Joanne M. Hamilton

The myth of testing construct validity using factor analysis or correlations with normal or mixed clinical populations: Lessons from memory assessment

For nearly a century, the primary method employed by psychologists to define and test the validity of constructs evaluated by assessment instruments has been shared-variance techniques such as intervariable correlations or factor analysis with large normative or mixed clinical samples. To illustrate the shortcomings of this approach, we conducted (1) correlational analyses of immediate- and delayed-memory measures separately in normal participants and in homogeneous samples of patients with either Alzheimers disease or Huntingtons disease; and (2) factor analysis of immediate and delayed-recall and recognition measures in a large, homogeneous sample of patients with Alzheimers disease. The findings revealed that cognitive measures that share variance in the intact brain-thereby giving the facade of assessing a unitary construct-can dissociate and contribute to unique variance in the damaged brain, but only if the pathology occurs in brain regions known to disrupt vital cognitive processes tapped by those measures. The results illustrate that shared-variance procedures applied to normal or mixed clinical populations can mask some of the most vital cognitive constructs, such as the classic distinction between short- and long-term memory. Implications of these findings for research and clinical practice are discussed.

Behavioural abnormalities contribute to functional decline in Huntington’s disease

The independent and relative contributions of motor, cognitive, and behavioural deficits to functional decline in patients with Huntington’s disease are examined. Twenty two patients with Huntington’s disease were assessed with rating scales for motor dysfunction, cognitive measures of executive functions, and behavioural measures of apathy, executive dysfunction, and disinhibition. Their functional status was assessed with informant based and clinician based ratings of activities of daily living (ADL). A composite apathy/executive dysfunction behavioural index was strongly related to decline in ADL independently and after controlling for motor and cognitive deficits. These results suggest that behavioural dysfunction contributes to functional decline in patients with Huntington’s disease and may impede their ability to utilise motor or cognitive skills that remain available in the early stages of the disease.

In vivo evidence of cerebellar atrophy and cerebral white matter loss in Huntington disease

Objective: To investigate the regional pattern of white matter and cerebellar changes, as well as subcortical and cortical changes, in Huntington disease (HD) using morphometric analyses of structural MRI. Methods: Fifteen individuals with HD and 22 controls were studied; groups were similar in age and education. Primary analyses defined six subcortical regions, the gray and white matter of primary cortical lobes and cerebellum, and abnormal signal in the cerebral white matter. Results: As expected, basal ganglia and cerebral cortical gray matter volumes were significantly smaller in HD. The HD group also demonstrated significant cerebral white matter loss and an increase in the amount of abnormal signal in the white matter; occipital white matter appeared more affected than other cerebral white matter regions. Cortical gray and white matter measures were significantly related to caudate volume. Cerebellar gray and white matter volumes were both smaller in HD. Conclusions: The cerebellum and the integrity of cerebral white matter may play a more significant role in the symptomatology of HD than previously thought. Furthermore, changes in cortical gray and cerebral white matter were related to caudate atrophy, supporting a similar mechanism of degeneration.

A comparison of episodic memory deficits in neuropathologically-confirmed Dementia with Lewy bodies and Alzheimer's disease.

Little is known about possible differences in the memory deficits that occur in Dementia with Lewy bodies (DLB) and Alzheimers disease (AD). We compared 24 autopsy-confirmed DLB and 24 age-, education-, and MMSE-matched autopsy-confirmed AD patients on the California Verbal Learning Test (CVLT) and the Wechsler Memory Scale-Revised Logical Memory subtest. The DLB and AD groups were similarly impaired on CVLT Total Learning (Trials 15) and Long Delayed Free Recall, but the DLB group demonstrated relative improvement in Savings scores and on recognition testing compared to the AD group. Likewise, the patient groups were equally impaired on Logical Memory immediate and delayed recall, but the DLB groups Saving scores were significantly better than those of the AD patients. These results indicate that while both DLB and AD patients exhibit significant memory impairment, the ability to consolidate information may be less severely impaired in DLB patients than in AD patients.

Rate and correlates of weight change in Huntington’s disease

Objective: To determine the rate and correlates of weight change in a large, well characterised sample of patients with Huntington’s disease followed at 44 sites by the Huntington Study Group. Participants and methods: Weight change was assessed in 927 adults with a definite diagnosis of Huntington’s disease who were followed prospectively for (mean (SD)) 3.4 (1.4) years. The unified Huntington’s disease rating scale was used to assess weight, motor dysfunction (including chorea and dystonia), depressive symptoms, and functional decline. Results: Random effects modelling determined that patients gained an average of 0.11 (1.7) kg/year and their chorea scores increased by 0.36 (0.78) points/year. There were significant but weak relations between weight loss and increasingly severe chorea (r  =  −0.13), worse baseline motor performance (r  =  −0.12), less severe baseline depressed mood (r  =  0.14), and poorer baseline independence ratings (r  =  0.07). Patients who were within 0 to 2 years of symptom onset at the time of the baseline visit gained more weight than those with longer disease duration. Conclusions: Weight loss following symptom onset is not a consistent feature of Huntington’s disease. The mechanisms contributing to weight change in this condition are unclear and probably multifactorial. Future studies examining asymptomatic carriers of the mutation could be helpful in identifying incipience of low body weight and may be better suited for identifying clinical correlates of weight loss than studies in symptomatic patients.

Cognitive and Functional Decline in Huntington's Disease: Dementia Criteria Revisited

The importance of designating criteria for diagnosing dementia lies in its implications for clinical treatment, research, caregiving, and decision‐making. Dementia diagnosis in Huntingtons disease (HD) is often based on criteria developed for Alzheimers disease requiring memory loss. However, it is likely that other cognitive deficits contribute to functional impairment in HD before memory declines. The goal is to identify cognitive deficits that contribute to functional impairment to support dementia criteria that reflect HD neuropathology. Eighty‐four HD mutation‐positive subjects completed neuropsychological tests and the Unified Huntingtons Disease Rating Scale Functional Independence Scale (FIS). Functional impairment was defined as 80 or below on the FIS. Speed of processing, initiation, and attention measures accounted for 70.0% of the variance in FIS ratings (linear regression) and correctly classified 91.7% of subjects as functionally impaired or intact (logistic regression). Measures of memory, motor impairment except dysarthria, neuroleptic use, and depressed mood did not improve prediction. A definition of HD dementia that includes cognitive impairment in at least two areas of cognition but does not require a memory deficit, in the context of impaired functional abilities and a deteriorating course, more accurately reflects HD neuropathology and could lead to improved research methods and patient care.

Odor detection, learning, and memory in Huntington's disease.

We compared 7 mildly affected Huntingtons disease (HD) patients to 7 age- and education-matched healthy controls (NC) on an odor detection test, the California Odor Learning Test, and the California Verbal Learning Test. Results demonstrated that odor detection sensitivity, but not group membership, accounted for significant variance in total olfactory learning. Both groups learned fewer items in the olfactory modality compared to the verbal modality, but retained a similar amount following a delay. No group differences were demonstrated for verbal recognition discriminability, but the HD group demonstrated significantly impaired odor recognition discriminability. Finally, odor detection provided excellent classification sensitivity and specificity between the patients and controls, suggesting that olfactory testing may provide a sensitive measure of the early disease process in HD.

Neocortical disconnectivity disrupts sensory integration in Alzheimer's disease.

The cortical pathology in Alzheimers disease (AD) should lead to the loss of effective interaction between distinct neocortical areas. This study compared 2 conditions within a single sensory integration task that differed in the demands placed on effective cross-cortical interaction. AD patients were impaired in their ability to bind distinct visual features of a stimulus when this binding placed greater demands on cross-cortical interaction (i.e., motion and color) but were not impaired when this binding placed lesser demands on such interaction (i.e., motion and luminance). In contrast, neurologically intact individuals and patients with Huntingtons disease were able to effectively bind features under both conditions. These results provide psychophysical support for the presence of functional disconnectivity in AD and demonstrate the utility of AD for investigating the neurocognitive substrates of sensory integration.

Identifying the “source” of recognition memory deficits in patients with Huntington's disease or Alzheimer's disease: Evidence from the CVLT-II

The present study compared the performance of individuals with Huntingtons disease (HD) and Alzheimers disease (AD) on three types of California Verbal Learning Test–Second Edition (CVLT-II) recognition discriminability indices (RDI): Source, Novel, and Total. The HD and AD groups did not differ significantly on Source RDI (all 16 targets versus the 16 previously presented, List B, distractors). However, HD patients performed significantly better than AD patients on Total RDI (all 16 targets versus all 32 distractors) and Novel RDI (all 16 targets versus 16 new distractors). Implications of these findings on the differentiation of the memory disorders associated with HD and AD are discussed.

Ideomotor limb apraxia in Huntington's disease: implications for corticostriate involvement

Ideomotor limb apraxia, a disorder of goal-directed movement, has been attributed to lesions in the frontal and parietal lobes, but the role of subcortical structures is less certain. In order to determine its prevalence in a disorder affecting the basal ganglia and corticostriatal connections, we examined imitation of hand gestures in Huntingtons disease (HD) patients. We also assessed the relationship between apraxia and cognitive and motor dysfunction in an effort to better understand the neural underpinnings of apraxia in HD. If damage restricted to the basal ganglia produces ideomotor limb apraxia, then we would expect to find evidence of apraxia in patients who were early in the disease course when selective striatal damage is most common. Such a pattern, however, was not found in our sample. Instead, patients with greater neurological impairment and with a longer duration of disease were more likely than less affected patients to demonstrate apraxia. Apraxia was not related to severity of chorea, but was associated with greater impairment in eye movements, voluntary movements, and verbal fluency. These findings suggest that apraxia in HD results from damage to the corticostriate pathways and the basal ganglia rather than from damage restricted to the basal ganglia.