Huntington's disease

Huntington's disease (HD) is an autosomal dominant progressive neuropsychiatric disorder, characterized by abnormalities of movement, emotion and cognition. The most important pathological feature is selective neuronal loss, primarily in the striatum and cerebral cortex. HD is caused by the expansion of a CAG trinucleotide repeat in the gene encoding huntingtin. The expanded repeat encodes an abnormally long polyglutamine tract, and many lines of evidence now strongly suggest that this mutation is neurotoxic. In this review, we first detail the clinical, genetic and pathological features of HD. We then describe how clues from neurotoxicological, biochemical, cell, transgenic mouse, and invertebrate models of HD lead to a multifactored model of HD pathogenesis. We conclude by discussing how the model of HD serves as a guide to the development of rational therapeutics for this devastating disease.     

Crime in Huntington's disease

OBJECTIVES—To clarify the clinical and neuropsychological aspects of transient epileptic amnesia (TEA) based on 10 personally studied cases as well as review of 21 previously published cases; and to propose tentative diagnostic criteria for the diagnosis of TEA.
METHODS—All 10 patients and informants underwent a standardised clinical interview. The radiological and neurophysiological (EEG) data were also reviewed in all cases. The diagnosis of transient epileptic amnesia was made on the basis of the following criteria: (1) there was a history of recurrent witnessed episodes of transient amnesia; (2) cognitive functions other than memory were judged to be intact during typical episodes by a reliable witness; (3) there was evidence for a diagnosis of epilepsy. This evidence was provided by either (a) wake or sleep EEG, or (b) the co-occurrence of other seizure types (if their roughly concurrent onset or close association with episodes of transient amnesia suggested a connection), or (c) a clear cut response to anticonvulsant therapy, or by a combination of these three factors. In addition all patients were administered a comprehensive neuropsychological test battery designed to assess verbal and non-verbal anterograde memory and retrograde memory for famous personalities and personal events. Their results were compared with those of 25 age and IQ matched normal controls.
RESULTS—TEA usually begins in later life, with a mean age of 65 years in this series. Episodes are typically brief, lasting less than one hour, and recurrent, with a mean frequency of three a year. Attacks on waking are characteristic. Repetitive questioning occurs commonly during attacks. The anterograde amnesia during episodes is, however, often incomplete so that patients may later be able to "remember not being able to remember". The extent of the retrograde amnesia during attacks varies from days to years. Most patients experience other seizure types compatible with an origin in the temporal lobes, but transient amnesia is the only manifestation of epilepsy in about one third of patients. Epileptiform abnormalities arising from the temporal lobes are most often detected on interictal sleep EEG. Despite normal performance on tests of anterograde memory, many patients complain of persistent interictal disturbance of autobiographical memory, involving a significant but variable loss of recall for salient personal episodes. The epochs affected may predate the onset of epilepsy by many years.
CONCLUSIONS—TEA is an identifiable syndrome and comprises episodic transient amnesia with an epileptic basis, without impairment of other aspects of cognitive function. Future studies should consider the question of whether TEA reflects ictal activity or a postictal state, and the mechanism of the persistent autobiographical amnesia. It is hypothesised that the latter may result in part from impairment of very long term memory consolidation as a result of epileptic activity in mesial temporal structures.

     

Olanzapine in Huntington's disease

OBJECTIVES: To study the effect of olanzapine (OL) in Huntington's disease (HD) patients. DESIGN AND METHODS: Eleven HD patients (five men), aged 47.6 +/- 11.4 years and with disease duration of 11.2 +/- 3.3 years received OL. Assessment was carried out using the Clinical Global Impression of Change Scale (CGIC) and the Unified Huntington's Disease Rating Scale behavioral (UHDRS - b) and motor (UHDRS - m) at 6 month intervals. RESULTS: Nine patients were treated for 9.8 +/- 5.9 months. The mean OL dose/patient was 11.4 +/- 8.5 mg/day (median 10 mg/day). Mean CGIC was 2.1 +/- 0.8. UHDRS - b improved significantly (P < 0.0001) and UHDRS - m did not change. Chorea improved in five patients and two dropped out because of drug eruption and lack of efficacy. CONCLUSION: OL is a good alternative treatment in HD, mainly for the psychiatric symptoms and moderately effective for the motor symptoms, possibly because of its effect on chorea. We suggest OL should be used in HD patients with the adult onset form, severe chorea and/or severe psychiatric disturbances.     

Bradykinesia in Huntington's disease

Huntington's disease (HD) is characterized by the presence of hyperkinesias, but bradykinesia is also present in most patients. We studied the motor performance of 18 patients with genetically proven HD (age, 38.5 +/- 10 y; clinical stage, 1.7 +/- 1.7; (CAG) triplet length, 49.2 +/- 6.8 triplets; all but three patients were free from neuroleptics) and compared with a control group (n = 18) and with a typical Parkinson's disease (PD) group (n = 20). Motor study included the four timed tests commonly used for PD: Pronation-supination (PS), finger dexterity (FD), movement between two points (MTP) and walking test (WT). Tests were done at 9 AM. The PD group was studied in "off" condition, with no medication given for 12 hours. The HD group was slower than the controls on all tasks (all tests significant, p < 0.01, Mann-Whitney U test) and even slower than PD group (for FD, p < 0.05). A significant correlation was found between each test and clinical stage (for PS, r = 0.84; for FD, r = 0.75; for MTP, r = 087, and for WT, r = 0.77, Pearson). Severe bradykinesia was present in HD, and motor impairment is related to clinical stage.     

Dysphagia in Huntington's disease

Dysphagia is a common complication of Huntington's disease (HD) that is frequently responsible for the potentially lethal respiratory events of aspiration or asphyxiation. Twelve patients who had HD and a history of dysphagia underwent extensive multidisciplinary clinical examinations. All of the patients, regardless of the clinical severity of their disease, demonstrated impaired control of many voluntary aspects of food intake that affected swallowing efficiency. Abnormalities of the rate of food consumption, mastication, bolus transfer, respiration, and swallow initiation seem to be responsible for most dysphagic symptoms in HD. Less prominent abnormalities of the pharyngoesophageal phases of ingestion were also noted. Dysphagia therapy was initiated in 11 of 12 patients. All of the patients' conditions improved; a majority (8/11) of the patients returned to an unrestricted diet. This improvement persisted for as long as three years, while other clinical features of HD intensified.     

Alzheimer-type lesions in Huntington's disease

Summary. Cognitive changes in Huntington's disease (HD) are variously related to diffuse cortical atrophy with neuron loss and dystrophic neurites leading to disruption of striato-frontal or limbic circuitries, while recent studies suggest an increasing prevalence of Alzheimer-like lesions in HD brain. A comparative morphological study of 27 autopsy cases of HD (age 34 to 75 years) and of 26 age- and sex-matched non-demented controls was performed. Absence of Alzheimer-type lesions was seen in 33% of HD brains (mean age 49 years); 48% showed early non-neuritic tau pathology in limbic areas (Braak stages I and II) without amyloid deposits occurring as early as age 34 years (mean age 54 years), while Braak stages II and Ill with amyloid plaques were present in 19%, the youngest such HD patient being 42 years (mean age 54 years). In controls, similar tau pathology changes with later onset (age 45 years) and occurrence of amyloid plaques in 26% – all aged over 60 years – were observed. No probable or definite cases of Alzheimer disease (AD) according to CERAD criteria were seen in both cohorts. Those data confirm previous studies on the rare coexistence of HD and AD, although initial stages of Alzheimer-like lesions develop rather early in HD patients, but obviously show less rapid progress even in advanced age. The reasons for the early onset but mild progress of Alzheimer-like lesions in HD and their contribution to cognitive decline await further elucidation. Received January 13, 1998; accepted February 17, 1998     

Irritability in pre-clinical Huntington's disease

Irritability, together with depression and anxiety, form three salient clinical features of pre-symptomatic Huntington's disease (HD). To date, the understanding of irritability in HD suffers from a paucity of experimental data and is largely based on questionnaires or clinical anecdotes. Factor analysis suggests that irritability is related to impulsivity and aggression and is likely to engage the same neuronal circuits as these behaviours, including areas such as medial orbitofrontal cortex (OFC) and amygdala.16 pre-symptomatic gene carriers (PSCs) and 15 of their companions were asked to indicate the larger of two squares consecutively shown on a screen while undergoing functional magnetic resonance imaging (fMRI). Despite correct identification of the larger square, participants were often told that they or their partner had given the wrong answer. Size differences were subtle to make negative feedback credible but detectable.Although task performance, baseline irritability, and reported task-induced irritation were the same for both groups, fMRI revealed distinct neuronal processing in those who will later develop HD. In controls but not PSCs, task-induced irritation correlated positively with amygdala activation and negatively with OFC activation. Repetitive negative feedback induced greater amygdala activations in controls than PSCs. In addition, the inverse functional coupling between amygdala and OFC was significantly weaker in PSCs compared to controls.Our results argue that normal emotion processing circuits are disrupted in PSCs via attenuated modulation of emotional status by external or internal indicators. At later stages, this dysfunction may increase the risk for developing recognised, HD-associated, psychiatric symptoms such as irritability.     

Motor imagery in Huntington's disease

We investigated the role of the basal ganglia (BG) in motor imagery in patients with Huntington's disease (HD). A visually guided pointing task assessed whether patients could predict actual movement time (MT) through motor imagery. Executed and imagined movements were performed when vision was constrained centrally, or was free to move. Participants completed a series of imagined and actual movements, with and without central fixation, between two target circles. Patients with HD and controls' imagined MTs were significantly faster than their executed MTs. In compliance with Fitt's law, both actual and imagined MTs increased as a function of increasing task difficulty. We conclude that motor imagery is relatively preserved in HD.     

Ornithine aminotransferase in Huntington's disease

Ornithine aminotransferase (Orn-T) activities in Huntington's disease (HD) brains were found to be reduced, when compared to age-matched control brains, by 34–49% in the frontal cortex, parietal cortex, caudate nucleus and putamen. Such changes were not observed in senile dementia of Alzheimer type or schizophrenia. Alterations in choline acetyltransferase activities were consistent with previous findings for these disorders. If Orn-T is involved in the synthesis of neurotransmitter glutamate, the reported losses of Orn-T activity may reflect deterioration of the corticostriatal glutamatergic neurons in HD.     

Psychiatric syndromes in Huntington's disease

Thirty patients with Huntington's disease, a genetically transmitted neuropsychiatric disorder that can be diagnosed reliably, were evaluated systematically for psychopathology, followed for extended periods, and treated with psychopharmacological medications when necessary. DSM-III criteria were used for establishing syndromic diagnoses. Twenty-four individuals demonstrated substantial behavioral abnormalities, including affective and schizophrenic syndromes, changes of personality, and disorders that could not be classified adequately. Pharmacotherapy was modestly beneficial in some cases. Consideration of the array of behavioral disturbances encountered in this pathogenetically unified disorder suggests that a dimensional approach to symptom classification might prove more useful heuristically than present typological methods.     

Protein aggregates in Huntington's disease

Huntington's disease (HD) is an incurable neurodegenerative disease characterized by abnormal motor movements, personality changes, and early death. HD is caused by a mutation in the IT-15 gene that expands abnormally the number of CAG nucleotide repeats. As a result, the translated protein huntingtin contains disease-causing expansions of glutamines (polyQ) that make it prone to misfold and aggregate. While the gene and mutations that cause HD are known, the mechanisms underlying HD pathogenesis are not. Here we will review the state of knowledge of HD, focusing especially on a hallmark pathological feature-intracellular aggregates of mutant Htt called inclusion bodies (IBs). We will describe the role of IBs in the disease. We speculate that IB formation could be just one component of a broader coping response triggered by misfolded Htt whose efficacy may depend on the extent to which it clears toxic forms of mutant Htt. We will describe how IB formation might be regulated and which factors could determine different coping responses in different subsets of neurons. A differential regulation of IB formation as a function of the cellular context could, eventually, explain part of the neuronal vulnerability observed in HD.