Disease Mutation Carriers Research Articles

Acceleration of cortical thinning in familial Alzheimer's disease

MRI in presymptomatic autosomal dominant Alzheimer's disease mutation carriers (MC) provides an opportunity to detect changes that pre-date symptoms or clinical diagnosis. We used automated cortical thickness (CTh) measurement to compare the grey matter of such a group with cognitively normal controls. 9 presymptomatic mutation carriers (4 PSEN1, 5 APP) and 25 healthy, age and sex-matched controls underwent longitudinal volumetric MRI brain imaging. CTh measurement was performed across the whole brain using a validated, automated technique. Four regions of interest (ROI) (entorhinal cortex (ERC), parahippocampal gyrus (PHG), posterior cingulate cortex and precuneus) and two control regions (paracentral and pericalcarine) were selected on the basis of imaging data in existing Alzheimer's disease (AD) literature. Linear mixed models were used to describe normal ageing in controls and the extent to which mean CTh in cases differed from controls according to time since clinical diagnosis, adjusting for normal ageing. An accelerating decline in CTh was observed across all ROI in the MC group. No such decline was demonstrated in the control regions for the MC group. Relative to controls, and adjusting for normal ageing, there was evidence (p=0.05, one-sided test) of lower CTh in the posterior cingulate up to 1.8 years prior to diagnosis and in the precuneus up to 4.1 years prior to diagnosis in the MC group. Automated CTh analysis is a relatively practical, rapid and effective technique for assessing subtle structural change in AD. There is evidence that cortical thickness is reduced in mutation carriers a number of years prior to clinical diagnosis.

Contralateral risk-reducing mastectomy in BRCA1/2 mutation carriers and other high-risk women in the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab)

1509 Background: Contralateral risk-reducing mastectomy (CRRM) reduces contralateral breast cancer (BC) risk by up to 97%. Few studies have examined the prevalence and predictors of CRRM in BC patients at high familial risk of a second primary BC. Methods: Participants were women with unilateral BC and a strong family history of the disease, including BRCA1 and BRCA2 mutation carriers. Data were collected by interview, self-administered questionnaire, and review of pathology and surgical reports. Associations between having CRRM and potential predictors were assessed using multivariate logistic regression. Results: Of 1018 study participants (median follow-up 5.5 years), 154 (15%) underwent CRRM. The median time from initial BC to CRRM was 1 year. More likely to undergo CRRM were women who were younger at the time of their BC diagnosis (odds ratio [OR] = 0.94 per year of age, p < 0.001), those diagnosed more recently (OR = 1.16 per calendar year, p < 0.001), those who underwent mastectomy rather than breast conservation as their initial definitive BC treatment (OR = 5.2, p < 0.001) and those who underwent risk-reducing salpingo-oophorectomy (OR = 3.4, p < 0.001). BRCA1/2 mutation status and tumor characteristics were not independently associated with CRRM uptake. A contralateral BC event occurred in 177 (20.5%) of the 864 women who did not have CRRM, compared with one chest wall event (0.6%) in the 154 women post-CRRM. Conclusions: Younger women with more recently diagnosed BC treated with mastectomy were most likely to elect CRRM. BRCA1/2 mutation status and the competing risk of BC recurrence and death did not appear to influence decision making. No significant financial relationships to disclose.

Not on the face alone: perception of contextualized face expressions in Huntington's disease

Numerous studies have demonstrated that Huntington's disease mutation-carriers have deficient explicit recognition of isolated facial expressions. There are no studies, however, which have investigated the recognition of facial expressions embedded within an emotional body and scene context. Real life facial expressions are typically embedded in contexts which may dramatically change the emotion recognized in the face. Moreover, a recent study showed that the magnitude of the contextual bias is modulated by the similarity between the actual expression of the presented face and the facial expression that would typically fit the context, e.g. disgust faces are more similar to anger than to sadness faces and, consequently, are more strongly influenced by contexts expressing anger than by contexts expressing sadness. Since context effects on facial expression perception are not explicitly controlled, their pattern serves as an implicit measure of the processing of facial expressions. In this study we took advantage of the face-in-context design to compare explicit recognition of face-expressions by Huntington's disease mutation-carriers, with evidence for processing the expressions deriving from implicit measures. In an initial experiment we presented a group of 21 Huntington's disease mutation-carriers with standard tests of face-expression recognition. Relative to controls, they displayed deficits in recognizing disgust and anger faces despite intact recognition of these emotions from non-facial images. In a subsequent experiment, we embedded the disgust faces on images of people conveying sadness and anger as expressed by body language and additional paraphernalia. In addition, sadness and anger faces were embedded on context images conveying disgust. In both cases participants were instructed to categorize the facial expressions, ignoring the context. Despite the deficient explicit recognition of isolated disgust and anger faces, the perception of the emotions expressed by the faces was affected by context in Huntington's disease mutation-carriers in a similar manner as in control participants. Specifically, they displayed the same sensitivity to face-context pairings. These findings suggest that, despite their impaired explicit recognition of facial expressions, Huntington's disease mutation-carriers display relatively preserved processing of the same facial configurations when embedded in context. The results also show intact utilization of the information elicited by contextual cues about faces expressing disgust even when the actually presented face expresses a different emotion. Overall, our findings shed light on the nature of the deficit in facial expression recognition in Huntington's disease mutation-carriers as well as underscore the importance of context in emotion perception.

P1-282: Decreased activation in the left medial parietal lobe in presymptomatic familial Alzheimer's disease mutation carriers in FMRI during an unrelated word pair memory task

P1-282: Decreased activation in the left medial parietal lobe in presymptomatic familial Alzheimer's disease mutation carriers in FMRI during an unrelated word pair memory task

P3-101: A unique gene expression signature discriminates familial Alzheimer’s disease mutation carriers from their wild type siblings

P3-101: A unique gene expression signature discriminates familial Alzheimer’s disease mutation carriers from their wild type siblings

Arrhythmogenic right ventricular cardiomyopathy due to a novel plakophilin 2 mutation: Wide spectrum of disease in mutation carriers within a family

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial disease, with male preponderance, characterized by progressive fibrofatty replacement of the right ventricle and ventricular arrhythmias. Mutations in plakophilin-2 (PKP2), a desmosomal protein, have been reported to underlie familial ARVC. We report a novel ARVC PKP2 mutation and present the clinical findings in three female mutation carriers. We sequenced PKP2 from genomic DNA isolated from peripheral blood lymphocytes in a female proband who presented with cardiac arrest and in her four first-degree relatives. Clinical testing and diagnosis of ARVC was based on International Task Force criteria. The proband was diagnosed with ARVC due to right ventricular enlargement and regional hypokinesis, along with repolarization abnormalities and frequent ventricular ectopy. A novel 28 bp insertion in exon 11 of the PKP2 gene was found which causes a frameshift in the coding region. This results in a change in the amino acid sequence of the protein with a premature stop codon at position 740. Of the four relatives, only the mother and younger sister were identified as mutation carriers. The mother was phenotypically normal, while the younger sister has repolarization abnormalities and frequent ventricular ectopy. We report a novel PKP2 mutation that causes familial ARVC. All mutation carriers in this kindred group were women, and the family showed incomplete penetrance and variable expression of ARVC. Premature truncation of the plakophilin-2 protein appears to be the predominant mechanism whereby PKP2 mutations elicit the ARVC phenotype.

Mixtures of Wild-type and a Pathogenic (E22G) Form of Aβ40 in Vitro Accumulate Protofibrils, Including Amyloid Pores

Although APP mutations associated with inherited forms of Alzheimer's disease (AD) are relatively rare, detailed studies of these mutations may prove critical for gaining important insights into the mechanism(s) and etiology of AD. Here, we present a detailed biophysical characterization of the structural properties of protofibrils formed by the Arctic variant (E22G) of amyloid-β protein (Aβ40 ARC) as well as the effect of Aβ40 WT on the distribution of the protofibrillar species formed by Aβ40 ARC by characterizing biologically relevant mixtures of both proteins that may mimic the situation in the heterozygous patients. These studies revealed that the Arctic mutation accelerates both Aβ oligomerization and fibrillogenesis in vitro. In addition, Aβ40 ARC was observed to affect both the morphology and the size distribution of Aβ protofibrils. Electron microscopy examination of the protofibrils formed by Aβ40 ARC revealed several morphologies, including: (1) relatively compact spherical particles roughly 4–5 nm in diameter; (2) annular pore-like protofibrils; (3) large spherical particles 18–25 nm in diameter; and (4) short filaments with chain-like morphology. Conversion of Aβ40 ARC protofibrils to fibrils occurred more rapidly than protofibrils formed in mixed solutions of Aβ40 WT/Aβ40 ARC, suggesting that co-incubation of Aβ40 ARC with Aβ40 WT leads to kinetic stabilization of Aβ40 ARC protofibrils. An increase in the ratio of Aβ WT/Aβ MUT(Arctic), therefore, may result in the accumulation of potential neurotoxic protofibrils and acceleration of disease progression in familial Alzheimer's disease mutation carriers.

Perceptual Categorization Is Impaired in Huntington’s Disease: An Electrophysiological Study

Recent evidence raised the possibility that the neostriatum and the corticostriatal circuits could play an important role in semantic categorization. In this study, we examined the electrophysiological correlates of natural scene categorization in Huntington’s disease (HD) patients and their asymptomatic relatives who were Huntington’s disease mutation carriers (HDC). Event-related potentials were recorded in HD patients, HDC subjects, and age-matched control subjects using a natural scene categorization task. The subjects had to decide whether a briefly presented image contained animals or no animals. Concerning the N1 component (150–250 ms), the mean amplitudes were more negative for nonanimal scenes as compared with stimuli containing animals at all electrode sites in the control group and at all but the lateral temporal electrode sites (T3, T4) in the HD group. Between-group comparison demonstrated that the N1 amplitudes were significantly smaller for both kinds of stimuli in the HD group in spite of a normal primary occipital component (P100). The HDC subjects were not significantly different from the controls concerning the N1 amplitudes. These results suggest that perceptual (N1) processes related to the categorization of natural scenes are specifically impaired in HD. The findings are in agreement with the hypothesis emphasizing the importance of neostriatal mechanisms in human categorization functions.

Huntington's disease progression. PET and clinical observations.

Using serial [(11)C]SCH 23390- and [11C]raclopride-PET, we have measured the rate of loss of striatal dopamine D1 and D2 receptor binding over a mean of 40 months in nine asymptomatic adult Huntington's disease mutation carriers, four patients with symptomatic disease, seven mutation-negative controls and three subjects at risk for the disease. Eight of the nine asymptomatic Huntington's disease mutation carriers had serial [11C]raclopride-PET and showed a mean annual loss of striatal D2 binding of 4.0%. Only five of these eight, however, showed active progression, and they had a mean annual loss of D2 binding of 6.5%. All nine asymptomatic mutation carriers had serial [11C]SCH 23390-PET and showed a mean annual loss of striatal D1 binding of 2. 0%. Four of these subjects demonstrated active progression and they had a mean annual loss of 4.5%. Our four symptomatic Huntington's disease patients showed a mean annual loss of D2 binding of 3.0% and of D1 binding of 5.0%. Loss of striatal D1 and D2 binding was significantly greater in the known mutation carriers than in the combined at-risk and gene-negative groups (P < 0.05). At follow-up PET all subjects were clinically assessed using the Unified Huntington's Disease Rating Scale. Scores for motor function and total functional capacity correlated with PET measures of striatal dopamine receptor binding both in the asymptomatic mutation carriers (D1, P < 0.01) and across the combined asymptomatic and clinically affected Huntington's disease mutation carrier group (D1 and D2, P < 0.001). We conclude that PET measures of striatal D1 and D2 dopamine binding can be used to identify asymptomatic Huntington's disease mutation carriers who are actively progressing and who would thus be suitable for putative neuroprotective therapies. Measures of disease progression rates in Huntington's disease patients and asymptomatic mutation carriers will be of critical importance in future trials of experimental restorative treatments.

The impact of molecular genetic analysis of theVHL gene in patients with haemangioblastomas of the central nervous system

OBJECTIVESHaemangioblastoma of the CNS occurs as a sporadic entity and as a manifestation of the autosomal dominant von Hippel-Lindau disease with the major additional components retinal angioma, renal cancer, and...

Evidence for specific cognitive deficits in preclinical Huntington's disease.

The performance of 54 subjects genetically at risk for Huntington's disease was examined in double-blind fashion on a series of computerized tests from the Cambridge Neuropsychological Test Automated Battery. None of the subjects exhibited clinical movement disorder characteristic of Huntington's disease. Of the 54 subjects, 22 were Huntington's disease mutation carriers and 32 were non-carriers. On a comprehensive battery of neuropsychological tests previously shown to be sensitive to the early stages of clinical Huntington's disease, Huntington's disease mutation carriers exhibited highly specific cognitive deficits. In particular, Huntington's disease mutation carriers performed significantly less well than non-carriers, matched for age and IQ, on tests of attentional set shifting and semantic verbal fluency. Furthermore, performance on these two tests was significantly correlated, even after partialling out the effects of age and IQ. It is suggested that these cognitive impairments relate to a common deficit in inhibitory control mechanisms, under the control of striatofrontal mechanisms, and that such a deficit is present in Huntington's disease mutation carriers prior to the onset of definite motor symptomatology. The implications for the nature of the cognitive decline seen in Huntington's disease, and possible future treatment strategies, are discussed.

The relationship between striatal dopamine receptor binding and cognitive performance in Huntington's disease

Seventeen individuals at risk for Huntington's disease and five symptomatic patients, who had previously undergone [11C]SCH23390 and [11C]raclopride PET to assess in vivo levels of striatal dopamine D1 and D2 receptor binding, had neuropsychological assessment on a series of tests known to be sensitive to symptomatic Huntington's disease, including tests of verbal fluency, memory, attention and planning. Compared with age- and IQ-matched healthy volunteers, clinically symptomatic carriers of the Huntington's disease mutation were found to be impaired on tests of verbal fluency, spatial span, planning and sequence generation, as were clinically asymptomatic Huntington's disease mutation carriers. In asymptomatic individuals, both striatal dopamine receptor levels and cognitive performance were lower in subjects approaching their estimated age of onset. In addition, performance on these tasks was found to correlate with PET measures of striatal D1 and D2 receptor binding levels, especially D2 binding. These results are consistent with a role for the striatum, as part of the complex corticobasal ganglia-thalamocortical circuitry, in the optimal scheduling and sequencing of responses, and suggest that cognitive manifestations of striatal dysfunction can be evidenced in carriers of the Huntington's disease mutation prior to the onset of overt clinical movement disorder.

Positron emission tomography in asymptomatic gene carriers of Machado-Joseph disease

OBJECTIVESThe metabolic changes in the brain of symptomatic subjects affected with Machado-Joseph disease have been previously documented using PET with fluorine-18-fluorodeoxyglucose (FDG). The aim of this study was to evaluate...

Striatal glucose metabolism and dopamine D2 receptor binding in asymptomatic gene carriers and patients with Huntington's disease.

We used PET scans with the tracers [18F]fluorodeoxyglucose (FDG) and [11C]raclopride (RACLO) to study glucose metabolism and dopamine D2 receptor binding in the caudate nucleus and putamen of 18 carriers of the Huntington's disease gene mutation (10 asymptomatic subjects and eight untreated symptomatic Huntington's disease patients in an early disease stage). We also performed MRI scans and measured the bicaudate ratio (BCR) in the same subjects. Data were compared with those from nine mutation-negative members of Huntington's disease families and separate groups of age matched controls. The PET scans were repeated 1.5-3 years later in six of the asymptomatic gene carriers. Symptomatic Huntington's disease patients showed a marked reduction of FDG and RACLO uptake in the caudate nucleus and putamen and a significant increase of BCR. Asymptomatic mutation carriers revealed significant hypometabolism in the caudate nucleus and putamen. The RACLO binding was significantly decreased in the putamen. Decrements of caudate nucleus tracer uptake, particularly RACLO, correlated significantly with BCR increases in both symptomatic and asymptomatic gene carriers. In asymptomatic carriers, metabolic and receptor binding decreases were also significantly associated with the CAG repeat number but not with the individual's age. Discriminant function analysis correctly classified clinical and genetic status in 24 of 27 subjects on the basis of their striatal PET values (83% sensitivity and 100% specificity). Three asymptomatic mutation carriers were classified/grouped together with mutation-negative subjects, indicating that these individuals had normal striatal RACLO and FDG uptake. Follow-up PET data from gene-positive subjects showed a significant reduction in the mean striatal RACLO binding of 6.3% per year. Striatal glucose metabolism revealed an overall non significant 2.3% decrease per year. These data indicate that asymptomatic Huntington's disease mutation carriers may show normal neuronal function for a long period of life. These findings also suggest that it may be possible to predict when an asymptomatic gene carrier will develop clinical symptoms from serial PET measurements of striatal function.