Apraxia of eyelid closure in Huntington's disease

Summary. We report a patient with genetically confirmed Huntington's disease (HD) presenting apraxia of eyelid closure (AEC). She was unable to close her eyes at command but was able to blink. Chorea and AEC ameliorated significantly during treatment with olanzapine and riluzole, an inhibitor of glutamate release. AEC is reported in progressive supranuclear palsy, Creutzfeldt-Jakob's disease, amyotrophic lateral sclerosis, and as post-stroke AEC. No report on HD is available so far, although oculomotor disturbances are quite common in this disease. Received September 5, 2001; accepted December 5, 2001     

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.     

Expression of the receptor for advanced glycation end products in Huntington's disease caudate nucleus

The accumulation of amyloid-beta and increased expression of its receptor RAGE (the receptor for advanced glycation end products) have been implicated in the pathogenesis of Alzheimer's disease (AD). Here we have used immunohistochemistry and double labelling to localize RAGE expression in Huntington's disease (HD) caudate nucleus (CN). Results showed that RAGE is expressed in at least two cell types in the CN, medium spiny projection neurons and astrocytes, with stronger staining in astrocytes than in neurons. The percentage of the total number of neurons positive for RAGE was significantly higher in G2 and G3 HD CN when compared with controls. What is more interesting however was the heterogeneous distribution of RAGE staining in CN. In controls, astrocytic RAGE staining was seen only in the superficial layer of the subependymal layer (SEL). In G1 HD cases, staining was seen throughout the entire width of SEL but extended into the CN in G2, 3 and 4. Neuronal RAGE staining was stronger in the medial CN than in the lateral CN in control and G1 cases. In G2, 3 and 4 cases, this staining gradient was not observed; more neuronal RAGE staining was however seen in the dorsal part of the CN when compared with the ventral part. The distribution of RAGE staining in neurons appeared to correlate with the ordered cell death seen in HD CN. Identification of the ligand for RAGE in HD brain and further functional studies are needed to clarify the role of RAGE in the pathogenesis of HD.     

Functional imaging in Huntington's disease

Huntington's disease (HD) is a genetic brain disease characterized by loss of capacity in movement control, cognition, and emotional regulation over a period of about 30 years. Since it is well established that clinical impairments and brain atrophy can be detected decades prior to receiving a clinical diagnosis, functional neuroimaging efforts have gained momentum in HD research. In most brain disorders, there is accumulating evidence that the clinical manifestations of disease do not simply depend on the extent of tissue loss, but represent a complex balance among neuronal dysfunction, tissue repair, and circuitry reorganization. Based upon this premise, functional neuroimaging modalities may be more sensitive to the earliest changes in HD than are structural imaging approaches. For this review, PET and fMRI studies conducted in HD samples were summarized. Strengths and limitations of the utilization of functional imaging in HD are discussed and recommendations are offered to facilitate future research endeavors.     

Predictive testing for Huntington's disease

Worldwide, predictive testing for Huntington's disease has become an accepted clinical application that has allowed many individuals from HD-families to proceed with their life without the uncertainty of being at risk. International guidelines have extensively contributed to establishing counselling programmes of high quality, and have served as a model for other genetic disorders. Psychological follow-up studies have increased the insight into the far-reaching impact of test results for all individuals involved. Although the guidelines have served as a useful frame of reference, clinical experience has shown the importance of a case-by-case approach to do justice to the specific needs of the individual test candidate. Issues such as ambiguous test results, lack of awareness in a test candidate of early signs of the disease, non-compliance to the test protocol, or the test candidate's need for information on the relationship between age at onset and CAG-repeat require careful consideration. Receiving a test result is only one of the transition points in the life of an individual at risk; such result needs to be valued from a life-cycle perspective.     

Late stage care in Huntington's disease

Huntington's disease (HD) is a relentlessly progressive neurodegenerative disease, which is presently incurable. Despite the hope for future therapies that exists for the families, they meantime are aware that there is little that their clinicians can do to delay either onset or progression of the disease. There are unique issues to address in a disorder where patients are aware in advance that their ability to communicate, as well as their cognitive capacity, will become impaired. Most affected individuals have experience of the disease in its late stages because of their parent's and other family member's illness. Many have their own ideas and anxieties about how their own care ought to proceed. There are no published guidelines for management of this stage of disease, although all clinicians involved in the care of HD will have their own experiences to share. This paper describes one method for such management, which includes discussion about placement for care advance directives for feeding and treatment.     

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.     

Genetic criteria for Huntington's disease pathogenesis

Genetic analysis aims to identify the variations in DNA sequence whose functional consequences produce heritable variations in phenotype. In one of the first successes of unbiased molecular genetic analysis in human disease, the Huntington's disease (HD) gene was mapped and cloned without any prior knowledge of the nature of its protein product or of the molecular defect that underlies the characteristic phenotype of the disorder. However, while the cloning of HD and recognition of its trinucleotide repeat expansion spawned a plethora of approaches to investigating HD through its distinctive neuropathology, the role for genetic strategies in HD research did not end there. The use of genetic analysis has remained a critical tool for defining the characteristics of the mechanism that triggers the pathogenic process, permitting the investigation of early events that occur long before traditionally recognized pathology. Delineation of these events can reveal molecular targets for development of therapies that prevent onset of HD. Most recently, an extension of genetic analysis to the identification of non-linked genetic variations that alter the course of HD pathogenesis has offered the promise of identifying modifier genes to reveal biological pathways active throughout the disease process and to provide valid targets for pharmacological intervention. Thus, unbiased genetic strategies have not only provided a crucial entrée into molecular investigation of HD via a root cause that was previously unsuspected, they also represent a continuing route to accelerate the ultimate goal of developing an effective treatment for HD.     

Long-term effect of a single dose of flunarizine in Huntington's disease

We report a preliminary pilot study on the clinical efficacy of flunarizine (FNZ), a calcium-entry blocker that causes extrapyramidal side-effects, in 10 patients with Huntington's disease (HD). FNZ (20 mg) administered by the sublingual route resulted in a decrease in choreic movements and improved dexterity in performing several tests. These effects lasted for at least 7 days after a single dose. Therefore, FNZ seems to exert the same effect as a long-acting neuroleptic agent in our HD patients.     

Changes in nocturnal sleep in Huntington's and Parkinson's disease

Summary There have been no reports of studies on nocturnal sleep or quantitative studies of sleep spindle density in Huntington's disease, whereas sleep in Parkinson's disease has been extensively reported. We therefore examined nocturnal sleep changes in patients with Parkinson's and Huntington's disease and compared them with a control group. The previously reported decrease in sleep spindle density was observed in patients with Parkinson's disease. The patients with Huntington's disease, however, had a significant increase in sleep spindle density, the nocturnal sleep pattern being normal in other respects when compared with the control group. This observation may provide a further diagnostic criterion in Huntington's disease.     

Imaging microglial activation in Huntington's disease

Activated microglia have been proposed to play a major role in the pathogenesis of Huntington's Disease (HD). PK11195 is a ligand which binds selectively to peripheral benzodiazepine binding sites, a type of receptor selectively expressed by activated microglia in the central nervous system. Using (11)C-(R)-PK11195 positron emission tomography (PET), we have recently shown in vivo evidence of increased microglial activation in both symptomatic and presymptomatic HD gene carriers and that the degree of microglial activation in the striatum correlates with the severity of striatal dopamine D2 receptor dysfunction measured with (11)C-raclopride PET. Our findings indicate that microglial activation is an early process in the HD pathology, occurring before the onset of symptoms. The close spatial and temporal relationship between microglial activation and neuronal dysfunction lends further support to the pathogenic link between the two processes in HD. Further longitudinal studies are needed to fully elucidate this link.     

Electrophysiological measures as potential biomarkers in Huntington's disease: Review and future directions

Neuroimaging is fundamental to identifying quantifiable and objective biomarkers in symptomatic and pre-diagnostic Huntington's disease (HD). However, the challenge remains to find reliable biomarkers with high sensitivity and specificity that can be used to track the functional decline over time and test efficacy of therapeutic intervention. While many recent studies have focused on neuroimaging techniques based on brain hemodynamic activity, comparatively fewer have utilized electroencephalography (EEG) and event-related potentials (ERPs). This review aims to summarise and integrate key electroencephalographical findings from the last two decades in symptomatic and pre-diagnostic HD, in context with recent neuroimaging data, and to use this information to identify promising candidate markers for future research and clinical consideration.     

Fas and Fas-L expression in Huntington's disease and Parkinson's disease

The Fas/Fas-L signalling system plays a role in the control of cell death and the survival of lymphocytes, in the regulation of the immune system, and in the progression of autoimmune diseases. Studies in the nervous system have shown Fas/Fas-L activation in multiple sclerosis and in various paradigms leading to neuronal death. Enhanced Fas and Fas-L expression has also been documented in astrocytomas and glioma cell lines. However, little is known about the possible implication of Fas/Fas-L signals in primary human neurodegenerative diseases. In an attempt to gain understanding of the mechanisms commanding cell death and neurone loss in Huntington's disease (HD) and Parkinson's disease (PD), Fas and Fas-L expression has been examined in the brains of patients with HD and PD with Western blotting and immunohistochemistry. Fas and Fas-L expression levels are reduced in the caudate and putamen, but not in the parietal cortex, in HD, as revealed in Western blots. Moreover, Fas and Fas-L immunoreactivity is reduced in striatal neurones in HD. Fas and Fas-L immunoreactivity is also decreased in neurones of the substantia nigra pars compacta in PD. Reduced Fas and Fas-L expression is observed equally in Lewy body-bearing and non-Lewy body-bearing neurones. Yet increased Fas and Fas-L immunoreactivity occurs in normal astrocytes in control brains and in reactive astrocytes in diseased brains. The meaning of increased Fas and Fas-L expression in astrocytes is still unclear. However, the present results suggest that Fas/Fas-L signals are minimized in sensitive neurones in HD and PD.     

High suicidal ideation in persons testing for Huntington's disease

This study examined the first participants who registered for the Huntington's disease predictive testing program 1990-1995 in Stockholm, Sweden. A psychosocial investigation was performed to evaluate potential effects of the presymptomatic testing. The results showed no significant differences between 13 gene carriers and 21 noncarriers in pretest attitudes, expectations, general well-being, life satisfaction and lifestyle, the need for support, estimated sense of wellbeing or degree of health. However, both groups showed high suicidal ideation and self-injurious behavior. Noncarriers had a very high frequency of attempted suicide, and both groups had similarly pronounced psychiatric dysfunction. Their relatives also had high frequencies of psychiatric diseases, suicide or suicidal attempts. Most of the participants had a desire to meet a psychologist or a social worker. The need for counseling, using a well designed protocol, and the importance of focusing on suicide risk of participants in predictive testing programs is emphasized.     

Brain muscarinic cholinergic receptors in Huntington's disease

Summary Muscarinic cholinergic receptors and choline acetyltransferase (ChAT) activity were studied in postmortem brain tissue from patients with Huntington's disease and matched control subjects. In comparison with controls, reductions in ChAT activity were found in the hippocampus, but not in the temporal cortex in Huntington's disease. Patients with Huntington's disease showed reduced densities of the total number of muscarinic receptors and of M-2 receptors in the hippocampus while the density of M-1 receptors was unaltered. Muscarinic receptor binding was unchanged in the temporal cortex. These results indicate a degeneration in Huntington's disease of the septo-hippocampul cholinergic pathway, but no impairment of the innominato-cortical cholinergic system.     

Ideomotor limb apraxia in Huntington's disease

Introduction Ideomotor limb apraxia is the disturbance of planning and of execution of motor activity,which is not caused by a dysfunction of the motor or sensory nervous system. Apraxia is a diagnostic criterion in dementialike Alzheimer's disease. However, this symptom may also occur in dementia with subcortical lesions like Huntington's disease (HD), a hereditary, devastating neurodegenerative disease leading to neurological and psychiatric dysfunction. The aim of our study is to determine the correlation between the occurrence of ideomotor limb apraxia and neuropsychological deficits in HD. Methods To assess the correlation between apraxia and neuropsychological abilities in HD, 41 patients with HD and 33 age- and sex-matched controls were examined. The De Renzi test for apraxia and an apraxia test battery containing tests of i) imitation of meaningless gestures of hands, ii) imitation of meaningless gestures of fingers, iii) performance of meaningful gestures on demand, and iv) pantomime of tool use were used to assess apraxia. Moreover, neuropsychological function was rated by the Mini Mental State Examination (MMSE), the Rey Complex Figure Memory Test, the Trail Making Test A and B, the California Verbal Learning Test (German version), the Stroop Color and Word Test, the Controlled Oral Word Association Test, and the Mehrfachwahl- Wortschatz-Intelligenztest for measuring verbal intelligence. Motor function was assessed in all HD patients by the Unified HD Rating Scale (UHDRS), rating oculomotor and orolingual function, fine motor tasks, parkinsonism, dystonia, chorea and statics and gait. Results Apraxic HD patients showed worse results than non-apraxic HD patients in three items of the Rey Complex Figure Memory Test (Organisation, short-term and longterm memory), but not in other assessed neuropsychological tests. In assessment of meaningful gestures on demand 39.3% of HD patients were apraxic, in assessment of pantomime of tool use 67.9% of HD patients showed apraxia. Patients with HD showed highly significant worse results than controls in the De Renzi test, in hands' and fingers' imitation, in performance of gestures on demand, in pantomime of tool use and every neuropsychological test except for the test measuring verbal intelligence. Apraxic HD patients showed worse results than non-apraxic HD patients in the UHDRS total motor score and the score for oculomotor function. Conclusion This is the largest study on apraxia in HD. Ideomotor limb apraxia is a common sign in HD patients, occurring in a high percentage. In contrast to the opinion of several authors, occurrence of apraxia in HD is independent from neuropsychological decline and the severity of most neurological symptoms.     

Synaptophysin expression in the striatum in Huntington's disease

Summary This immunohistochemical study compares the expression of synaptophysin (SYP) in the striatum in Huntington's disease (HD) with that of calcineurin (CaN), a marker for striatal medium-sized spinous neurons. As compared to controls, in the HD striatum there was a significant loss of SYP immunoreactivity with residual staining displaying an inhomogeneous pattern, which strikingly resembled that of CaN. Our results may indicate that there is a synaptic loss in the striatum with HD and this is most likely due to loss of medium-sized spinous neurons characteristic of this disease.