comparing two age-, education-, and gender-matched groups: patients with AD (n=69) and comparators (n=69). Significant differences (p<0.001) were observed on the RBANS Total score, all 5 Indexes, and all 12 subtests, with patients performing worse than the comparison participants. An optimal balance between sensitivity and specificity on RBANS scores was obtained when cutoffs of one and one and a half standard deviations below the mean of the comparison sample were implemented. Areas under the Receiver Operating Characteristic curves for all RBANS Indexes were impressive though Immediate and Delayed Memory Indexes were excellent (0.96 and 0.98, respectively). Results suggest that RBANS scores yield excellent estimates of diagnostic accuracy and that the RBANS is a useful screening tool in detection of cognitive deficits associated with AD.

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 Huntingtons 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 R2 0.14, P < 0.0001) and smaller striatal volumes (partial R2 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.

Evidence-based indicators of neuropsychological change in the individual patient: relevant concepts and methods.

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.

Age- and Education-Corrected Independent Normative Data for the RBANS in a Community Dwelling Elderly Sample

The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS, Randolph, 1998) is likely to become a popular screening instrument for measuring cognitive functioning, particularly in elderly patients. As such, the present study attempted to extend the original normative data by reporting on RBANS performances in a group of 718 community dwelling older adults. Participants were recruited from an outpatient primary care setting, and were assessed for demographic, medical status, functional status, and quality of life information. Utilizing four empirically supported overlapping midpoint age ranges, individual subtest raw scores were converted to age-corrected scaled scores based on their position within a cumulative frequency distribution. These age-corrected scaled scores were also converted into education-corrected scaled scores using the same methodology across four education levels. Independent Index and Total scores were also calculated based on the data from this large elderly sample. These data may considerably advance the clinical utility of the RBANS by allowing clinicians to interpret individual subtests and make direct comparisons between subtests. Practitioners and researchers who elect to use the current normative data are encouraged to consider the similarities and differences between the present sample and their individual patients or research participants.

White matter volume and cognitive dysfunction in early Huntington's disease

Background:Structural abnormalities of the striatum and cognitive impairments have consistently been shown in patients with Huntingtons disease (HD). Fewer studies have examined other cerebral structures in early HD and potential associations with cognition. Method:Ten patients with early HD and 10 matched control subjects underwent magnetic resonance imaging to provide quantitative measures (volumes) of cortical gray and white matter and the caudate, putamen, and thalamus. Patients completed the Unified Huntingtons Disease Rating Scale, including three cognitive tasks. Results:Although striatal volumes were clearly reduced, white matter was also morphologically abnormal. Cortical gray matter volume was not significantly correlated with cognitive performance. However, the cognitive tasks were most highly correlated with cerebral white matter and, to a lesser degree, striatal volume. Conclusions:Cerebral white matter volume may be an important variable to examine in future studies of HD.

Earliest functional declines in Huntington disease

We examined the gold standard for Huntington disease (HD) functional assessment, the Unified Huntingtons 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.

Estimation of WAIS-III Intelligence from Combined Performance and Demographic Variables: Development of the OPIE-3

Data from the WAIS-III standardization sample (The Psychological Corporation, 1997) was used to generate several FSIQ estimation formulas that used demographic variables and current WAIS-III subtest performance. The standardization sample (N =2,450) was randomly divided into two groups, the first was used to develop the formulas and the second group was used to validate the prediction equations. Age, education, ethnicity, gender, region of the country as well as Vocabulary, Information, Matrix Reasoning, and Picture Completion subtests raw scores were used as predictor variables. Regression formulas were generated using four subtest, two subtest, single verbal, two performance subtest, and single performance algorithms. The four-subtest model combined Information, Vocabulary, Matrix Reasoning, and Picture Completion raw scores with demographic variables. The two-subtest algorithm used Vocabulary and Matrix Reasoning raw scores with demographic variables. Formulas to estimate FSIQ using only verbal or performance subtests were developed for use with lateralized populations. The formulas for estimating premorbid FSIQ were highly significant and accurate in predicting FSIQ scores of participants in the WAISIII normative sample.

Test-Retest Stability and Practice Effects of the RBANS in a Community Dwelling Elderly Sample

Repeated neuropsychological assessments are common with older adults, and the determination of true neurocognitive change is important for diagnostic assessment. Several statistical formulas are available to assist in this determination, but they rely on access to test-retest stability coefficients and practice effect values. The current study presents data on these psychometric properties of the RBANS in a large community dwelling elderly sample. Across a one-year retest interval, stability coefficients ranged from .58 to .83 for the Index scores, and from .51 to .83 for the subtest scores. Practice effects were largely absent, with most performances slightly decreasing at retest. These psychometric properties are contrasted with those reported in the RBANS manual, and possible reasons for these differences are discussed. A case example is provided that demonstrates the use of the current findings in conjunction with existing change formulas.