Diffusion tensor imaging in presymptomatic and early Huntington's disease: Selective white matter pathology and its relationship to clinical measures.

Atrophy of cortical and subcortical gray matter is apparent in Huntington's disease (HD) before symptoms manifest. We hypothesized that the white matter (WM) connecting cortical and subcortical regions must also be affected early and that select clinical symptoms were related to systems degeneration. We used diffusion tensor magnetic resonance imaging (DTI) to examine the regional nature of WM abnormalities in early HD, including the preclinical period, and to determine whether regional changes correlated with clinical features. We studied individuals in early stages (HD), presymptomatic individuals known to carry the genetic mutation that causes HD (Pre-HD), and matched healthy controls. DTI indices of tissue integrity were obtained from several regions of interest, including the corpus callosum (CC), internal capsule (IC), and basal ganglia, were compared across groups by t tests, and were correlated to cognitive and clinical measures. WM alterations were found throughout the CC, in the anterior and posterior limbs of the IC, and in frontal subcortical WM in HD subjects, supporting the selective involvement of the pyramidal tracts in HD; a similar distribution of changes was seen in Pre-HD subjects, supporting presymptomatic alterations. There was a significant relationship between select DTI measures and cognitive performance. Alterations in diffusion indices were also seen in the striatum that were independent of atrophy. Our findings support that WM alterations occur very early in HD. The distribution of the changes suggests that these changes contribute to the disruption of pyramidal and extrapyramidal circuits and also support a role of compromised cortical circuitry in early cognitive and subtle motor impairment during the preclinical stages of HD.     

Psychopathology in Huntington's disease patients

A retrospective study of 30 Huntington's disease families (110 patients: 75 alive and 35 dead) known to a regional genetic centre, using multiple sources of information, showed the minimum lifetime prevalence of depression to be 39% in the prodrome and the diagnosed disease phase of the illness. The frequency of symptomatic schizophrenia was found to be about 9% and significant personality changes were found in 72% of the sample, some of them leading to gross behavioural anomalies. The findings reinforce the point that depression and schizophrenia, unaccompanied or preceded by organic personality changes and/or very early neural symptoms, are unlikely to lead to the eventual manifestation of the disease.     

Circadian rhythm and autonomic dysfunction in presymptomatic and early Huntington's disease

IntroductionSleep and circadian rhythm disturbances are common in patients with neurodegenerative diseases such as Huntington's disease (HD). The aim of this study was to evaluate variability in circadian blood pressure (BP) to determine the association between abnormal circadian BP and sleep quality in patients with HD.MethodsCross-sectional, multicenter study of 38 HD mutation carriers (23 premanifest and 15 early stage patients) who were compared to 38 age- and sex-matched controls. BP was evaluated by ambulatory blood pressure monitoring (ABPM). Based on the percentage decrease in nocturnal BP, subjects were classified as either dippers (≥10%) or non-dippers (<10%). Sleep quality and daytime sleepiness were measured, respectively, using the Pittsburgh Sleep Quality Index (PSQI) and the Epworth Daytime Sleepiness Scale (ESS) and the scores on these indices were correlated with the ABPM findings.ResultsSixty-three percent HD mutation carriers were non-dippers (86.7% of the symptomatic and 47.8% of the premanifest patients) versus 23.7% of controls (p = 0.001). In the HD group, sleep quality was significantly more impaired (PSQI>5) (p = 0.016) with more excessive daytime sleepiness (ESS>9) (p = 0.001) than in the control group. Nocturnal non-dipping was associated with worse sleep quality in patients (p = 0.011) but not in controls.ConclusionThese results show that patients with HD present early disturbances in the circadian rhythm of BP and that this altered nocturnal BP is associated with poor sleep quality. These findings suggest the potential role of subtle hypothalamic dysfunction in this population.     

Spectrum of gait impairments in presymptomatic and symptomatic Huntington's disease

The purpose of this study was to quantify gait impairments in presymptomatic and symptomatic Huntington's disease (HD) subjects, and examine sensitivity of gait measures. Our sample (n = 65) included presymptomatic mutation carriers (PMC) (n = 15), symptomatic HD subjects (SHD) (n = 30) and healthy controls (n = 20). Participants were requested to walk at their preferred speed on a computerized walkway that recorded spatiotemporal variables. We administered the Unified HD Rating Scale (UHDRS) for PMC and SHD. PMC demonstrated decreased gait velocity (P < 0.01), stride length (P < 0.008), and increased time in double support (P < 0.001); and demonstrated higher variability in stride length (P < 0.01) and step time (P < 0.004) compared with controls. These impairments worsened with increasing disease severity for SHD. Gait impairments were correlated with predicted years to onset in PMC (velocity = ?0.65; cadence = ?0.70, step time = 0.71) and demonstrated high sensitivity and specificity in distinguishing between controls and mutation carriers. In contrast, UHDRS scores did not reveal impairments in gait and balance. Gait bradykinesia and dynamic balance impairments begin in the presymptomatic stage of HD and continue to worsen in the symptomatic stages. Gait measures are sensitive in differentiating between mutation positive and negative individuals even when impairments were not detected by clinical neurological examination. © 2008 Movement Disorder Society     

Hyperhomocysteinaemia in treated patients with Huntington's disease homocysteine in HD.

Significantly increased plasma total homocysteine levels (t-Hcys) appeared in treated Huntington disease (HD) patients compared to controls and untreated HD subjects. Because the protein Huntingtin interacts with the homocysteine metabolism modulating enzyme cystathionine beta-synthase, we hypothesize that homocysteine promotes neurodegeneration in HD.     

Mitochondrial impairment in patients and asymptomatic mutation carriers of Huntington's disease.

Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disorder caused by a CAG repeat expansion in the IT-15 gene; however, it remains unknown how the mutation leads to selective neurodegeneration. Several lines of evidence suggest impaired mitochondrial function as a component of the neurodegenerative process in HD. We assessed energy metabolism in the skeletal muscle of 15 HD patients and 12 asymptomatic mutation carriers in vivo using 31P magnetic resonance spectroscopy. Phosphocreatine recovery after exercise is a direct measure of ATP synthesis and was slowed significantly in HD patients and mutation carriers in comparison to age- and gender-matched healthy controls. We found that oxidative function is impaired to a similar extent in manifest HD patients and asymptomatic mutation carriers. Our findings suggest that mitochondrial dysfunction is an early and persistent component of the pathophysiology of HD.     

Huntington's disease like-2 neuropathology.

Huntington's disease like-2 (HDL-2) neurodegeneration is a recently described autosomal dominant disorder with features similar to Huntington's disease (HD). Only one case report has described neuropathology from an affected patient. We describe the clinical presentation and illustrate the pathology in two additional molecularly confirmed patients, compare these with the previously published case, and contrast them with HD. We examined two patients with HDL-2. Their charts were reviewed, their brains were examined using standard neuropathology techniques, including immunoperoxidase stains, and their diagnoses were confirmed with a PCR-based assay for repeat length. The first patient presented with obsessive suspiciousness, while the second had depression and decreased visual acuity. Both patients developed increased tone and cogwheel rigidity, but neither developed choreoathetosis. Extensive degeneration affected the caudate nucleus and putamen, especially dorsally and laterally. In addition, the first patient showed lateral temporal, lateral frontal, and orbitofrontal cortical atrophy, while the second patient displayed marked degeneration in the occipital and parietal cortices. Neither patient showed significant changes in the cerebellum or brainstem. Both cases had ubiquitin-immunoreactive neuronal intranuclear inclusions (NII). The patients with of HDL-2 reviewed here were remarkable for significant frontal inhibition with parkinsonism, a lack of choreiform movements, and African ancestry. Pathologically, HDL-2 is similar to HD in its effect on the neostriatum but may differ, at least in some cases, in its degree of focal cortical involvement, including the occipital lobe.     

Aberrant brain network connectivity in presymptomatic and manifest Huntington's disease: A systematic review

Resting‐state functional magnetic resonance imaging (rs‐fMRI) has the potential to shed light on the pathophysiological mechanisms of Huntington's disease (HD), paving the way to new therapeutic interventions. A systematic literature review was conducted in three online databases according to PRISMA guidelines, using keywords for HD, functional connectivity, and rs‐fMRI. We included studies investigating connectivity in presymptomatic (pre‐HD) and manifest HD gene carriers compared to healthy controls, implementing seed‐based connectivity, independent component analysis, regional property, and graph analysis approaches. Visual network showed reduced connectivity in manifest HD, while network/areas underpinning motor functions were consistently altered in both manifest HD and pre‐HD, showing disease stage‐dependent changes. Cognitive networks underlying executive and attentional functions showed divergent anterior–posterior alterations, possibly reflecting compensatory mechanisms. The involvement of these networks in pre‐HD is still unclear. In conclusion, aberrant connectivity of the sensory‐motor network is observed in the early stage of HD while, as pathology spreads, other networks might be affected, such as the visual and executive/attentional networks. Moreover, sensory‐motor and executive networks exhibit hyper‐ and hypo‐connectivity patterns following different spatiotemporal trajectories. These findings could potentially help to implement future huntingtin‐lowering interventions.     

Factors contributing to institutionalization in patients with Huntington's disease

The objective of this study was to determine which factors are predictive of institutionalization in Huntington's disease. Seven hundred and ninety‐nine subjects with 4313 examinations from the Baltimore Huntington's Disease Center were included in the data set; 88 of these patients with an average follow‐up time of 9.2 years went from living at home to being institutionalized while being observed in our clinic. We examined demographic, genetic, and clinical variables for a relationship with institutionalization using linear regressions, a Cox proportional hazards model, and χ² or t tests in certain cases. In our linear models, scores on the Quantified Neurologic Examination (R² = 0.203, P < .001), Huntington's disease Activities of Daily Living Scale (R² = 0.259, P < .001), and Motor Impairment Score (R² = 0.173, P < .001) were found to have the strongest correlation with time until institutionalization. In addition, CAG repeat length (R² = 0.248, P < .001) was significantly associated with disease duration at institutionalization, when controlling for age at onset. In the Cox proportional hazards model, scores on the Activities of Daily Living Scale, Mini–Mental State Examination, Quantified Neurologic Examination, and Motor Impairment Score all significantly predicted placement in long‐term care. Finally, institutionalized patients were shown to have a higher CAG number and a lower level of educational attainment than patients who avoided institutionalization for at least 15 years after disease onset. Neurologic findings, functional capacity, cognitive impairment, and CAG repeat length are all likely determinants of institutionalization. In contrast with other dementing conditions like Parkinson's and Alzheimer's, psychiatric symptoms were not shown to predict institutionalization in Huntington's disease. This may illustrate the especially debilitating nature of the movement disorder of Huntington's disease in comparison with the other dementias. © 2011 Movement Disorder Society     

Visual scanning and cognitive performance in prediagnostic and early‐stage Huntington's disease

The objective of this study was to evaluate visual scanning strategies in carriers of the Huntington disease (HD) gene expansion and to test whether there is an association between measures of visual scanning and cognitive performance. The study sample included control (NC, n = 23), prediagnostic (PDHD, n = 21), and subjects recently diagnosed with HD (HD, n = 19). All participants completed a uniform clinical evaluation that included examination by neurologist and molecular testing. Eye movements were recorded during completion of the Digit Symbol Subscale (DS) test. Quantitative measures of the subject's visual scanning were evaluated using joint analysis of eye movements and performance on the DS test. All participants employed a simple visual scanning strategy when completing the DS test. There was a significant group effect and a linear trend of decreasing frequency and regularity of visual scanning from NC to PDHD to HD. The performance of all groups improved slightly and in a parallel fashion across the duration of the DS test. There was a strong correlation between visual scanning measures and the DS cognitive scores. While all individuals employed a similar visual scanning strategy, the visual scanning measures grew progressively worse from NC to PDHD to HD. The deficits in visual scanning accounted, at least in part, for the decrease in the DS score. © 2008 Movement Disorder Society     

Seizures in juvenile Huntington's disease: Frequency and characterization in a multicenter cohort

Little is known about the epilepsy that often occurs in the juvenile form of Huntington's disease (HD), but is absent from the adult‐onset form. The primary aim of this study was to characterize the seizures in juvenile HD (JHD) subjects with regard to frequency, semiology, defining EEG characteristics, and response to antiepileptic agents. A multicenter, retrospective cohort was identified by database query and/or chart review. Data on age of HD onset, primary HD manifestations, number of CAG repeats, the presence or absence of seizures, seizure type(s), antiepileptic drugs used, subjects' response to antiepileptic drugs (AEDs), and EEG results were assembled, where available. Ninety subjects with genetically confirmed JHD were included. Seizures were present in 38% of subjects and were more likely to occur with younger ages of HD onset. Generalized tonic‐clonic seizures were the most common seizure type, followed by tonic, myoclonic, and staring spells. Multiple seizure types commonly occurred within the same individual. Data on EEG findings and AED usage are presented. Seizure risk in JHD increases with younger age of HD onset. Our ability to draw firm conclusions about defining EEG characteristics and response to AEDs was limited by the retrospective nature of the study. Future prospective studies are required. © 2012 Movement Disorder Society     

Reduced Purkinje cell density in Huntington's disease

We studied, in a "blind" and quantitative fashion, the density of cerebellar Purkinje cells in 17 adult cases of Huntington's disease (HD), 17 patients with other movement disorders, 17 with schizophrenia, and 23 normal controls. There was a highly significant reduction in Purkinje cell density in HD compared with any of the other three groups. A much smaller difference in neuronal density between patients with other movement disorders and normal controls was barely significant. Eight of the 17 HD patients and only 1 of the other 57 subjects had Purkinje cell density less than 50% of the mean for the normal controls. The low density of Purkinje cells in HD could not be attributed to aging, seizures, or cause of death, nor was it merely a part of a generalized brain atrophy. The loss of large Purkinje cells suggests that the neuronal loss in HD may not be restricted to small and medium-size neurons.     

Visual object recognition and attention in Parkinson's disease patients with visual hallucinations

Visual hallucinations (VH) are common in Parkinson's disease (PD) and are hypothesized to be due to impaired visual perception and attention deficits. We investigated whether PD patients with VH showed attention deficits, a more specific impairment of higher order visual perception, or both. Forty‐two volunteers participated in this study, including 14 PD patients with VH, 14 PD patients without VH and 14 healthy controls (HC), matched for age, gender, education level and for level of executive function. We created movies with images of animals, people, and objects dynamically appearing out of random noise. Time until recognition of the image was recorded. Sustained attention was tested using the Test of Attentional Performance. PD patients with VH recognized all images but were significantly slower in image recognition than both PD patients without VH and HC. PD patients with VH showed decreased sustained attention compared to PD patients without VH who again performed worse than HC. In conclusion, the recognition of objects is intact in PD patients with VH; however, these patients where significantly slower in image recognition than patients without VH and HC, which was not explained by executive dysfunction. Both image recognition speed and sustained attention decline in PD, in a more progressive way if VH start to occur. © 2008 Movement Disorder Society     

Prevalence of Huntington's disease in Southern Sardinia,Italy

BackgroundThe frequency of Huntington's disease (HD) may vary considerably, with higher estimates in non Asian populations. In Italy, two recent studies performed in Ferrara county and Molise provided different prevalence estimates, varying from 4.2 × 10⁵ to 10.8 × 10⁵. Here we present a study performed in the Southern part of Sardinia, a large Italian mediterranean island that is considered a genetic isolate.MethodsThe study area included the two neighbouring counties of South Sardinia and Cagliari with 353,830 and 431,955 inhabitants respectively on December 31st, 2017 (prevalence date). Case-patients were ascertained through multiple sources in Sardinia and Italy.ResultsWe identified 54 individuals with HD, of whom 47 were alive on prevalence date. The resulting prevalence rate was 5.98 × 10⁵ in the overall study area, however with marked variations between South Sardinia and Cagliari (9.6 × 10⁵ vs. 3.0 × 10⁵, p = 0.02). In the two study areas, we found similar CAG repeat length in normal alleles (17.5 ± 2.1 vs. 17.7 ± 2.2, p = 0.5).ConclusionsThe overall prevalence of HD in Sardinia is close to the correspondent estimates in Europeans. Our findings also highlighted the possibility of local microgeographic variations in the epidemiology of HD.     

Clinical correlates of mitochondrial function in Huntington's disease muscle.

Huntington's disease (HD) is caused by an abnormally expanded CAG repeat in the IT-15 gene, which encodes a widely expressed protein called huntingtin. Abnormalities of mitochondrial respiratory chain function, specifically complex II/III, have been identified in HD striatum and defects of energy metabolism have been demonstrated in vivo in skeletal muscle in both symptomatic and presymptomatic HD patients. We have investigated respiratory chain function using histochemical and biochemical methods in HD skeletal muscle from 12 patients and compared these with 12 age and sex-matched controls. The data from the HD patients were related to clinical parameters of HD including the Unified Huntington's Disease Rating Scale (UHDRS). There were positive correlations between CAG repeat years (a product of CAG repeat length and age) and both motor (P < 0.002) and cognitive (P < 0.01) scores of the UHDRS. There was no significant difference in the activities of complexes I to IV compared to age-matched controls. However, there were significant correlations for individual HD complex II/III activities with disease duration (P = 0.017), repeat years (P = 0.032), and cognitive scores (P = 0.019). There was also evidence from ultrastructural studies that inclusion formation may occur in HD muscle. These results provide additional evidence that mutant huntingtin influences mitochondrial complex II/III function in non-neuronal tissue (skeletal muscle) and suggest that muscle may be a potential marker of disease progression in HD.     

Psychiatric symptoms in neurologically asymptomatic Huntington's disease gene carriers: a comparison with gene negative at risk subjects

OBJECTIVE: Psychiatric profiles of two at-risk groups [Huntington's disease (HD) gene carriers and non-carriers] were compared by means of a computerized battery and a structured interview. METHOD: To avoid confounding, only subjects who were free from neurological and cognitive deficits (neurologically asymptomatic) were included in the study. To avoid evaluation biases, all subjects were seen before the genetic testing was undertaken. RESULTS: Gene carriers had significantly worse recognition memory and scored higher in measures of irritability than controls. The groups also differed in terms of the factor structure of their psychiatric symptoms. None of the subjects qualified for a psychiatric diagnosis at the time of assessment. CONCLUSION: The groups differed with respect to their profile of psychiatric symptoms. It is hypothesized that these differences are the expression of different mechanisms, i.e. that cognitive deficits relate more to genetic factors and neurotic complaints more to being brought up in a disturbed family background. Issues concerning instrument sensitivity, selection bias and the advantage of seriatim assessments are discussed.     

Clinical relevance of electrophysiological tests in the assessment of patients with Huntington's disease.

Assessment programs recently designed to follow-up patients with Huntington's disease (HD) in therapeutic trials have not included electrophysiological testing in the list of mandatory examinations. This omission is likely due to the current lack of data establishing a clear correlation between the electrophysiological results and those of clinical assessment. We address this issue in a cohort of 36 patients at relatively early stages of the disease (I and II). Electrophysiological studies comprised the recording of palmar sympathetic skin responses (SSRs), blink reflexes (BRs), thenar long latency reflexes (LLRs), cortical somatosensory evoked potentials (SEPs), and electromyographic silent periods evoked by transcranial magnetic stimulation (SPs). Results were analyzed with reference to disease duration and staging and to specific cognitive, psychiatric, and motor alteration. SEPs were the most and very sensitive markers, because they were abnormal in 94% of patients. Except for LLRs, alteration of electrophysiological results increased in parallel to the evolution of the disease. Except for LLRs and SSR latency, electrophysiological results correlated with those of specific clinical examinations. In particular, an increased BR latency or a reduced amplitude of the N20 component of SEPs correlated with the extent of bradykinesia, whereas a reduced amplitude of SSRs or of the N30 component of SEPs correlated with hyperkinesia. Overall, electrophysiological tests, in particular SEPs and BRs, appeared sensitive and interesting in the follow-up of HD patients and correlated with various clinical parameters, suggesting that these easy to perform and noninvasive repeatable examinations could be added fruitfully to the assessment programs for HD.     

Verb and noun generation tasks in Huntington's disease.

We compared noun- and verb-generation tasks in a demented group (n = 9, Dementia Rating Scale < or = 129) and in a non-demented group (n = 17, Dementia Rating Scale > 129) of Huntington's disease (HD) patients compared to 26 matched normal subjects. We did not find a specific deficit for verb production in non-demented patients who had a performance similar to but weaker than that of the controls across the four tasks. The profile of results was different in the demented group because, apart from a global deficit whatever the task in comparison with both non-demented and control groups, the demented patients exhibited increased difficulties in the two tasks implying verb production. The deficit of verb production observed in demented HD patients is discussed in relation to the damage to the motor loop in HD patients at later stages of disease.