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.     

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.     

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     

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.     

Late-onset Huntington's disease: Diagnostic and prognostic considerations

ObjectiveTo address diagnostic and prognostic issues in patients with late-onset Huntington's disease (HD).MethodsWe analyzed a cohort of 41 late-onset (≥60 years) HD patients and compared them to 39 late-onset patients referred for HD testing that were negative for the HD-expansion and to 290 usual-onset (20–59 years) HD patients. Disease severity was assessed by the Total Functional Capacity Scale.ResultsLate-onset HD comprised 11.5% of our HD cohort. In total, 70.7% of late-onset HD patients had positive family history compared to 15.4% of late-onset expansion-negative patients (p < 0.001). Clinical features at onset or presentation could not usefully distinguish between late-onset expansion-positive and negative patients, excepting hemichorea, which was absent from the HD group (p = 0.024). Chorea was the first clinical feature in 53.7% and a presenting feature in 90.2% of late-onset HD. The mutation hit rate for late-onset patients was 51.3%, lower than in usual-onset patients (p = 0.04). Frequencies of chorea, cognitive impairment and psychiatric manifestations at onset or presentation were not significantly different between late-onset and usual-onset HD patients. Gait unsteadiness however was more common at presentation in late-onset HD (p = 0.007). Late-onset HD patients reached a severe stage of illness on average 2.8 years earlier than usual-onset HD patients (p = 0.046).ConclusionsA positive family history suggestive of HD, although absent in a third of patients, remains a helpful clue in diagnosing late-onset HD. Prognosis of late-onset HD in terms of Total Functional Capacity appears no better and shows a trend of being somewhat less favorable compared to usual-onset HD.     

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.     

Striatal parvalbuminergic neurons are lost in Huntington's disease: implications for dystonia

Although dystonia represents a major source of motor disability in Huntington's disease (HD), its pathophysiology remains unknown. Because recent animal studies indicate that loss of parvalbuminergic (PARV+) striatal interneurons can cause dystonia, we investigated if loss of PARV+ striatal interneurons occurs during human HD progression, and thus might contribute to dystonia in HD. We used immunolabeling to detect PARV+ interneurons in fixed sections, and corrected for disease‐related striatal atrophy by expressing PARV+ interneuron counts in ratio to interneurons co‐containing somatostatin and neuropeptide Y (whose numbers are unaffected in HD). At all symptomatic HD grades, PARV+ interneurons were reduced to less than 26% of normal abundance in rostral caudate. In putamen rostral to the level of globus pallidus, loss of PARV+ interneurons was more gradual, not dropping off to less than 20% of control until grade 2. Loss of PARV+ interneurons was even more gradual in motor putamen at globus pallidus levels, with no loss at grade 1, and steady grade‐wise decline thereafter. A large decrease in striatal PARV+ interneurons, thus, occurs in HD with advancing disease grade, with regional variation in the loss per grade. Given the findings of animal studies and the grade‐wise loss of PARV+ striatal interneurons in motor striatum in parallel with the grade‐wise appearance and worsening of dystonia, our results raise the possibility that loss of PARV+ striatal interneurons is a contributor to dystonia in HD.     

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.     

The current clinical management of Huntington's disease

Huntington's disease is a neurodegenerative condition, characterized by movement disorders, cognitive decline, and psychiatric disturbance. We review the pharmacological management of the various movement disorders associated with the disease, the cognitive decline and the commonly encountered behavioral disturbances. We discuss the nonclassical features of the disease, important in the management of these patients. Nonpharmacological support including genetic counseling and therapy and the importance of palliative care are also addressed. Finally, experimental approaches that may soon impact upon clinical practice are discussed. © 2008 Movement Disorder Society     

Deficits induced by quinolinic acid lesion to the striatum in a position discrimination and reversal task are ameliorated by permanent and temporary lesion to the globus pallidus: a potential novel treatment in a rat model of Huntington's disease.

Symptoms in the early stages of Huntington's disease (HD) are assumed to reflect basal ganglia circuit dysfunction secondary to degeneration of striatal projections to the external segment of the globus pallidus (GPe). The hypothesis that GPe lesion would ameliorate HD symptoms by "normalizing" the circuit's functioning was tested in a rat model of this disease. The performance of rats sustaining quinolinic acid lesion to the striatum (a rat model of HD) in a position discrimination and reversal task was compared with the performance of rats sustaining in addition a bilateral excitotoxic lesion to the globus pallidus (GP) carried out simultaneously with the striatal lesion (Experiment 1) or 1 month after the striatal lesion (Experiment 2), as well as a unilateral temporary lesion of the GP (Experiment 3). The striatal lesion-induced deficit in the task was effectively reversed by a bilateral excitotoxic GP lesion carried out simultaneously or 1 month after the striatal lesion, as well as by a temporary unilateral GP inactivation. Given that a similar dysfunction of basal ganglia circuitry is thought to subserve the behavioral alterations seen in quinolinic acid lesioned rats and some of the symptoms in HD, these results raise the possibility that lesion or inactivation of the GPe may alleviate some of HD symptoms.     

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     

Inhibitory control during smooth pursuit in Parkinson's disease and Huntington's disease

The basal ganglia are involved in the preferential selection and suppression of competing responses. Parkinson's disease and Huntington's disease are 2 prototypical basal ganglia disorders that feature impaired inhibitory control, a function of poor conflict resolution. Previous saccadic studies showed that individuals with Parkinson's disease experience difficulty suppressing unwanted ocular motor responses, whereas evidence for a similar difficulty in Huntington's disease is more equivocal. Relative to saccades, few research studies have examined inhibitory control processes in the context of an ongoing smooth pursuit task. In this study, we examined the ability of 16 patients with Parkinson's disease and 12 patients with Huntington's disease to suppress automatic responses to irrelevant distracters that transiently appeared during the tracking of a moving visual stimulus. Compared with an equivalent number of age‐matched controls, patients with Parkinson's disease generated proportionately more saccades to distracter stimuli. This was particularly evident for distracters appearing far away from the target. Conversely, whereas individuals with early‐stage Huntington's disease and healthy controls made a comparable number of errors toward distracter stimuli, those in a more advanced clinical stage demonstrated significantly poorer inhibitory control. The current findings in parkinsonian patients replicate those previously reported in the saccadic and manual response literature, demonstrating difficulty inhibiting a competing motor response. However, in Huntington's disease we demonstrate for the first time that inhibitory control declines in more advanced‐disease stages. This suggests that ocular motility may provide a sensitive marker of clinical disease progression in Huntington's disease. © 2011 Movement Disorder Society     

Plasma melatonin is reduced in Huntington's disease

This study was undertaken to determine whether the production of melatonin, a hormone regulating sleep in relation to the light/dark cycle, is altered in Huntington's disease. We analyzed the circadian rhythm of melatonin in a 24‐hour study of cohorts of control, premanifest, and stage II/III Huntington's disease subjects. The mean and acrophase melatonin concentrations were significantly reduced in stage II/III Huntington's disease subjects compared with controls. We also observed a nonsignificant trend toward reduced mean and acrophase melatonin in premanifest Huntington's disease subjects. Onset of melatonin rise was significantly more temporally spread in both premanifest and stage II/III Huntington's disease subjects compared with controls. A nonsignificant trend also was seen for reduced pulsatile secretion of melatonin. Melatonin concentrations are reduced in Huntington's disease. Altered melatonin patterns may provide an explanation for disrupted sleep and circadian behavior in Huntington's disease, and represent a biomarker for disease state. Melatonin therapy may help the sleep disorders seen in Huntington's disease. © 2014 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.     

Association of obsessive-compulsive disorder and pathological gambling with Huntington's disease in an Italian pedigree: possible association with Huntington's disease mutation

This paper describes a pedigree with Huntington's disease (HD), in which three cases of obsessive-compulsive disorder (OCD) and two cases of pathological gambling (PG) were identified. The mutation analysis of the HD gene was carried out in the examined individuals who were at risk for HD. In fact, OCD and PG only occurred in carriers of the HD expansion. The possible implications of this finding are discussed.     

The relationship between uric acid levels and Huntington's disease progression

Uric acid (UA) may be associated with the progression of Parkinson's disease and related neurodegenerative conditions; however, its association with Huntington's disease (HD) progression has not been explored. A secondary analysis of 347 subjects from the CARE‐HD clinical trial was performed to examine the relationship between baseline UA levels and the level of functional decline in HD. Outcomes included change in scores at 30 months for the Unified Huntington's Disease Rating Scale components. There was less worsening of total functional capacity over time with increasing baseline UA levels (adjusted mean worsening in scores: 3.17, 2.99, 2.95, 2.28, 2.21, from lowest to highest UA quintile, P = 0.03). These data suggest a possible association between higher UA levels and slower HD progression, particularly as measured by total functional capacity. If confirmed, UA could be an important predictor and potentially modifiable factor affecting the rate of HD progression. © 2009 Movement Disorder Society     

Autopsy case of concurrent Huntington's disease and neurofibromatosis type 1

We report here an autopsy case of concurrent Huntington's disease (HD) and neurofibromatosis type 1 (NF1), also known as von Recklinghausen's disease. The patient was a Japanese woman with a significant hereditary burden: seven of her family members within four generations were affected by either NF1 or concurrent HD and NF1. She was diagnosed as having NF1 at age 24. At age 40, she showed signs of irritability, aggressive and childish behaviour, which became progressively worse. At age 48, rigidity and spastic gait were observed. One year later, choreoathetoid involuntary movements became apparent. Diagnosis of HD was made by identification of the abnormally expanded cytosine‐adenine‐guanine repeats in the Huntington's disease gene. Her condition deteriorated gradually to an apallic state and she died at age 60. Post‐mortem examination revealed extensive brain atrophy, which was particularly severe in the frontal and temporal cortices and the striatum. The degree of neurodegenerative change seemed to correspond to grade IV. Polyglutamine positive inclusions were seen frequently in all layers of the cerebral cortex and in the amygdala and hippocampus. Inclusions were also present in the striatum, but there were fewer than in the cortex. Remarkably, neuronal intranuclear inclusions were present in the cerebellum, although they are usually not seen in HD. Features associated with the central nervous system involvement of NF1 were not found in the brain, but HD pathology might have been accelerated by the concurrence of NF1. This is the third report of a case with concurrent HD and NF1 in the world, and the first study in which occurrence of polyglutamine inclusions was confirmed on post‐mortem examination.     

Falls and gait disturbances in Huntington's disease

Falls are common in patients with Huntington's disease, but the incidence, falling circumstances and contributing factors have never been examined. We recorded falls in 45 early to midstage Huntington's disease patients, both retrospectively (12 months) and prospectively (3 months). Fall rates were related to relevant baseline measures, including the Unified Huntington's Disease Rating Scale (UHDRS) and quantitative measures of balance (using angular velocity sensors) and gait (using a pressure‐sensitive walkway). Balance and gait measures were compared between patients and 27 healthy age‐matched controls. Twenty‐seven patients (60%) reported two or more falls in the previous year and were classified as fallers. During prospective follow‐up 40% reported at least one fall. A high proportion of falls (72.5%) caused minor injuries. Compared to nonfallers, fallers showed significantly higher scores for chorea, bradykinesia and aggression, as well as lower cognitive scores. Compared to controls, Huntington patients had a decreased gait velocity (1.15 m/s versus 1.45 m/s, P < 0.001) and a decreased stride length (1.29 m versus 1.52 m, P < 0.001). These abnormalities were all significantly greater in fallers compared to nonfallers. In addition, fallers had an increased stride length variability and a significantly greater trunk sway in medio‐lateral direction compared to nonfallers. We conclude that falls are common in Huntington's disease. Contributing factors include a combination of “motor” deficits (mainly gait bradykinesia, stride variability and chorea, leading to excessive trunk sway), as well as cognitive decline and perhaps behavioral changes. These factors should be considered as future targets for therapies that aim to reduce falls in Huntington's disease. © 2008 Movement Disorder Society     

Basal ganglia atrophy in prodromal Huntington's disease is detectable over one year using automated segmentation

Future clinical trials of neuroprotection in prodromal Huntington's (known as preHD) will require sensitive in vivo imaging biomarkers to track disease progression over the shortest period. Since basal ganglia atrophy is the most prominent structural characteristic of Huntington's pathology, systematic assessment of longitudinal subcortical atrophy holds great potential for future biomarker development. We studied 36 preHD and 22 age-matched controls using a novel method to quantify regional change from T(1) -weighted structural images acquired 1 year apart. We assessed cross-sectional volume differences and longitudinal volumetric change in 7 subcortical structures-the accumbens, amygdala, caudate, hippocampus, pallidum, putamen, and thalamus. At baseline, accumbens, caudate, pallidum, and putamen volumes were reduced in preHD versus controls (all P < .01). Longitudinally, atrophy was greater in preHD than controls in the caudate, pallidum, and putamen (all P < .01). Each structure showed a large between-group effect size, especially the pallidum where Cohen's d was 1.21. Using pallidal atrophy as a biomarker, we estimate that a hypothetical 1-year neuroprotection study would require only 35 preHD per arm to detect a 50% slowing in atrophy and only 138 preHD per arm to detect a 25% slowing in atrophy. The effect sizes calculated for preHD basal ganglia atrophy over 1 year are some of the largest reported to date. Consequently, this translates to strikingly small sample size estimates that will greatly facilitate any future neuroprotection study. This underscores the utility of this automatic image segmentation and longitudinal nonlinear registration method for upcoming studies of preHD and other neurodegenerative disorders.