Factors associated with slow progression in Huntington's disease

The rate of disease progression was assessed for 42 persons affected by Huntington's disease who had been neurologically examined at least six times and followed up for at least 3 years. Disease progression was assessed by a disability rating scale administered at each examination. Slow progression was associated with older age at onset of disease and with heavier weight (body mass index) at the first examination. Men tended to have a slower disease progression than did women, and this was particularly evident among men inheriting Huntington's disease from affected mothers. Neither the butyrophenone haloperidol nor the tricyclic antidepressant imipramine were related to rate of progression. Assessments of depression, hostility, and tobacco use were also unrelated to rate of progression. Clinical trials in Huntington's disease should consider these factors when designing therapeutic studies.     

Language impairment in Huntington's disease

Language alterations in Huntington's disease (HD) are reported, but their nature and correlation with other cognitive impairments are still under investigation. This study aimed to characterize the language disturbances in HD and to correlate them to motor and cognitive aspects of the disease. We studied 23 HD patients and 23 controls, matched for age and schooling, using the Boston Diagnostic Aphasia Examination, Boston Naming Test, the Token Test, Animal fluency, Action fluency, FAS-COWA, the Symbol Digit Modalities Test, the Stroop Test and the Hooper Visual Organization Test (HVOT). HD patients performed poorer in verbal fluency (p<0.0001), oral comprehension (p<0.0001), repetition (p<0.0001), oral agility (p<0.0001), reading comprehension (p=0.034) and narrative writing (p<0.0001). There was a moderate correlation between the Expressive Component and Language Competency Indexes and the HVOT (r=0.519, p=0.011 and r=0.450, p=0.031, respectively). Language alterations in HD seem to reflect a derangement in both frontostriatal and frontotemporal regions.     

Memory performance in Huntington's disease

In this study the influence of special memory tasks, the effect of cues and the influence of the severity of the disease on the performance of short-term memory of patients suffering from Huntington's disease was examined. Stimulus material consisted of 30 nouns for reproduction and 20 nouns to be subsumed to 5 categories. Depending on experimental condition, assistance was given or withheld. 16 healthy subjects and 48 patients suffering from Huntington's disease took part in the study. Between these groups there was a significant effect of the factor "memory task." Furthermore, it could be demonstrated that the performance level decreases and differences between individuals increase with increasing severity of the disease. There was no significant effect of the factor "cues."     

Memory failure in Huntington's disease

Patients with Huntington's disease (HD) were compared to normal controls of equivalent age and verbal intelligence on a set of verbal learning tasks. Although the HD patients showed the expected deficit in secondary (long-term) memory, their performance was otherwise comparable to that of the control groups. Primary (short-term) memory was normal, there was normal sensitivity to proactive interference, and the patients showed an advantage, albeit reduced, in recall of related compared to unrelated word lists. The findings suggest that mnemonic input is encoded semantically in HD though less efficiently than in unafflicted individuals, and that difficulty accessing information in semantic (knowledge-based) memory may be partially responsible for the memory disorder of HD.     

Clinical impairment in premanifest and early Huntington's disease is associated with regionally specific atrophy

TRACK‐HD is a multicentre longitudinal observational study investigating the use of clinical assessments and 3‐Tesla magnetic resonance imaging as potential biomarkers for future therapeutic trials in Huntington's disease (HD). The cross‐sectional data from this large well‐characterized dataset provide the opportunity to improve our knowledge of how the underlying neuropathology of HD may contribute to the clinical manifestations of the disease across the spectrum of premanifest (PreHD) and early HD. Two hundred and thirty nine gene‐positive subjects (120 PreHD and 119 early HD) from the TRACK‐HD study were included. Using voxel‐based morphometry (VBM), grey and white matter volumes were correlated with performance in four domains: quantitative motor (tongue force, metronome tapping, and gait); oculomotor [anti‐saccade error rate (ASE)]; cognition (negative emotion recognition, spot the change and the University of Pennsylvania smell identification test) and neuropsychiatric measures (apathy, affect and irritability). After adjusting for estimated disease severity, regionally specific associations between structural loss and task performance were found (familywise error corrected, P < 0.05); impairment in tongue force, metronome tapping and ASE were all associated with striatal loss. Additionally, tongue force deficits and ASE were associated with volume reduction in the occipital lobe. Impaired recognition of negative emotions was associated with volumetric reductions in the precuneus and cuneus. Our study reveals specific associations between atrophy and decline in a range of clinical modalities, demonstrating the utility of VBM correlation analysis for investigating these relationships in HD. Hum Brain Mapp, 2013. © 2011 Wiley Periodicals, Inc.     

Presymptomatic neuropsychological impairment in Huntington's disease

Ten asymptomatic individuals at risk for Huntington's disease (HD) were determined by the use of linked DNA probes to have a high (HD+ group) or low (HD- group) probability of having inherited the mutant gene. Neuropsychological examination, performed without knowledge of DNA results, revealed impairments in five of seven subjects in the HD+ group. Abnormalities were related to visuospatial abilities or to functions associated with the frontal lobes. All three subjects in the HD- group showed no neuropsychological impairment. Statistical analyses confirmed differences between the HD+ and HD- groups. Affected parents of subjects were at least 12 years older at symptom onset. These results demonstrate that clear neuropsychological impairment may be present in HD even when overt signs and symptoms are not expected for a number of years.     

Neuropsychiatric symptoms are associated with progression from mild cognitive impairment to Alzheimer's disease

BACKGROUND: Neuropsychiatric disturbances are common in mild cognitive impairment (MCI). Depression and apathy may identify a subset of MCI subjects at higher risk of progression to Alzheimer's disease (AD). However, it remains uncertain whether a broader spectrum of psychopathology is associated with progression to AD. METHODS: Fifty-one MCI subjects were assessed for neuropsychiatric symptoms using the Neuropsychiatric Inventory. Subjects were followed for an average of 2 years. Twelve subjects (23.5%) progressed from MCI to possible/probable AD and 39 subjects (76.5%) remained stable or improved. Baseline Neuropsychiatric Inventory indices were compared between groups. RESULTS: Subjects progressing to AD had a significantly higher prevalence of psychopathology than subjects who remained stable or improved (100 vs. 59%). Depression (67 vs. 31%) and apathy (50 vs. 18%) were more common in subjects who were later diagnosed with AD. After statistical adjustments for other baseline demographic variables, these specific symptoms were less robust predictors of progression to AD than the presence of any psychopathology. CONCLUSIONS: These findings suggest that neuropsychiatric symptoms in MCI are a predictor of progression to AD. Depression and apathy appear to be most useful for identifying MCI subjects at highest risk of developing dementia.     

Differential cognitive impairment in Alzheimer's disease and Huntington's disease

The differentiation between cortical and subcortical dementias requires that the cognitive characteristics of dementias attributable to different causes be discriminable. For large samples of Alzheimer's disease and Huntington's disease patients, distinct cognitive profiles were obtained on the Mini-Mental State Exam. The profile differences were independent of severity of dementia and were sufficiently robust to classify patients as Alzheimer's disease or Huntington's disease with 84% accuracy. The qualitative differences in cognitive functioning may also be typical of other cortical and subcortical dementias.     

Memory impairment in Cushing's disease

In the present study the cognitive performance of 25 patients with Cushing's disease (CD) was extensively evaluated in comparison with normal control subjects, matched one by one. The results indicate a selective impairment of memory functions: the number of patients showing a significantly impaired mnesic performance increases with age. Moreover, the neuropsychological impairment tends to recover in those cases who underwent further controls after surgical treatment. The neuropsychological data are discussed in the light of recent evidence in the literature concerning the effects of adrenal steroids on the brain.     

Striatal neuronal loss correlates with clinical motor impairment in Huntington's disease

Huntington's disease (HD) is characterized clinically by chorea, motor impairment, psychiatric manifestations, and dementia. Atrophy of the striatum is the neuropathological hallmark of HD, and previous studies have suggested that striatal atrophy correlates more closely with motor impairment than with chorea. Motor impairment, as measured by motor impairment score, correlates with functional disability in HD patients, but chorea does not. In this study, we investigated the relation between neuronal loss and these motor features. We conducted neuropathological and stereologic assessments of neurons in putamen and subthalamic nuclei in HD patients and age‐matched controls. In putamen, we estimated the total number and volume of medium spiny neurons labeled with dopamine‐ and cAMP‐regulated phosphoprotein 32 kDa (DARPP‐32). In subthalamic nuclei, we estimated the total number of neurons on hematoxylin & eosin/luxol fast blue stains. In putamen of HD, immunohistochemistry showed DARPP‐32 neuronal atrophy with extensive disruption of neurites and neuropil; stereologic studies found significant decreases in both the number and size of DARPP‐32 neurons; we also detected a significant reduction of overall putamen volume in HD patients, compared to controls. In subthalamic nuclei, there was a mild, but significant, neuronal loss in the HD group. The loss of neurons in putamen and subthalamic nuclei as well as putaminal atrophy were significantly correlated with severity of motor impairment, but not with chorea. Our findings suggest that neuronal loss and atrophy in striatum and neuronal loss in subthalamic nuclei contribute specifically to the motor impairment of HD, but not to chorea. © 2012 Movement Disorder Society     

Differential impairment of spatial location memory in Huntington's disease

OBJECTIVE: To determine whether a differential impairment of spatial memory exists in Huntington's disease (HD). METHODS: Patients with HD and age matched neurologically normal subjects, as well as patients with Alzheimer's disease (AD) and Parkinson's disease (PD), learned the locations of nine items on a 3 x 3 grid over as many as 10 trials. Delayed recall of the items and their spatial locations was tested. RESULTS: Patient with HD performed worse than normal subjects on all measures, and intermediate between AD and PD patients. However, they were the only subject group in whom delayed recall of spatial locations was poorer than delayed recall of object identity. This effect was independent of the severity of dementia. CONCLUSIONS: HD patients have a differential impairment in memory for object-location information. This finding may relate to the involvement of the caudate nucleus, the primary site of pathology in HD, in corticostriatal circuits linking it with parietal association cortex. It is also consistent with views of the dorsal striatum as responsible for the acquisition over trials of specific place responses.     

The influence of gender on phenotype and disease progression in patients with Huntington's disease

IntroductionHuntington's disease (HD) is an autosomal dominant neurodegenerative disorder. The aim of this study is to determine whether gender plays a role in the phenotypic expression and progression of HD.Methods1267 patients with HD (636 women) from the Registry project of the EHDN were included. A cross-sectional analysis (ANCOVA) controlling for differences in age at onset, disease burden, disease duration, smoking status, alcohol abuse, depression and the number of years of education, was performed to evaluate if there were differences between men and women in UHDRS motor, function and cognitive scores. Additionally, analyses on follow-up data using linear mixed models with the same covariates were performed to test for gender-related differences in progression.ResultsBaseline features did not differ between genders, with the exception of a higher frequency of past and current depression among women, and a higher number of years of education as well as more frequent alcohol abuse and smoking among men. In the cross-sectional ANCOVA analyses of patients with a mid-age HD onset, women showed worse scores than men in the functional domain (TFC, P = 0.001; UHDRS functional, P = 0.033), UHDRS motor (P = 0.033). The longitudinal analyses showed a faster rate of progression in women in the functional assessment (P = 0.025), the motor assessment (P = 0.032) and the independence scale (P = 0.008).ConclusionsThese results suggest a complex gender effect on the phenotypical presentation and the rate of disease progression in HD, with slightly more severe phenotype and faster rate of progression in women in especially the motor and functional domains.     

Assessment of simple movements and progression of Huntington's disease

Instrumental measurement of simple motion sequences reflects impairment in patients with Huntington's disease (HD). The objectives were to study the progress of symptoms of HD and tapping results in 42 patients with HD, without symptomatic drug treatment over 3 years. Assessment moments were at baseline, and at years 1, 2 and 3. Unified Huntington's Disease Rating Scale (UHDRS) total score and UHDRS arm score significantly increased. Motor test outcomes considerably worsened. Instrumental test results significantly correlated with both UHDRS scores at each assessment. Assessment of simple movement sequences is an additional simple method to follow impairment in patients with HD in addition to clinical rating.