CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion.

OBJECTIVE: Age at onset of diagnostic motor manifestations in Huntington disease (HD) is strongly correlated with an expanded CAG trinucleotide repeat. The length of the normal CAG repeat allele has been reported also to influence age at onset, in interaction with the expanded allele. Due to profound implications for disease mechanism and modification, we tested whether the normal allele, interaction between the expanded and normal alleles, or presence of a second expanded allele affects age at onset of HD motor signs. METHODS: We modeled natural log-transformed age at onset as a function of CAG repeat lengths of expanded and normal alleles and their interaction by linear regression. RESULTS: An apparently significant effect of interaction on age at motor onset among 4,068 subjects was dependent on a single outlier data point. A rigorous statistical analysis with a well-behaved dataset that conformed to the fundamental assumptions of linear regression (e.g., constant variance and normally distributed error) revealed significance only for the expanded CAG repeat, with no effect of the normal CAG repeat. Ten subjects with 2 expanded alleles showed an age at motor onset consistent with the length of the larger expanded allele. CONCLUSIONS: Normal allele CAG length, interaction between expanded and normal alleles, and presence of a second expanded allele do not influence age at onset of motor manifestations, indicating that the rate of HD pathogenesis leading to motor diagnosis is determined by a completely dominant action of the longest expanded allele and as yet unidentified genetic or environmental factors.

Disgust and happiness recognition correlate with anteroventral insula and amygdala volume respectively in preclinical Huntington's disease.

Patients with Huntington's disease (HD) can show disproportionate impairments in recognizing facial signals of disgust, but the neural basis of this deficit remains unclear. Functional imaging studies have implicated the anterior insula in the ability to recognize disgust, but have identified other structures as well, including the basal ganglia. In view of variable insula and basal ganglia volume changes in HD, we used voxel-based morphometry to map regional variations in gray matter (GM) volume in participants carrying the mutation for HD, and correlated this with their performance on a test of facial emotion recognition for six basic emotions (disgust, fear, anger, happiness, sadness, surprise). The volume of the anteroventral insula was strongly correlated with performance on the disgust recognition task. The amygdala volume (bilaterally) correlated with the ability to recognize happy facial expressions. There was marked specificity of the regional correlations for the emotion involved. Recognition of other emotion expressions, or more general cognitive or motor performance as measured by a standardized rating scale, did not correlate with regional brain volume in this group. Control participants showed no effect for any measure. The strong linear correlations for disgust and happiness recognition imply direct involvement of the anterior insula in disgust appreciation, and a similar role for the amygdala in recognizing happy facial expressions. The absence of a significant correlation with the basal ganglia suggests a less critical role for these structures in disgust recognition than has previously been suggested. The findings also highlight the role of neurodegenerative diseases combined with statistical imaging techniques in elucidating the brain basis of behavior and cognition.

Progression of structural neuropathology in preclinical Huntington's disease: a tensor based morphometry study.

BACKGROUND AND OBJECTIVES: Regional cerebral atrophy occurs in carriers of the Huntington's disease (HD) gene mutation before clinical diagnosis is possible. The current inability to reliably measure progression of pathology in this preclinical phase impedes development of therapies to delay clinical onset. We hypothesised that longitudinal statistical imaging would detect progression of structural pathology in preclinical carriers of the HD gene mutation, in the absence of measurable clinical change. METHODS: Thirty subjects (17 preclinical mutation positive, 13 mutation negative) underwent serial clinical and magnetic resonance imaging (MRI) assessments over an interval of 2 years. Statistically significant changes in regional grey and white matter volume on MRI were analysed using tensor based morphometry (TBM). This technique derives a voxel-wise estimation of regional tissue volume change from the deformation field required to warp a subject's early to late T1 images. RESULTS: Over 2 years, there was progressive regional grey matter atrophy in mutation-positive relative to negative subjects, without significant clinical progression of disease. Significant grey matter volume loss was limited to bilateral putamen and globus pallidus externa (GPe), left caudate nucleus, and left ventral midbrain in the region of the substantia nigra. CONCLUSIONS: While these results are consistent with previous cross sectional pathologic and morphometric studies, significant progression of atrophy in HD before the onset of significant clinical decline is now demonstrable with longitudinal statistical imaging. Such measures could be used to assess the efficacy of potential disease modifying drugs in slowing the progression of pathology before confirmed clinical onset of HD.

Huntington's disease: clinical correlates of disability and progression.

OBJECTIVE: To define the phenotypic variation in a large population of patients with Huntington disease (HD) and to identity clinical features that predict disability and the rate of disease progression. METHODS: The authors analyzed data on 1,026 patients, followed for a median of 2.7 years, using a mixed effects model. The factors studied included the age at onset, the major clinical feature at onset, the severity of motor and cognitive impairment, and the level of disability. RESULTS: The mean age at onset was 41.5 (range 8 to 83) years, and patients were enrolled at all stages of disease. Younger onset was associated with more dystonia, less chorea, and a faster rate of motor, cognitive, and functional progression. The rate of progression was not related to the major clinical feature at onset or the sex of the affected parent. Disability correlated with the motor score (excluding chorea and dystonia) and the symbol-digit modalities test. Weight loss correlated with severe chorea. CONCLUSIONS: The rate of progression of HD was significantly more rapid with a younger age at onset. Therefore, CAG repeat length may be an important determinant of not only the age at onset, but also the rate of disease progression. Chorea was associated with weight loss, but chorea and dystonia were not major determinants of disability.

Genetically confirmed clinical Huntington's disease with no observable cell loss.

Huntington's disease (HD) results from neurodegeneration of the neostriatum. The mutation on chromosome 4 is an expansion in a triplet repeat (CAG)(n) located within the IT15 gene. Only six patients have been reported with clinical features of HD in association with limited neuropathology. Of these, only one has had the diagnosis confirmed by genetic (DNA) testing. We describe a patient with the clinical phenotype and genetically confirmed HD but unexpected limited neuropathology. The patient was seen because of aggressive behaviour and memory problems of two years duration. The differential diagnosis included HD although there was no family history. DNA testing was positive for the HD mutation. Clinical follow up three months later confirmed classic features of HD. Progression of the disease was rapid with death three years later. Neuropathology revealed a largely intact neostriatum with bilateral ischaemic damage and cell loss in the external globus pallidus. Such pathology alone could explain the clinical features of HD. This is only the second report of genetically confirmed clinically manifest HD with little evidence of HD neuropathology. There are several unusual features which could not have been predicted by the clinical picture, in particular the progressive course of bilateral ischaemic changes restricted to the external globus pallidus. The potential to miss other HD cases at post-mortem examination, and the implications of this for family members, are discussed.

Interaction of normal and expanded CAG repeat sizes influences age at onset of Huntington disease.

Huntington disease (HD) is a neurodegenerative disorder caused by the abnormal expansion of CAG repeats in the HD gene on chromosome 4p16.3. Past studies have shown that the size of expanded CAG repeat is inversely associated with age at onset (AO) of HD. It is not known whether the normal Huntington allele size influences the relation between the expanded repeat and AO of HD. Data collected from two independent cohorts were used to test the hypothesis that the unexpanded CAG repeat interacts with the expanded CAG repeat to influence AO of HD. In the New England Huntington Disease Center Without Walls (NEHD) cohort of 221 HD affected persons and in the HD-MAPS cohort of 533 HD affected persons, we found evidence supporting an interaction between the expanded and unexpanded CAG repeat sizes which influences AO of HD (P = 0.08 and 0.07, respectively). The association was statistically significant when both cohorts were combined (P = 0.012). The estimated heritability of the AO residual was 0.56 after adjustment for normal and expanded repeats and their interaction. An analysis of tertiles of repeats sizes revealed that the effect of the normal allele is seen among persons with large HD repeat sizes (47-83). These findings suggest that an increase in the size of the normal repeat may mitigate the expression of the disease among HD affected persons with large expanded CAG repeats.

The distribution of structural neuropathology in pre-clinical Huntington's disease.

Putative neuroprotective agents in Huntington's disease may have particular application before brain pathology becomes manifest clinically. If these agents were to be tested in clinical trials, a reliable marker of the burden and rate of progression of pathological change in the pre-clinical group would be needed. The present study investigates whether the Huntington's disease genotype is associated with regional differences in brain structure, particularly differences that could not be predicted from clinical or neuropsychological assessment. A secondary aim is to seek indirect evidence of pathological progression in the form of changes in local tissue volume with age, specific to the Huntington's disease genotype. Formal motor examination, neuropsychological assessment, and T(1)-weighted cerebral MRI were performed in 34 subjects who had undergone predictive genetic testing for Huntington's disease. Clinical and cognitive testing were performed blinded to gene status. A linear discriminant analysis revealed the combination of test scores (the 'optimal clinical score') which best differentiated 18 subjects carrying the Huntington's disease gene mutation (the 'gene-positive' group). Voxel-based morphometry (VBM) was used to identify regions of significant main effect of Huntington's disease gene status on grey and white matter volume and regions of significant interaction of gene status with age. In the gene-positive group, there was significant reduction in grey matter volume in the left striatum, bilateral insula, dorsal midbrain and bilateral intra-parietal sulcus relative to 'gene-negative' controls. There was a significant reduction of periventricular white matter volume with age bilaterally in the gene-positive relative to the gene-negative group. Changes remained significant when controlled for differences in optimal clinical score between subjects. This study provides evidence of distributed grey matter pathology and progressive white matter atrophy with age before clinical onset of Huntington's disease. This suggests that VBM may be useful in monitoring cross-sectional and longitudinal changes in brain structure in pre-clinical Huntington's disease and for determining the efficacy of neuroprotective agents.

Prevalence of Huntington disease in New South Wales in 1996.

OBJECTIVE: To estimate the prevalence of Huntington disease (HD) in New South Wales on Australian Census Day (6 August) 1996. DESIGN: Survey of records of the Huntington Disease Service and major hospitals, and of neurologists, psychiatrists, clinical geneticists and genetic counsellors. SUBJECTS AND SETTING: All patients in NSW who, on Census Day 1996, either had a definite diagnosis of HD (motor signs of chorea or ataxia and family history of HD or positive DNA test result) or would have had signs and later received a definite diagnosis (assessed 1 April 1997 to 1 July 1999). MAIN OUTCOME MEASURES: Prevalence (HD patients per 100,000 population); patient characteristics; year and basis of diagnosis. RESULTS: 380 patients with definite HD were identified, giving a prevalence of HD in NSW in 1996 of 6.29 per 100,000 population (95% CI, 5.68-6.96). A third of HD patients were aged 60 years or older. Diagnosis was confirmed by DNA testing for 171 patients (45%), including 30 (8%) with no recorded family history. Average numbers of new diagnoses per year were 11.8 (1984-1988), 21.8 (1989-1993) and 28.6 (1994-1998). Estimated number of people with a 50% risk of inheriting the HD mutation was 25.2 per 100,000 population. Estimated incidence of HD in 1996 was 0.65 per 100,000 population. CONCLUSIONS: Prevalence of HD in NSW is similar to estimated prevalence in other Australian and Western populations. Increasing numbers of cases are being diagnosed, and the 18 chronic care beds currently designated for HD patients in NSW are unlikely to be sufficient.

Huntington's disease: neurological assessment of potential gene carriers presenting for predictive DNA testing.

One hundred and fifty-six potential gene carriers who were 50% 'at risk' of inheriting the Huntington's disease (HD) mutation, and who presented for predictive testing, underwent neurological assessment before their gene status had been determined. The association between pre-gene result symptoms and minimal neurological signs (insufficient for diagnosis in their own right) and subsequent gene status was determined. Of these, 38% tested positive for the HD mutation. Fifty-one individuals had minor neurological signs. After exclusions, 61% of gene-positive patients had minor neurological signs, whereas only 8% testing gene negative had signs. Minimal chorea observed in the toes and feet with the subject supine, and the patient being stressed by a mental task carried 96% specificity and 86% positive predictive value for gene-positive status. Neurological symptoms did not distinguish gene status, but behavioural and cognitive symptoms were more often reported by the gene-positive group. Although an 'at-risk' individual may receive a gene-positive result, neurological examination remains the most accessible, reliable and cost effective means of determining clinical disease onset.

Regional specificity of brain atrophy in Huntington's disease.

The present study analyzes the relationship between cortical and subcortical brain volumes in patients with Huntington's disease. The brains of seven patients with a clinical diagnosis and positive family history of Huntington's disease and 12 controls were collected at autopsy with consent from relatives. Detailed clinical assessments were available for all study subjects with genotype confirmation for patients with Huntington's disease. Volume analysis of the brain on serial 3-mm coronal slices was performed as previously described. All patients with Huntington's disease exhibited significant brain atrophy resulting from volume reductions in both cortical and subcortical grey matter. Atrophy of the cortex was relatively uniform, although the medial temporal lobe structures were spared. The caudate nucleus and putamen were strikingly reduced in all cases and this atrophy correlated with the severity of cortical atrophy, suggesting an associated disease process. The rate of cortical but not subcortical atrophy correlated with CAG repeat numbers. Loss of frontal white matter correlated with both cortical and striatal atrophy. Age of onset of chorea correlated with the amount of subcortical atrophy, while duration of chorea correlated negatively with atrophy of the white matter. These results suggest a more widespread and global disease process in patients with Huntington's disease.

Occupational risk factors for Alzheimer disease: a case-control study.

There is evidence to support the role of a number of environmental factors in Alzheimer disease (AD). This study examines the role of chemical and physical exposures in the occupational environment. The sample included 170 patients with AD and 170 medical-practice-based controls, matched for age and sex, who were assessed for histories of occupational exposures to a range of chemical and physical agents, including hydrocarbon solvents, lead, mercury, organophosphates, aluminum, asbestos and other silicates, vibration, and physical underactivity. Occupational histories were obtained from informants for both patients and controls. Exposure was assessed by a panel of occupational hygienists, blinded to the case or control status of each subject, using the occupational histories and the Job-Exposure Matrix of the U.S. National Institute for Occupational Safety and Health. No statistically significant associations were found between any of the exposures and the occurrence of AD, either in the overall study group or in patients with a family history of AD. The findings suggest the absence of any occupational cause for AD.

Significant loss of pyramidal neurons in the angular gyrus of patients with Huntington's disease.

The primary site of pathology in Huntington's disease (HD) is the caudate nucleus. However, cortical changes are also commonly reported. While many researchers have studied pathology in the frontal lobe, little attention has been paid to posterior cortical regions. The aim of this study is to examine pathology in the parietal lobe in patients with HD as it has specific projections to the caudate nucleus. Post-mortem brain tissue was obtained from HD patients with both a positive family history and clinicopathological diagnosis (n = 6; Vonsattel grades 2-4) as well as from neurologically normal controls (n = 6). The angular gyrus of the parietal lobe was sampled and cellular quantification of SMI-32 immunohistochemically detected pyramidal neurons performed. Cortical blocks were sectioned at 50 microns on a cryostat and stained immunohistochemically using antigen retrieval methods and peroxidase visualization. HD subjects had noticeable histological changes including smaller neurons and a disruption of cortical laminar pattern. Quantification using a point counting method to find the areal fraction of immunoreactive neurons revealed a severe loss of pyramidal neurons in the angular gyrus of HD subjects compared with controls (reduced on average to 55% of mean control values, P = 0.038 using the Mann-Whitney U-test). This striking cortical pathology suggests that HD may preferentially target posterior cortical regions, particularly the angular gyrus which has a significant projection to the caudate nucleus in primates.

Age at onset and pattern of neuropsychological impairment in mild early-stage Alzheimer disease. A study of a community-based population.

OBJECTIVES: To examine the effects of age at onset on neuropsychological functioning in a group of patients with probable Alzheimer disease (AD) and, within this group, to scrutinize further those patients with mild early-onset disease as it was hypothesized that within this group specific patterns of cognitive impairment could be identified that correlated with neuropathological staging of the disease. DESIGN: Each patient underwent an extensive neuropsychological test battery to examine a wide range of cognitive processes to provide information to identify subtypes of dementia. SETTING: The Memory Clinic in the Department of Geriatric Medicine, Concord Hospital, Concord, New South Wales, Australia. PATIENTS: One hundred forty-five community-residing case patients with probable AD were studied; within this group, 51 case patients with mild AD and a Mini-Mental State Examination score greater than 19 were further examined; 36 similarly aged control patients who were part of a larger case-control study of AD in an urban population were also examined. A diagnosis of probable and possible AD was made if the case patient had evidence of memory impairment and met criteria according to the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association. OUTCOME MEASURES: Individual neuropsychological test scores were compared. The tests were then grouped into 7 cognitive domains. Patterns of early cognitive impairment were derived from these comparisons. RESULTS: With an earlier age at onset, significantly more impairment on tests of digit span and praxis was seen, while the duration of disease had no independent effect once the age at onset was fixed. Patients with mild early-onset dementia and a Mini-Mental State Examination score greater than 19 showed significant impairment in tests of attention, memory, frontal/executive functions, visuospatial ability, praxis, and visual agnosia compared with that shown by control patients. In this group, further analyses revealed that impairment in memory and frontal/ executive functions were the earliest signs of cognitive impairment. CONCLUSIONS: These data showed that when the duration of disease was adjusted for, case patients with an earlier age at onset of AD demonstrated significantly more impairment on tests of attention span and working memory (digit span), graphomotor function (copy loops), and apraxia than those with an older age at onset. Our findings support the view that the hippocampus and its connections are affected in the early stages of AD. The deficits in the frontal/executive functions also suggest that a disruption of cortical pathways to the frontal lobes and the pathological changes in this region occur early in the disease.

Peripheral blood lymphocyte subset distribution and function in patients with Alzheimer's disease and other dementias.

BACKGROUND: Until recently, new data on immune aspects of Alzheimer's disease (AD) have suggested that some facets of AD pathogenesis may be immune related. However, the effects of dementia itself on immune function have not been considered. AIM: To compare the distribution of peripheral blood lymphocyte subsets and their function in patients with AD and other dementias. METHODS: Peripheral blood lymphocyte numbers, T cell subset distribution, proliferative responses to mitogens and suppressor cell assay were studied in a well characterised group of patients with AD, and compared to patients with other forms of dementia. Age and sex matched elderly controls were screened to exclude dementia, and young controls were medical, paramedical and laboratory staff. Analysis of variance (ANOVA) and student's test were used for statistical analysis. RESULTS: The CD8+ lymphocyte population was reduced in AD and in other forms of dementia, when compared with non-demented elderly and young controls. Concanavalin A induced lymphocyte transformation was reduced in all dementia groups and in elderly compared with young controls. The changes in T cell numbers and function were not specific for Alzheimer's disease, but were found also in other forms of dementia.

Patient information leaflets on over-the-counter (OTC) medicines: the manufacturer's perspective.

A survey was undertaken to assess the views of the manufacturers of over-the-counter (OTC) products about (i) the value of patient information leaflets (PILs), (ii) the recent European Community directive relating to PILs and (iii) the procedures which are in place for producing and testing PILs. Although approximately half (15/31) of the respondents (response rate 31/58) thought that PILs were more important for OTC than prescription only medicines, this view was not unanimous. A majority (18/28) thought that the new EC directive would provide too much information to patients although only a small number (2/27) thought that the regulations were unnecessary. Indication for the product was thought to be the most important information for the immediate outer packaging. Only about one-third (35%) of patients are thought to read PILs, in contrast to the majority who read the outer packaging. A wide variety of departments contribute to preparing PILs. The marketing department had a major input particularly with respect to layout and testing of leaflets. On the whole the design and production of PILs involves considerable effort but their testing appears less structured and thorough.

Assessing the risk of Alzheimer's disease in first-degree relatives of Alzheimer's disease cases.

Family history of Alzheimer's disease (AD) was investigated using a telephone reinterview of 99 cases and 116 controls selected from a case-control study of 170 matched pairs. It was found that the family history method used in the initial interview was satisfactory in identifying first-degree relatives and assessing their ages of birth and death, but the number of first-degree relatives suffering from AD was probably under-estimated. Family history of AD was confirmed as a risk factor for AD. Higher estimates of cumulative incidence were obtained among case relatives than among control relatives. No evidence was found to support the hypothesis that a familial form of AD is more common in those with earlier onset AD (before age 75) in those who display early, prominent features of aphasia or apraxia, or that an AD gene may be sex-linked. The curves for cumulative incidence showed no tendency to reach an asymptote, as is implied by the theory that some forms of AD are due to the action of an autosomal dominant gene. Estimates of lifetime risk by age 90 were within the range found by other investigators. Much larger samples of the very old are needed to obtain estimates of total lifetime risk with smaller standard errors.

Control-informant agreement on exposure history in case-control studies of Alzheimer's disease.

Data on control-informant agreement from four published case-control studies of Alzheimer's disease are compared, using both the kappa statistic and proportion of agreement for the presence and absence of exposures. Agreement was best for exposures involving lifestyle, medical interventions or disorders of more recent origin, and worst for exposures which involved judgements by the respondent. Agreement levels are similar across studies, and are commensurate with levels of specificity and sensitivity to be expected in this type of enquiry. We discuss the problems and implications associated with the interpretation of data from such studies of the elderly.