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.     

Huntington's disease in Venezuela: neurologic features and functional decline

We studied 65 Huntington's disease patients and 225 at-risk individuals over the past 4 years. The rate of decline of these untreated patients from Venezuela was similar to that seen in US patients who had received neuroleptic drugs. Chorea, oculomotor dysfunction, and dysdiadochokinesis were early symptoms; parkinsonian features and dystonia came later. Juvenile patients declined nearly twice as fast as adult-onset patients. No distinctive neurologic phenotypes were seen in children of two affected parents.     

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 Huntington's disease (HD) is often based on criteria developed for Alzheimer's 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 Huntington's 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. © 2010 Movement Disorder Society     

Evidence of presymptomatic cognitive decline in Huntington's disease.

Asymptomatic persons at risk for Huntington's disease (HD) (N = 28) were assessed with neuropsychological, psychiatric, and neurologic tests while undergoing genetic linkage studies to determine their probability of carrying the HD gene. Those participants who were subsequently identified as probable gene carriers did not differ on neurologic or psychiatric examination from those subsequently identified as probable noncarriers. Neuropsychological data are presented for a subset of participants free of other conditions (such as alcoholism) putting them at risk for cognitive deficits. Among these subjects, probable gene carriers were inferior to probable noncarriers on the neuropsychological battery as a whole and on several individual tests involving learning and memory. The results suggest the presence of cognitive decline prior to identifiable motor impairments in HD.     

Evidence of presymptomatic cognitive decline in Huntington's disease

Abstract

Asymptomatic persons at risk for Huntington's disease (HD) (N = 28) were as-sessed with neuropsychological, psychiatric, and neurologic tests while undergoing genetic linkage studies to determine their probability of carrying the HD gene. Those participants who were subsequently identified as probable gene carriers did not differ on neurologic or psychiatric examination from those subsequently identified as probable noncarriers. Neuropsychological data are presented for a subset of participants free of other conditions (such as alcoholism) putting them at risk for cognitive deficits. Among these subjects, probable gene carriers were inferior to probable noncarriers on the neuropsychological battery as a whole and on several individual tests involving learning and memory. The results suggest the presence of cognitive decline prior to identifiable motor impairments in HD.     

Huntington aggregates may not predict neuronal death in Huntington's disease

The mechanism by which polyglutamine expansion in Huntington's disease (HD) results in selective neuronal degeneration remains unclear. We previously reported that the immunohistochemical distribution of N-terminal huntingtin in HD does not correspond to the severity of neuropathology, such that significantly greater numbers of huntingtin aggregates are present within the cortex than in the striatum. We now show a dissociation between huntingtin aggregation and the selective pattern of striatal neuron loss observed in HD. Aggregate formation was predominantly observed in spared interneurons, with few or no aggregates found within vulnerable spiny striatal neurons. Multiple perikaryal aggregates were present in almost all cortical NADPH-diaphorase neurons and in approximately 50% of the spared NADPH-diaphorase striatal neurons from early grade HD cases. In severe grade HD patients, aggregates were more prominent as nuclear inclusions in NADPH-diaphorase neurons, with less perikaryal and neuropil aggregation. In contrast, nuclear or perikaryal huntingtin aggregates were present in less than 4% of the vulnerable calbindin striatal neurons in all HD cases. These findings support the hypothesis that polyglutamine aggregation may not be a predictor of cell loss. Rather than a harbinger of neuronal death, mutant huntingtin aggregation may be a cytoprotective mechanism against polyglutamine-induced neurotoxicity.     

Quantitative assessment of daytime motor activity provides a responsive measure of functional decline in patients with Huntington's disease.

Voluntary motor impairment is a functionally important aspect of Huntington's disease (HD). Therefore, quantitative assessment of disturbed voluntary movement might be important in follow-up. We investigated the relation between quantitatively assessed daytime motor activity and symptom severity in HD and evaluated whether assessment of daytime motor activity is a responsive measure in the follow-up of patients. Sixty-four consecutive HD patients and 67 age- and sex-matched healthy controls were studied. Daytime motor activity was recorded using a wrist-worn activity monitor that counts all movements during a period of five consecutive days. Patients were rated clinically for voluntary motor impairment, dyskinesias, posture & gait, depression, cognitive impairment and functional capacity. Follow-up was available from 40 patients (mean follow-up 2.0 years) and 29 controls (mean follow-up 5.9 years). Despite chorea, patients had less daytime motor activity than controls (P < 0.005). This hypokinesia correlated with impaired voluntary movements (r = 0.37; P < 0.01), disturbed posture & gait (r = 0.38; P < 0.005) and especially with reduced functional capacity (r = 0.51; P < 0.0005). During follow-up, hypokinesia remained unchanged in clinically stable patients, but became worse in those whose functional disability progressed (P < 0.005). Hypokinesia seems a core symptom of HD which is related to functional capacity. Actimetric assessment of hypokinesia is responsive to disease progression and can be used as an objective tool for follow-up.     

PET scan investigations of Huntington's disease: cerebral metabolic correlates of neurological features and functional decline

Fifteen drug-free patients with early to midstage Huntington's disease were evaluated with quantitative neurological examinations, scales for functional capacity, computed tomographic (CT) scans, and positron emission tomographic (PET) scans of 18F-2-fluoro-2-deoxyglucose (18F-FDG) uptake. All patients had abnormal indices of caudate metabolism on PET scanning, whereas in patients with early disease indices of putamen metabolism and CT measures of caudate atrophy were normal. Indices of caudate metabolism correlated highly with the patients' overall functional capacity (r = 0.906; p less than 0.001) and bradykinesia/rigidity (r = -0.692; p less than 0.01). Indices of putamen metabolism correlated highly with motor functions: chorea (r = -0.841; p less than 0.01), oculomotor abnormalities (r = -0.849; p less than 0.01), and fine motor coordination (r = -0.866; p less than 0.01). Indices of thalamic metabolism correlated positively with dystonia (r = 0.559; p less than 0.05). The data suggest that PET scanning with 18F-FDG is a sensitive measure of brain dysfunction in Huntington's disease and that basal ganglia metabolism is highly correlated with the overall functional capacity of individual patients and with the degree of their motor abnormalities.     

Altered functional MRI responses in Huntington's disease

This study examined the effects of Huntington's disease (HD) on neural activity during performance of the Porteus maze task. fMRI data were acquired from three HD patients and three controls. Reduced fMRI signal was observed in the patients relative to the controls in occipital, parietal and somato-motor cortex and in the caudate, while increased signal was found in HD in the left postcentral and right middle frontal gyri. The altered fMRI responses in HD patients may result from neural, metabolic, neurovascular coupling and/or hemodynamic differences associated with this disorder.     

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.     

Rate of caudate atrophy in presymptomatic and symptomatic stages of Huntington's disease.

Previous research by our group demonstrated a longitudinal change in caudate volume for symptomatic subjects with Huntington's disease (HD), and suggested that volume of the caudate may be a useful outcome measure for therapeutic studies in symptomatic patients. The current study was designed to determine whether longitudinal change in caudate atrophy could be documented in presymptomatic carriers of the HD gene mutation, and to compare rate of change in these subjects with rate of change in mildly and moderately affected symptomatic patients. We measured caudate volumes on serial magnetic resonance image scans from 30 patients at three stages of HD: 10 presymptomatic; 10 with mild symptoms, as indicated by scores on the Quantified Neurological Exam (QNE) < or =35; and 10 with moderate symptoms (QNE >45). The mean interscan interval was 36 months. When analyzed separately, both symptomatic groups and the presymptomatic group demonstrated a significant change in caudate volume over time. Amount of change over time did not differ significantly among the three groups. We conclude that change in caudate volume may be a useful outcome measure for assessing treatment effectiveness in both presymptomatic and symptomatic subjects.     

Cellular immune responses in Huntington disease. Specificity of brain antigenicity detected with Huntington disease lymphocytes.

This study confirms the production of migration inhibition factor by Huntington disease lymphocytes in response to antigen found in Huntington disease but not normal brain tissue. Huntington disease lymphocytes also respond to the presence of multiple sclerosis brain tissue with migration inhibition factor production.     

Atypical onset of symptoms in Huntington disease: severe cognitive decline preceding chorea or other motor manifestations.

OBJECTIVE: To describe the onset of Huntington disease (HD) in a patient with atypical progression of symptoms. BACKGROUND: The authors report the case of a 39-year-old man with severe cognitive impairment and diffuse cortical atrophy before the onset of motor manifestations or symptoms of an extrapyramidal movement disorder. METHOD: Clinical examinations, neuropsychologic assessments, magnetic resonance imaging, electroencephalogram, and genetic testing were conducted. RESULTS AND CONCLUSIONS: Although HD was eventually confirmed through genetic testing, chorea was not part of the clinical picture until well after the patient had developed a frank dementia, with a decline in global intellectual functioning, memory deficits, slowed information processing speed, and executive dysfunction. This case indicates HD may present with atypical clinical features in the early course of the disease, and warrants diagnostic consideration in patients with early dementia of unknown etiology.