Leigh J. Beglinger

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.

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.

Mild cognitive impairment in prediagnosed Huntington disease

Background: Cognitive decline has been reported in Huntington disease (HD), as well as in the period before diagnosis of motor symptoms (i.e., pre-HD). However, the severity, frequency, and characterization of cognitive difficulties have not been well-described. Applying similar cutoffs to those used in mild cognitive impairment (MCI) research, the current study examined the rates of subtle cognitive dysfunction (e.g., dysfunction that does not meet criteria for dementia) in pre-HD. Methods: Using baseline data from 160 non–gene-expanded comparison participants, normative data were established for cognitive tests of episodic memory, processing speed, executive functioning, and visuospatial perception. Cutoff scores at 1.5 standard deviations below the mean of the comparison group were then applied to 575 gene-expanded pre-HD participants from the observational study, PREDICT-HD, who were stratified by motor signs and genetic risk for HD. Results: Nearly 40% of pre-HD individuals met criteria for MCI, and individuals closer to HD diagnosis had higher rates of MCI. Nonamnestic MCI was more common than amnestic MCI. Single-domain MCI was more common than multiple-domain MCI. Within the nonamnestic single-domain subtype, impairments in processing speed were most frequent. Conclusions: Consistent with the Alzheimer disease literature, MCI as a prodromal period is a valid concept in pre-HD, with nearly 40% of individuals showing this level of impairment before diagnosis. Future studies should examine the utility of MCI as a marker of cognitive decline in pre-HD.

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

Huntingtons 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 Huntingtons 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 Huntingtons 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 Huntingtons disease.

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.

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.

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.

Cognitive domains that predict time to diagnosis in prodromal Huntington disease

Background Prodromal Huntingtons disease (prHD) is associated with a myriad of cognitive changes but the domains that best predict time to clinical diagnosis have not been studied. This is a notable gap because some domains may be more sensitive to cognitive decline, which would inform clinical trials. Objectives The present study sought to characterise cognitive domains underlying a large test battery and for the first time, evaluate their ability to predict time to diagnosis. Methods Participants included gene negative and gene positive prHD participants who were enrolled in the PREDICT-HD study. The CAG–age product (CAP) score was the measure of an individuals genetic signature. A factor analysis of 18 tests was performed to identify sets of measures or latent factors that elucidated core constructs of tests. Factor scores were then fit to a survival model to evaluate their ability to predict time to diagnosis. Results Six factors were identified: (1) speed/inhibition, (2) verbal working memory, (3) motor planning/speed, (4) attention–information integration, (5) sensory–perceptual processing and (6) verbal learning/memory. Factor scores were sensitive to worsening of cognitive functioning in prHD, typically more so than performances on individual tests comprising the factors. Only the motor planning/speed and sensory–perceptual processing factors predicted time to diagnosis, after controlling for CAP scores and motor symptoms. Conclusions The results suggest that motor planning/speed and sensory–perceptual processing are important markers of disease prognosis. The findings also have implications for using composite indices of cognition in preventive Huntingtons disease trials where they may be more sensitive than individual tests.