Altered frontostriatal coupling in pre‐manifest Huntington’s disease: effects of increasing cognitive load

Background and purpose: Functional neuroimaging studies have suggested a dysfunction of prefrontal regions in clinically pre‐symptomatic individuals with the Huntington’s disease (HD) gene mutation (pre‐HD) during cognitive processing. The objective of this study was to test the impact of cognitive demand on prefrontal connectivity in pre‐HD individuals. Methods: Sixteen healthy controls and sixteen pre‐HD subjects were studied using functional MRI and a verbal working memory task with increasing cognitive load. Load‐dependent functional connectivity of the left dorsolateral prefrontal cortex (DLPFC) was investigated by means of psychophysiological interactions. Results: In pre‐HD subjects, aberrant functional connectivity of the left DLPFC was found at high working memory load levels only. Compared with healthy controls, pre‐HD individuals exhibited lower connectivity strength in the left putamen, the right anterior cingulate and the left medial prefrontal cortex. Pre‐HD individuals close to the onset of motor symptoms additionally exhibited lower connectivity strength in the right putamen and the left superior frontal cortex. The connectivity strength in the left putamen was associated with several clinical measures including CAG repeat length, Unified Huntington's Disease Rating Scale motor score and predicted years to manifest symptom onset. Conclusion: These findings suggest that early prefrontal connectivity abnormalities in pre‐HD individuals are modulated by cognitive demand.     

Verbal episodic memory declines prior to diagnosis in Huntington's disease

Previous studies of verbal episodic memory in pre-diagnostic Huntington's disease (HD) have yielded mixed results; some evidence suggests that memory decline is evident prior to the onset of pronounced neurological signs of HD, whereas other data indicate that memory function remains normal throughout the pre-diagnostic period. This study examines verbal episodic memory in a sample of CAG expanded individuals who have not yet been clinically diagnosed, and who represent a wide range of points along the continuum from health to disease. The Hopkins Verbal Learning Test-Revised (HVLT-R) was administered to 479 participants (428 with the HD CAG expansion and 51 without), and performance was compared to neurobiological indices of disease progression, including a DNA-based estimate of proximity to clinical diagnosis, magnetic resonance imaging (MRI) measures of striatal volume, and neurologist ratings of motor signs. Lower HVLT-R scores were associated with closer proximity to clinical diagnosis and smaller striatal volumes; these relationships were found even in groups with no neurological signs of HD. The CAG expanded groups, including those with only minimal neurological signs, had significantly lower HVLT-R scores than the control group, and performance was worse in sub-groups that had more neurological signs consistent with HD. These findings indicate that verbal episodic memory is affected in early pre-diagnostic HD and may decline as striatal volumes decrease and individuals approach the motor diagnostic threshold.     

Natural variation in sensory‐motor white matter organization influences manifestations of Huntington's disease

While the HTT CAG‐repeat expansion mutation causing Huntington's disease (HD) is highly correlated with the rate of pathogenesis leading to disease onset, considerable variance in age‐at‐onset remains unexplained. Therefore, other factors must influence the pathogenic process. We asked whether these factors were related to natural biological variation in the sensory‐motor system. In 243 participants (96 premanifest and 35 manifest HD; 112 controls), sensory‐motor structural MRI, tractography, resting‐state fMRI, electrophysiology (including SEP amplitudes), motor score ratings, and grip force as sensory‐motor performance were measured. Following individual modality analyses, we used principal component analysis (PCA) to identify patterns associated with sensory‐motor performance, and manifest versus premanifest HD discrimination. We did not detect longitudinal differences over 12 months. PCA showed a pattern of loss of caudate, grey and white matter volume, cortical thickness in premotor and sensory cortex, and disturbed diffusivity in sensory‐motor white matter tracts that was connected to CAG repeat length. Two further major principal components appeared in controls and HD individuals indicating that they represent natural biological variation unconnected to the HD mutation. One of these components did not influence HD while the other non‐CAG‐driven component of axial versus radial diffusivity contrast in white matter tracts were associated with sensory‐motor performance and manifest HD. The first component reflects the expected CAG expansion effects on HD pathogenesis. One non‐CAG‐driven component reveals an independent influence on pathogenesis of biological variation in white matter tracts and merits further investigation to delineate the underlying mechanism and the potential it offers for disease modification. Hum Brain Mapp 37:4615–4628, 2016. © 2016 Wiley Periodicals, Inc.     

Psychomotor, executive, and memory function in preclinical Huntington's disease

The earliest changes in the development of Huntington's disease (HD) remain controversial. Studies of cognitive function in preclinical individuals who have the HD mutation have yielded contradictory results. This study compared cognitive and motor performance in 51 people with the HD mutation who had no clinical signs of HD, 85 at-risk individuals without the HD mutation and 43 individuals in the early stages of HD. Whereas highly significant differences were detected between the preclinical and early-HD groups, only subtle impairments were present in at-risk individuals with the HD mutation compared to those with normal HD alleles, principally for low-demand psychomotor tasks. Complementing these observations, longitudinal investigation showed that performance on psychomotor tasks in people with the mutation who were close to clinical onset of HD was intermediate between that of individuals many years from onset and those in the early stages of HD, suggesting a slowly insidious evolution of deficit. In contrast, memory performance showed a more precipitous decline around the time of clinical onset of HD. The findings, which suggest that HD patients' functional deficits do not evolve uniformly, help to resolve some of the disparities in the literature on preclinical HD.     

Longitudinal cognitive and motor changes among presymptomatic Huntington disease gene carriers.

OBJECTIVE: To determine whether longitudinal changes in cognitive and motor function can be detected among clinically presymptomatic individuals carrying the Huntington disease (HD) allele. DESIGN: A longitudinal, case-control, double-blind study comparing presymptomatic gene carriers and non-gene carriers at risk for HD examined an average of 3.7 years apart. SETTING: The Department of Medical and Molecular Genetics at a general clinic research center in Indianapolis, Ind. PARTICIPANTS: A sample of 43 at-risk individuals consisting of presymptomatic gene carriers (n = 12) and non-gene carriers (n = 31). MEASURES: Huntington disease gene status was determined by molecular testing of the HD gene. Subscales from the Wechsler Adult Intelligence Scale-Revised and a quantified neurologic rating scale were administered. RESULTS: Scores on the digit symbol subscale of the Wechsler Adult Intelligence Scale-Revised (P<.05) and 2 neurologic variables-optokinetic nystagmus (P<.01) and rapid alternating movements (P<.005)-declined more rapidly among presymptomatic gene carriers than among non-gene carriers. At follow-up examination, compared with nongene carriers, presymptomatic gene carriers had significantly lower scores on the digit symbol subscale (P = .02) and for 4 neurologic variables-rapid alternating movements (P<.005), optokinetic nystagmus (P<.001), overall ocular movements (P<.02), and chorea of the trunk (P<.02). CONCLUSIONS: Psychomotor speed, optokinetic nystagmus, and rapid alternating movements demonstrated significant decline early in the pathological process of HD. These results suggest that subtle worsening of psychomotor, oculomotor, and motor functions occurs before the onset of signs sufficient to make a clinical diagnosis in individuals who have inherited the HD allele.     

A four-year prospective study of cognitive functioning in Huntington's disease.

The contribution of neurologic, genetic, and demographic variables to decline in cognition was examined in 70 early- to mid-stage patients with Huntington's disease (HD) using random effects modeling. Study participants were followed prospectively at baseline and at four annual reevaluations. Only modest decline was noted on most neuropsychological variables. Neurologic dysfunction, assessed using the Quantified Neurologic Examination (QNE), proved to be the strongest predictor of cognitive decline. While significantly predictive of more rapid decline in neurologic functioning, CAG repeat length was not generally related to cognitive decline after adjusting for QNE, with the exception of performance on a single test of visual scanning and psychomotor speed (i.e., Trail Making Test, Part A). We propose that CAG repeat length is more closely linked with changes in basal ganglia that predominate in early- to mid-stage HD than with cortical degeneration seen later in disease progression. Such a relationship would explain the predictive value that CAG repeat length plays in changes associated with automatic motor response programs (e.g., QNE and Trail Making Test, Part A) but not in dysfunction on tasks requiring higher-order processing.     

Cognitive changes in asymptomatic carriers of the Huntington disease mutation gene

Huntington disease (HD) is a neurodegenerative disorder due to an excessive number of CAG repeats in the IT15 gene on chromosome 4. Studies of cognitive function in asymptomatic gene carriers have yielded contradictory results. This study compared cognitive performance in 44 subjects with the HD mutation (group of carriers) who had no clinical signs of HD and 39 at-risk individuals without HD mutation (group of non-carriers). Neuropsychological evaluation focused on global cognitive efficiency, psychomotor speed, attentional, executive and memory functions. Significant differences, with lower performances in the group of gene carriers, were detected for some measures of psychomotor speed, attention and executive functioning (all P  < 0.01). More differences between groups were observed for memory measures, in particular on the California Verbal Memory Test. Complementing these observations, cognitive scores were correlated with age in the group of gene carriers, but not in the group of non-carriers. This suggests that the cognitive changes precede the appearance of the motor and psychiatric symptoms in HD and that tests proved to be sensitive to early HD deficiencies are better suited than global cognitive efficiency scales to observe them.     

DNA testing for Huntington disease in the Turkish population

Huntington disease (HD) is an autosomal dominant inherited disease, characterized by involuntary movements, behavioral and personality changes and dementia. Although the mean age at onset is about 40 years, onset varies from 5 to 79 years. Therefore, at-risk individuals are never sure to have escaped the disease. The genetic defect is a CAG trinucleotide repeat expansion at the 5' end of the IT-15 gene on chromosome 4. In this study, we analyzed 127 patients with HD and 122 healthy controls. The numbers of CAG repeats varied from 38 to 78 (median: 42) in 127 HD patients, while in healthy controls we observed only 10-35 CAG repeats (median: 18). The length of the CAG repeat expansion in Turkish HD patients and normal controls was similar to that reported from other populations. Negative correlations (r = -0.67) were also found between age of disease onset and repeat length.     

青少年型亨廷顿病10例临床表型及基因突变分析

目的总结青少年型亨廷顿病患者临床表型及IT15基因胞嘧啶-腺嘌呤-鸟嘌呤(CAG)重复突变特点。方法采用聚合酶链反应结合荧光标记毛细管电泳片段分析方法,对159个亨廷顿病家系272名成员进行IT15基因CAG重复序列检测,并对其中10例青少年期发病患者的临床表现、影像学特征以及临床表型与基因型相关性进行分析。结果经基因检测共发现211例携带异常扩展的IT15基因CAG重复序列,其中10例为青少年型亨廷顿病患者,临床表现各异,主要以不自主运动和认知功能障碍为主;发病年龄平均(12.50±4.55)岁,IT15基因CAG重复序列平均(63.70±14.83)个,Pearson相关分析显示,二者呈负相关关系(r=-0.865,P=0.001)。结论青少年型亨廷顿病与成年型亨廷顿病患者临床表现不同,前者主要表现为认知功能障碍;对于无明确家族史、临床表现疑似亨廷顿病的患者,基因检测是明确诊断的依据;亨廷顿病发病年龄与IT15基因CAG重复次数呈负相关,但不能完全解释发病年龄的变异性,尤以青少年型亨廷顿病患者显著,可能存在其他遗传调节因素。     

Large‐scale brain network abnormalities in Huntington's disease revealed by structural covariance

Huntington's disease (HD) is a progressive neurodegenerative disorder that can be diagnosed with certainty decades before symptom onset. Studies using structural MRI have identified grey matter (GM) loss predominantly in the striatum, but also involving various cortical areas. So far, voxel‐based morphometric studies have examined each brain region in isolation and are thus unable to assess the changes in the interrelation of brain regions. Here, we examined the structural covariance in GM volumes in pre‐specified motor, working memory, cognitive flexibility, and social‐affective networks in 99 patients with manifest HD (mHD), 106 presymptomatic gene mutation carriers (pre‐HD), and 108 healthy controls (HC). After correction for global differences in brain volume, we found that increased GM volume in one region was associated with increased GM volume in another. When statistically comparing the groups, no differences between HC and pre‐HD were observed, but increased positive correlations were evident for mHD, relative to pre‐HD and HC. These findings could be explained by a HD‐related neuronal loss heterogeneously affecting the examined network at the pre‐HD stage, which starts to dominate structural covariance globally at the manifest stage. Follow‐up analyses identified structural connections between frontoparietal motor regions to be linearly modified by disease burden score (DBS). Moderator effects of disease load burden became significant at a DBS level typically associated with the onset of unequivocal HD motor signs. Together with existing findings from functional connectivity analyses, our data indicates a critical role of these frontoparietal regions for the onset of HD motor signs. Hum Brain Mapp 37:67–80, 2016. © 2015 Wiley Periodicals, Inc.     

Molecular diagnosis of Huntington disease in Brazilian patients

Huntington disease (HD) is a progressive neurodegenerative disorder with autosomal dominant inheritance, characterized by choreiform movements and cognitive impairment. Onset of symptoms is around 40 years of age and progression to death occurs in approximately 10 to 15 years from the time of disease onset. HD is associated with an unstable CAG repeat expansion at the 5' and of the IT15 gene. We have genotyped the CAG repeat in the IT15 gene in 44 Brazilian individuals (42 patients and 2 unaffected family members) belonging to 34 unrelated families thought to segregate HD. We found one expanded CAG allele in 32 individuals (76%) belonging to 25 unrelated families. In these HD patients, expanded alleles varied from 43 to 73 CAG units and normal alleles varied from 18 to 26 CAGs. A significant negative correlation between age at onset of symptoms and size of the expanded CAG allele was found (r=0.6; p=0.0001); however, the size of the expanded CAG repeat could explain only about 40% of the variability in age at onset (r2=0.4). In addition, we genotyped 25 unrelated control individuals (total of 50 alleles) and found normal CAG repeats varying from 16 to 33 units. The percentage of heterozigocity of the normal allele in the control population was 88%. In conclusion, our results showed that not all patients with the "HD" phenotype carried the expansion at the IT15 gene. Furthermore, molecular diagnosis was possible in all individuals, since no alleles of intermediate size were found. Therefore, molecular confirmation of the clinical diagnosis in HD should be sought in all suspected patients, making it possible for adequate genetic counseling.     

Evidence of thalamic dysfunction in Huntington disease by proton magnetic resonance spectroscopy.

Our objective was to investigate thalamic neuronal dysfunction in patients with Huntington disease (HD). We performed localized single-voxel proton magnetic resonance spectroscopy (MRS) of the thalamus in 22 HD patients and 25 healthy individuals. The mean age of patients was 48.5 years (ranging from 32 to 71 years). Age at onset varied between 20 and 66 years (mean 38.9 years). The expanded CAG repeat ranged from 40 to 52 (mean 45.2) CAGs. The mean age of control group was 35.4 years, ranging from 19 to 67 years. N-acetylaspartate (NAA) relative to creatine (NAA/Cr) values in the thalamus of HD patients were decreased when compared with controls (P = 0.0001). The spectroscopic findings were not correlated with motor impairment. However, there was a positive correlation between duration of disease and motor impairment (P = 0.02, r = 0.48), and a tendency for positive correlation between duration of disease and NAA/Cr (P = 0.059, r = 0.4). We found decreased NAA/Cr values in the thalamus of patients with HD, indicating neuronal loss or dysfunction. This is in agreement with previous studies that indicated the involvement of mitochondrial dysfunction in the neurodegenerative process of HD.     

Tongue force analysis assesses motor phenotype in premanifest and symptomatic Huntington's disease

Motor symptoms in Huntington's Disease (HD) are commonly assessed by the Unified Huntington's Disease Rating Scale‐Total Motor Score (UHDRS‐TMS). However, the UHDRS‐TMS is limited by interrater variability, its categorical nature, and insensitivity in premanifest subjects. More objective and quantitative measures of motor phenotype may complement the use of the UHDRS‐TMS as outcome measure and increase the power and sensitivity of clinical trials. Deficits in tongue protrusion are well acknowledged in HD and constitute a subitem of the UHDRS‐TMS. We, therefore, investigated whether objective and quantitative assessment of tongue protrusion forces (TPF) provides measures that (1) correlate to the severity of motor phenotype detected in the UHDRS‐TMS in symptomatic HD, (2) detect a motor phenotype in premanifest HD gene‐carriers, and (3) exhibit a correlation to the genotype as assessed by a disease burden score (based on CAG‐repeat length and age). Using a precalibrated force transducer, the ability of premanifest gene carriers (n = 15) and subjects with symptomatic HD (n = 20) to generate and maintain isometric TPF at three target force levels (0.25, 0.5, and 1.0 N) was assessed and compared with age‐matched controls (n = 20) in a cross‐sectional study. Measures of variability of TPF and tongue contact time distinguished controls, premanifest, and symptomatic HD groups and correlated to the UHDRS‐TMS and disease burden score, suggesting a strong genotype‐phenotype correlation. Group distinction was most reliable at the lowest target force level. We conclude that assessment of TPF may be a useful objective and quantitative marker of motor dysfunction in premanifest and symptomatic HD. © 2010 Movement Disorder Society     

Psychomotor,Executive, and Memory Function in Preclinical Huntington's Disease

The earliest changes in the development of Huntington's disease (HD) remain controversial. Studies of cognitive function in preclinical individuals who have the HD mutation have yielded contradictory results. This study compared cognitive and motor performance in 51 people with the HD mutation who had no clinical signs of HD, 85 at-risk individuals without the HD mutation and 43 individuals in the early stages of HD. Whereas highly significant differences were detected between the preclinical and early-HD groups, only subtle impairments were present in at-risk individuals with the HD mutation compared to those with normal HD alleles, principally for low-demand psychomotor tasks. Complementing these observations, longitudinal investigation showed that performance on psychomotor tasks in people with the mutation who were close to clinical onset of HD was intermediate between that of individuals many years from onset and those in the early stages of HD, suggesting a slowly insidious evolution of deficit. In contrast, memory performance showed a more precipitous decline around the time of clinical onset of HD. The findings, which suggest that HD patients' functional deficits do not evolve uniformly, help to resolve some of the disparities in the literature on preclinical HD.     

What is the impact of education on Huntington's disease?

Huntington's disease (HD) is a neurodegenerative disease caused by a cytosine adenosine guanine (CAG) expansion in the huntingtin gene. The length of the triplet repeat is the most important factor in determining age of onset and the severity of the disease, but substantial variability of these parameters is attributed to other factors. To investigate the relationship between the years of education and the age at onset and the severity of the phenotype in patients with HD, we applied multiple linear regression analysis to examine the impact of education on the age at onset and the severity of the clinical scores assessed by the Unified Huntington's Disease Rating Scale (UHDRS) of 891 patients with HD from the multinational observational study “Registry” conducted by the European Huntintgton's Disease Network. The model was adjusted for CAG repeat length and age at the time of assessment. Patients with lengthier education exhibited earlier estimated age at onset but less severe clinical scores (motor = ?3.6, P = 0.006; cognitive = 27.0, P < 0.001; behavioral = ?3.0, P < 0.001; and functional capacity = 1.1 points, P < 0.001) than those with shorter education, after controlling for age and number of CAG repeats. These differences persisted throughout all quartiles of disease severity. An earlier recognition of symptoms and manifestations among the more educated patients could explain the earlier estimated age at onset in this group. The link between better clinical UHDRS scores and higher education might reflect a beneficial effect of education or its covariates on the course of HD. © 2011 Movement Disorder Society     

少年型亨廷顿病临床与基因突变分析

研究背景亨廷顿病是一种常染色体显性遗传性神经系统退行性疾病.临床主要表现为舞蹈样动作、进行性认知功能减退及精神症状,神经影像学检查显示尾状核和大脑皮质萎缩.其致病基因IT15定位于4p16.3,由67个外显子组成编码亨廷顿蛋白,在其第1个外显子内存在一段多态胞嘧啶.腺嘌呤-鸟嘌呤(CAG)三核苷酸重复序列,正常范围为6～35次、异常36～250次.亨廷顿病多于成年期发病,具有外显不完全和延迟外显现象,而青少年型亨廷顿病临床较为少见.本研究针对一例少年期发病的亨廷顿病患者临床表型及其家系IT15基因CAG重复动态突变特征进行细致分析.方法 采用聚合酶链反应结合荧光标记毛细管电泳片段分析方法,对115例临床拟诊为亨廷顿病家系的先证者进行IT15基因CAG重复次数分析,经pMD18-T载体克隆测序验证部分阳性或携带中间重复等位基凶的样本.结果 经基因分析共发现109例患者携带异常扩展的IT15基因CAG重复序列,其中一例为少年期发病患者,临床以认知功能障碍和运动功能减退为首发症状,其父母临床表型正常.基因片段分析显示,患者IT15基因CAG重复次数为15/68次;其父母分别为17/37次和15117次.结论 (1)少年期发病的亨廷顿病与成年型临床表型不同,后者临床表现以舞蹈样运动、智能减退和精神异常为主,而少年型患者大多以认知功能障碍发病.(2)IT15基因扩展CAG重复序列在代问传递过程中会出现动态突变.引起发病年龄逐代提前,症状加重,即遗传早现.该家系患者之父携带中间等位基因37次重复,遗传给患者成为68次重复.在代间传递过程中发生了大幅度扩展,使CAG三核苷酸重复次数增加了31次,提示重复序列在父系遗传更不稳定.     

Longitudinal functional magnetic resonance imaging of cognition in preclinical Huntington's disease

Neuropsychological and functional neuroimaging studies have revealed early changes of cognition and brain function in individuals with the Huntington's disease (HD) gene mutation who are presymptomatic for the motor symptoms of the disease (preHD). However, little is known about whether changes of neural function progress over time. In this study, we used neuropsychological tests of attention, working memory and executive function, functional magnetic resonance imaging and voxel-based analyses of high-resolution structural data to explore the temporal dynamics of potential cognitive, functional and structural biomarkers in far from onset preHD (n = 13, mean time to the estimated motor symptom onset = 19.5 years) and healthy controls (n = 13) followed over a 2-year period. Behavioral measures were similar in preHD individuals and controls at baseline and remained normal 2 years later. At both time points, the left dorsolateral prefrontal cortex was less active in preHD than in controls during working memory performance. The left dorsolateral prefrontal cortex did not exhibit further loss of activity over time. Regions showing less gray matter volume in preHD at baseline did not show further volume loss over time. These data indicate that the activity in brain regions contributing to working memory processing differs consistently in HD expansion mutation carriers while cognitive performance remains normal. However, the present data do not support the notion of a progressive decline of left prefrontal cortex activity in far from onset preHD followed over a 2-year period.     

Evidence of impaired neurocognitive functioning in school‐age children awaiting cardiac surgery

Aim Children with congenital heart disease (CHD) are at risk of developing neurocognitive problems. However, as these problems are usually identified after cardiac surgery, it is unclear whether they resulted from the surgery or whether they pre‐existed and hence might be explained by complications and events associated with the heart disease itself. The purpose of this study was to examine whether neurocognitive deficits commonly reported after cardiac surgery are present before surgery. Method Forty‐five children (22 males, 23 females; mean age 11y 6mo, SD 3y 0mo) with cyanotic and acyanotic heart diseases scheduled for elective cardiac surgery were compared with 41 healthy peers (17 males, 24 females; mean age 11y 10mo, SD 2y 10mo) for attention and processing speed, construction, motor speed, motor planning and fluency, and visual memory. Twenty‐three children in the patient group were awaiting their first cardiac surgery and 22 were awaiting follow‐up surgery. Results The patients showed manifest neurocognitive difficulties. Their performance was inferior to that of the healthy comparison group for motor planning (p=0.02) and visual memory (p=0.01). The same neurocognitive profile was found in the group of patients awaiting their first cardiac operation. Interpretation School‐age children with various forms of CHD are at risk of neurocognitive impairments before cardiac surgery.     

Huntington's disease: a multidisciplinary study

Huntington's disease (HD) is characterized by the presence of movement disorders, cognitive decline and psychiatric disturbances. Recently, the gene responsible for HD has been found. As a result, a more direct test for HD is available. This may lead to a comprehensive approach to HD, since it is now possible to study HD patients without uncertainties in diagnosis. We carried out a clinical-genetic study on 45 patients with HD. We performed molecular analysis on 39 patients. All had an abnormal expansion of (CAG)n ranging from 41 to 90 triplets (mean 50.8 ± 11.5 S.D.). There was a strong inverse correlation between (CAG)n expansion and age at onset Gender of the affected parent influenced age at onset (p < 0.001) and number of triplets (p < 0.001). A significant impairment of akinesia (p < 0.001), chorea (p < 0.005), MMSE (p < 0.01) and Rey scores (p < 0.05) occurred across successive stages of functional disability. Hooper Visual Organization Test (HVOT) scores did not change significantly across stages, but this test was extremely useful to discriminate between patients at an early stage and controls. A significant correlation was found between functional disability and motor-cognitive decline; correlation was stronger for motor (akinesia, r = 0.77; chorea, r = 0.61) than for cognitive aspects (MMSE, r = - 0.54; Rey, r = - 0.51; HVOT, r = -0.35).     

Polymorphism of HD and UCHL-1 genes in Huntington’s disease

This study analyzed the association between the polymorphism of the Huntington’s disease (HD) and ubiquitin carboxyl-terminal hydrolase L1 (UCHL-1) genes and the age of HD onset. We examined the size of trinucleotide CAG repeats in the HD gene of 53 individuals from families with a history of HD, six unrelated HD patients, and 51 healthy controls. Polymerase chain reaction and restriction fragment length polymorphism was performed to examine UCHL-1 S18Y polymorphism prevalence in this group. We identified five HD patients in the families and four pre-clinical HD patients in their high-risk offspring. The differences in S18Y allele prevalence between families and healthy controls were not statistically significant. The SY genotype was identified most frequently (prevalence >50%). The YY genotype was not identified in non-related HD patients, and the SS genotype had a higher prevalence than the SY genotype. The S allele was identified more frequently than the Y allele, and the difference with healthy controls was significant. Multiple linear regression analysis revealed that UCHL-1 S18Y polymorphism accounted for 15.6% of variance in the age of disease onset among 11 patients. The number of CAG repeats accounted for 71.4% of the variance. The size of CAG repeats in the HD gene is an important factor affecting the age at disease onset, but is not the only factor. UCHL-1 S18Y polymorphism is a modifier of HD with a modest regulatory role in the age at disease onset, suggesting that UCHL-1 may be involved in HD pathogenesis.