Preclinical Carriers Research Articles

Measurement of retinal nerve fiber layer thickness in Leber hereditary optic neuropathy by optical coherence tomography

To evaluate retinal nerve fiber layer (RNFL) thickness in patients and unaffected carriers of Leber hereditary optic neuropathy (LHON) by optical coherence tomography (OCT). This case-control study enrolled 42 LHON maternal family members with mitochondrial DNA G11778A mutation and 100 normal volunteers. RNFL thickness was measured by Stratus OCT in each participant. Mean RNFL thickness of each quadrant, as well as 360° average were calculated and compared in normal controls, LHON carries and LHON patients. Among LHON maternal family members, 15 cases were unaffected carriers who were subgrouped as normal-fundus-appearing carriers (10 cases) and preclinical carriers (5 cases). Twenty seven LHON patients included 9, 5, and 13 cases in the early, advancing and advanced stages, respectively. Normal fundus-appearing carriers showed normal RNFL thickness of each quadrant and 360° average. Preclinical carriers and early-staged patients showed no significant difference in RNFL thickness of each quadrant and 360° average (P = 0.138 to 0.645), yet both showed thicker RNFL in temporal, superior and inferior quadrant, as well as 360° average, if compared with normal controls (P = 0.000 to 0.018). Compared with normal controls, preclinical carriers and early-staged patients, advancing LHON patients showed thinner RNFL in temporal and inferior quadrant, as well as 360° average (P = 0.000 to 0.005). Advanced LHON patients showed thinner RNFL in each quadrant and 360° average, compared with normal controls, LHON carriers, and advancing cases (P = 0.000 to 0.037). RNFL thickness in LHON patients and unaffected carriers was characterized by OCT in this study, which would improve the understanding of the natural course of LHON.

A04 Default-mode network changes in preclinical Huntington's disease

Background The default-mode network (DMN) is a set of brain regions which shows greater activity during rest relative to a cognitive task. Altered function of this network has been associated with a decline of cognition in several neurodegenerative diseases and related at-risk conditions. In Huntington9s disease (HD), an autosomal dominant inherited neurodegenerative disorder, several studies so far have shown abnormal brain activation patterns even in preclinical carriers of the HD disease gene mutation (preHD). To date, however, the functional integrity of the DMN has not been addressed in this population. Aims The aim of this study was to study the functional connectivity of the DMN in 18 preHD individuals and 18 healthy controls during cognitive performance. Methods Participants underwent functional MRI during an attention task, and a group independent component analysis was applied to identify spatiotemporally distinct patterns of two DMN subcomponents. Results Compared to controls, preHD individuals showed lower component-specific connectivity in the anterior medial prefrontal cortex (aMPFC), the left inferior parietal (lIPL) and the posterior cingulate cortex (p Conclusions These results highlight the biomarker-potential of DMN connectivity in preHD, and suggest a possible role of DMN function in maintaining optimal cognitive performance. Future longitudinal studies could consider using DMN for tracking disease-progression and disease-related cognitive decline.

Default-mode network changes in preclinical Huntington's disease

The default-mode network (DMN) refers to as a set of brain regions which are active when the brain does not engage in a cognitive task and which are deactivated with task-related cognitive effort. Altered function of the DMN has been associated with a decline of cognition in several neurodegenerative diseases and related at-risk conditions. In Huntington's disease, an autosomal dominant inherited neurodegenerative disorder, several studies so far have shown abnormal task-related brain activation patterns even in preclinical carriers of the Huntington's disease gene mutation (preHD). To date, however, the functional integrity of the DMN has not been addressed in this population. The aim of this study was to study the functional connectivity of the DMN in 18 preHD and 18 healthy controls who underwent functional magnetic resonance imaging during an attention task. A group independent component analysis identified spatiotemporally distinct patterns of two DMN subsystems. The spatial distribution of these components in preHD was similar to controls. However, preHD showed lower subsystem-specific connectivity in the anterior medial prefrontal cortex, the left inferior parietal and the posterior cingulate cortex (p<0.05, cluster-corrected). Connectivity between the two DMN subsystems was increased in preHD compared to controls. In preHD individuals lower functional connectivity of the left inferior parietal cortex was associated with shorter reaction times in the attention task. This suggests that some functionally critical regions of the DMN may have to remain active to maintain or optimise cognitive performance in preHD.

The amyloid-β isoform pattern in cerebrospinal fluid in familial PSEN1 M139T- and L286P-associated Alzheimer's disease

There are several familial forms of Alzheimer's disease (AD) most of which are caused by mutations in the genes that encode the presenilin enzymes involved in the production of amyloid-β (Aβ) from the amyloid precursor protein (APP). In AD, Aβ forms fibrils that are deposited in the brain as plaques. Much of the fibrillar Aβ found in the plaques consists of the 42 amino acid form of Aβ (Aβ1-–2) and it is now widely accepted that Aβ is related to the pathogenesis of AD and that Aβ may both impair memory and be neurotoxic. In human cerebrospinal fluid (CSF) several C- and N-terminally truncated Aβ isoforms have been detected and their relative abundance pattern is thought to reflect the production and clearance of Aβ. By using immunoprecipitation and mass spectrometry, we have previously demonstrated that carriers of the familial AD (FAD)-associated PSEN1 A431E mutation have low CSF levels of C-terminally truncated Aβ isoforms shorter than Aβ1-40. Here we replicate this finding in symptomatic carriers of the FAD-causing PSEN1 L286P mutation. Furthermore, we show that preclinical carriers of the PSEN1 M139T mutation may overexpress Aβ1-42 suggesting that this particular mutation may cause AD by stimulating γ-secretase-mediated cleavage at amino acid 42 in the Aβ sequence.

Impact of Huntington's across the entire disease spectrum: the phases and stages of disease from the patient perspective.

Ho AK, Hocaoglu MB for the European Huntington's Disease Network Quality of Life Working Group. Impact of Huntington disease across the entire disease spectrum: the phases and stages of disease from the patient perspective.Although Huntington's disease (HD) is a neurodegenerative disease characterized by motor, cognitive and behavioural disturbances, there has been little empirical data examining what patients are most concerned about throughout the different stages of disease, which can span many years. Semi-structured face-to-face interviews were individually conducted with 31 people living with different stages of Huntington's, from pre-clinical gene carriers to advanced stage. We examined how often participants raised issues and concerns regarding the impact of Huntington's on everyday life. The Physical/functional theme hardly featured pre-clinically, but was strongly present from Stage 1, rose steadily and peaked at Stage 5. There were no significant changes between stages for the Emotional, Social, and Self themes that all featured across all stages, indicating that these issues were not raised more frequently over the course of the disease. Likewise, the more rarely mentioned Financial and Legal themes also remained similar across stages. However, the Cognitive theme only featured between Stages 1 and 4, and hardly at all pre-clinically and at Stage 5. These findings provide insight into patients' important and unique perspective and have implications for the management and development of interventions across the spectrum of HD stages.Section Editor: Aad Tibben, email: a.Tibben@lumc.nl

G06 Verbal learning and memory in preclinical Huntington's disease

BackgroundHuntington's disease (HD) is associated with progressive cognitive impairments.AimsThe aim of this ongoing study was to examine verbal episodic learning and memory in preclinical HD.MethodsParticipants were recruited from the predictive...

Changes in striatal dopamine D2 receptor binding in pre‐clinical Huntington’s disease

Carriers of the Huntington disease (HD) mutation develop a progressive neurodegenerative disorder after a pre-clinical phase. We examined the value of (11)C-raclopride PET (RAC) as a biomarker for pre-clinical HD pathophysiology. In a prospective cohort study with clinical and neuropsychological assessment we collected complete RAC data in 18 pre-clinical mutation carriers (HD-PMC) and 11 controls. Follow-up was 2 years. We calculated striatal RAC binding potential (BP) to measure dopamine D2 receptor availability. No HD-PMC had overt neuropsychological dysfunction. RAC-BP in putamen was abnormal in up to 44% of HD-PMC. The rate of RAC-BP decline (2.6% per year) was not significantly higher than in controls. Follow-up putaminal BP correlated weakly with predicted distance to onset of clinical HD (P = 0.034), but the rate of decline did not. Three HD-PMC developed motor abnormalities suspect for HD but did not show an increased rate of decline of putaminal BP. Many HD-PMC have striatal abnormalities but we found no clearly increased rate of D2 receptor changes around the onset of clinical HD. A longer follow-up of the present study cohort is needed to establish the value of RAC-BP in assessing the risk of clinical conversion from striatal D2 binding data.

Poster 11: Motor Symptom–Related Metabolic Network in Huntington's Disease

Objective To describe a brain metabolic network selectively expressed in symptomatic Huntington's disease (HD) gene carriers. Background A metabolic network specifically associated with HD motor symptoms may be useful in assessing new therapies. We used PET imaging and network analysis to identify a spatial covariance pattern expressed in newly symptomatic HD patients. Design/Methods We utilized serial FDG PET to study 12 presymptomatic HD gene carriers at baseline, 18, and 44 months. Four subjects became symptomatic by 44 months. Additionally, two phenoconverters and two non-phenoconverters were scanned at 68 months. To identify a symptom-related pattern, we conducted network analysis to compare the phenoconverted and non-phenoconverted scans at 44 months. Scans from 12 age-matched healthy controls were included for comparison. Results We identified an HD symptom-related metabolic covariance pattern (HDSP), which separated symptomatic and preclinical gene carriers ( p p p Conclusion The HDSP network emerged as preclinical HD subjects neared clinical onset; its expression also increased as symptoms progressed. A unique feature of the HDSP is its high sensitivity for the motor symptoms of HD. The correlation of pattern activity with clinical ratings indicates that this network may be particularly useful in assessing the emergence of HD symptoms and their response to therapy.

Production of spontaneous and posed facial expressions in patients with Huntington's disease: Impaired communication of disgust

Several studies have reported impairment in the recognition of facial expressions of disgust in patients with Huntington's disease (HD) and preclinical carriers of the HD gene. The aim of this study was to establish whether impairment for disgust in HD patients extended to include the ability to express the emotion on their own faces. Eleven patients with HD, and 11 age and education matched healthy controls participated in three tasks concerned with the expression of emotions. One task assessed the spontaneous production of disgust-like facial expressions during the smelling of offensive odorants. A second assessed the production of posed facial expressions during deliberate attempts to communicate emotion. The third task evaluated HD patients’ ability to imitate the specific facial configurations associated with each emotion. Foul odours induced fewer disgust-like facial reactions in HD patients than in controls, and patients’ posed facial expressions of disgust were less accurate than the posed disgust expressions of controls. The effect was selective to disgust; patients had no difficulty posing expressions of other emotions. These impairments were not explained by compromised muscle control: HD patients had no difficulty imitating the facial movements required to display disgust. Viewed together with evidence of difficulty in other aspects of disgust in HD, the findings suggest that a common substrate might participate in both the processing and the expression of this emotion.

Diffusion Tensor Imaging in Preclinical Huntington’s Disease

Diffusion tensor imaging was used to study brain related changes in white matter that may be associated with Huntington's Disease progression. Thirty-one preclinical gene-mutation carriers were imaged cross-sectionally using diffusion tensor and anatomical brain imaging. Subjects were individuals who had a known gene mutation for HD but did not manifest motor diagnostic criteria for HD. Fractional anisotropy scalar maps showed a positive correlation with five year probability of diagnosis (based upon gene repeat length and current age) in the putamen and a negative correlation in the external capsule. This study shows that scalar maps generated from diffusion tensor imaging may be directly related to the earliest stages of disease progression within HD, even before a diagnosis is given. Findings suggest that DTI measures, therefore, may have the ability to act as a biomarker for disease progression in clinical trials of pre-manifest subjects.

Basal ganglia volume and clinical correlates in ‘preclinical’ Huntington’s disease

To establish differences in basal ganglia and thalamic volume between preclinical carriers and non-carriers of the Huntington's disease (HD) gene and to link the volume to motor, cognitive and behavioural characteristics in carriers. Sixteen HD gene carriers without overt clinical motor signs and 14 non-gene carriers underwent clinical evaluation and a MRI scan. Volumes of the caudate nucleus, putamen, gobus pallidus and thalamus were measured using T1-weighted MR images. Motor, cognitive and behavioural functioning was assessed using the Unified Huntington's Disease Rating Scale (UHDRS), cognitive testing and the Beck Depression Inventory (BDI-II). Volumes of the caudate nucleus, putamen and globus pallidus were significantly smaller in carriers than in non-carriers while no differences between groups were found on clinical evaluation. In gene carriers smaller globus pallidus volume was associated with more motor abnormalities. A smaller putamen volume correlated significantly with worse psychomotor function on the Symbol Digit Modalities Task and the Trail Making Test B. In line with previous research we demonstrated that basal ganglia abnormalities precede overt disease manifestation of HD. Besides we showed that smaller basal ganglia volumes are related to subtle motor abnormalities and worse psychomotor performance in gene carriers without clinical diagnosis. Motor and psychomotor measures may be suitable clinical markers in future neuroprotective trials when combined with volumetric imaging.

Prefrontal cortex volume reduction on MRI in preclinical Huntington's disease relates to visuomotor performance and CAG number

Purpose To investigate grey matter volumes on magnetic resonance imaging (MRI) in preclinical Huntington's disease (HD), and their relationship to neuropsychology and CAG number. Material and methods Twenty preclinical HD carriers and 21 healthy controls matched for age, sex, and educational level were included in this study. Clinical (UHDRS), and detailed neuropsychological assessments, and 3D IR SPGR axial MR acquisition. Calculation of global, segmented (SIENAX), and focal (voxel based morphometry, VBM) grey matter volumes was carried out. An analysis of variance (ANOVA) and a general linear model for VBM analysis were used to compare preclinical HD carriers and controls. Small volume correction was used, and clusters at p < 0.05 were considered significant. Correlation analysis (VBM) with neuropsychology, and CAG number was also performed. Results Preclinical HD carriers showed, compared to controls, smaller global volumes of the brain (1279 ± 6 vs. 1331 ± 46, p = 0.003), total (666 ± 48 vs. 698 ± 34, p = 0.020) and cortical grey matter (551 ± 44 vs. 577 ± 32, p = 0.035). When compared to the controls, preclinical carriers showed focal volume losses, which were more prominent in the left prefrontal cortex, cerebellum, and right posterior temporal cortex. Preclinical HD performed slower in a visuomotor integration task, the 15-Objects test, than controls ( t (1,25.02) = 3.69; p = 0.001: pre-HD: 69.55 ± 28.86; controls: 45.79 ± 8.38). A correlation was found between volume loss in the prefrontal cortex, visuomotor performance, and CAG number. Conclusion Preclinical HD carriers show grey matter volume reduction involving the prefrontal cortex, which relates to the visuomotor performance and CAG number. This suggests that regionally selective neuronal loss/dysfunction occurs prior to the clinical onset of symptoms.

1H magnetic resonance spectroscopy in preclinical Huntington disease

Huntington disease (HD) is a hereditary brain disease, causing progressive deterioration after a preclinical phase. The pathophysiology of early brain abnormalities around disease onset is largely unknown. Some preclinical mutation carriers (PMC) show structural or metabolic changes on brain imaging but the most sensitive imaging modality has not been determined. 1H magnetic resonance spectroscopy (MRS) studies in PMC have reported conflicting results. We studied 19 PMC and 8 controls with MRS and determined relative metabolite peak areas for choline, creatine and N-acetyl aspartate (NAA) in putamen and thalamus. We found no significant differences in metabolite signals between PMC and controls. Decreases in the NAA concentration ratio of putamen relative to thalamus correlated weakly ( R 2 = 0.22, p = 0.04) with increases in the product of CAG repeat length and age, a predictor of striatal damage.Since other brain imaging methods have shown changes in these study subjects, MRS is not a very sensitive detector of early HD brain pathology.

Diffusion tensor imaging in preclinical and presymptomatic carriers of familial Alzheimer's disease mutations

Measures are needed that identify persons that will develop Alzheimer's disease in order to target them for preventative interventions. There is evidence from animal, pathological and imaging studies that disruption of white matter occurs in the course of Alzheimer's disease and may be an early event. Prior studies have suggested that late-myelinating regions or white matter connecting limbic structures are particularly susceptible to degradation. Persons destined to develop the disease by virtue of fully penetrant genetic alterations (familial Alzheimer's disease or FAD) provide a model in which early and even presymptomatic changes of the disease may be identified. In this study we performed diffusion tensor imaging (DTI) on 2 demented and 21 subjects at-risk for inheriting an FAD mutation. We compared global and localized fractional anisotropy (FA) measures in white matter between FAD mutation carriers and non-carriers in the preclinical (clinical dementia rating <1, n = 20) and presymptomatic (clinical dementia rating = 0, n = 15) stages of the disease. There were no significant differences between mutation carriers and non-carriers with regard to absolute age, age relative to the typical age of disease diagnosis in their family, gender or Mini-Mental Status Examination Score. Among preclinical FAD mutation carriers (n = 12), mean whole brain white-matter FA (P = 0.045), FA of the columns of the fornix (P = 0.012), area of the perforant pathways bilaterally (right side: P = 0.028, left side: P = 0.027) and left orbitofrontal lobe (P = 0.024) were decreased relative to that of non-carriers (n = 8). We also found that FA in the columns of the fornix (P = 0.008) and left orbitofrontal lobe white matter (P = 0.045) were decreased in the eight presymptomatic mutation carriers compared to seven non-carriers. Logistic regression demonstrated that FA of the columns of the fornix was a better predictor of mutation status than was cross-sectional area of the fornix, global mean white-matter FA and left frontal lobe white-matter FA. In a linear regression analysis, white-matter volume (P = 0.002), hippocampal volume (P = 0.023) and mutation status (P = 0.032) significantly predicted fornix FA. We conclude that FA is decreased in the white matter in preclinical and even presymptomatic FAD mutation carriers, particularly in the late-myelinating tracts connecting limbic structures. Decreased FA in of the columns of the fornix is particularly robust in early FAD and may provide a biomarker for early disease in sporadic Alzheimer's disease.

Thalamic metabolism and symptom onset in preclinical Huntington's disease.

The neural basis for the transition from preclinical to symptomatic Huntington's disease (HD) is unknown. We used serial positron emission tomography (PET) imaging in preclinical HD gene carriers (p-HD) to assess the metabolic changes that occur during this period. Twelve p-HD subjects were followed longitudinally with [11C]-raclopride and [18F]-fluorodeoxyglucose PET imaging, with scans at baseline, 18 and 44 months. Progressive declines in striatal D2-receptor binding were correlated with concurrent changes in regional metabolism and in the activity of an HD-related metabolic network. We found that striatal D2 binding declined over time (P < 0.005). The activity of a reproducible HD-related metabolic covariance pattern increased between baseline and 18 months (P < 0.003) but declined at 44 months (P < 0.04). These network changes coincided with progressive declines in striatal and thalamic metabolic activity (P < 0.01). Striatal metabolism was abnormally low at all time points (P < 0.005). By contrast, thalamic metabolism was elevated at baseline (P < 0.01), but fell to subnormal levels in the p-HD subjects who developed symptoms. These findings were confirmed with an MRI-based atrophy correction for each individual PET scan. Increases in network expression and thalamic glucose metabolism may be compensatory for early neuronal losses in p-HD. Declines in these measures may herald the onset of symptoms in gene carriers.

Decreased frontal choline and neuropsychological performance in preclinical Huntington disease

To study metabolic brain changes in preclinical carriers of Huntington disease (PreHD) using proton magnetic resonance spectroscopy (1H-MRS) and to examine their relationship to neuropsychological performance. Seventeen subjects with PreHD and 17 controls, matched for age and education, were studied. Frontal cortex and basal ganglia 1H-MRS, and a detailed neuropsychological battery, including visuomotor integration and speed, and memory, frontal, and visuospatial tests were performed. Statistical analysis included Student t-test and Pearson correlations (significance p < 0.05). Frontal choline-containing compounds (CHO) were decreased in PreHD [t (32) = -2.834, p = 0.008]. Subjects with PreHD performed worse than controls in the 15-Objects test [t (32) = 4.077, p = 0.000], Luria motor alternances [t (32) = -2.094, p = 0.044], and Symbol Digit tests [t (32) = -2.136, p = 0.040]. Decreased frontal CHO in PreHD correlated to slowing in visuomotor tasks (the 15-Objects test: r = -0.60, p = 0.000, and the Symbol Digit: r = 0.37, p = 0.047). As choline-containing compounds relate to membrane turnover, membrane dysfunction antedating neuronal death is suggested to occur in the frontal cortex in preclinical carriers of Huntington disease. This dysfunction may be responsible for some of the neuropsychological deficits observed.

Attention, inhibition, and proximity to clinical onset in preclinical mutation carriers for Huntington's disease

Research in preclinical mutation carriers for Huntington's disease (HD) aims to find measures sensitive to preclinical decline. This study investigated attentional abilities in mutation carriers and noncarriers. Mutation carriers demonstrated a normal “attentional blink” during rapid serial visual presentation, normal covert visual orienting, and normal directing of attention to tactile stimuli. However, they were more likely than noncarriers to make anticipatory responses before target presentation. Additionally, those closer to estimated onset of HD demonstrated larger “inhibition of return” effects. The findings suggest potential changes in cognitive inhibition of unwanted responses, and in automatic inhibition of visual orienting, in preclinical HD.

Specific Psychiatric Manifestations Among Preclinical Huntington Disease Mutation Carriers

Despite the need for significant clinical intervention owing to the psychiatric manifestations of Huntington disease (HD), there has been a paucity of studies specifically designed to evaluate these symptoms prior to disease diagnosis. To investigate whether the Symptom Checklist 90-Revised (SCL-90-R) and the Center for Epidemiological Studies Depression Scale can be used to detect psychiatric manifestations among preclinical mutation carriers with absent or minimal motor signs of HD. Individuals at risk for or recently diagnosed with HD were recruited and then evaluated at Indiana University School of Medicine, Indianapolis. All of the subjects completed a uniform clinical evaluation that included the Unified Huntington's Disease Rating Scale-99, molecular testing to determine HD mutation status, the SCL-90-R, and the Center for Epidemiological Studies Depression Scale. The sample was divided into 4 study groups: 171 individuals in the nonmutation carrier group; 29 with minimal, if any, motor signs of HD in the preclinical mutation carrier group 1; 20 with motor abnormalities suggestive of HD in the preclinical mutation carrier group 2; and 34 in the manifest HD group. Scores on the SCL-90-R and Center for Epidemiological Studies Depression Scale were compared. Five SCL-90-R symptom dimensions (obsessive-compulsive, interpersonal sensitivity, anxiety, paranoid ideation, and psychoticism) demonstrated a significant group effect (P < or = .04). The preclinical mutation carrier group 2 and the manifest HD group scored significantly higher on all 5 dimensions as compared with the nonmutation carrier group. The preclinical mutation carrier group 2 scored significantly higher than the nonmutation carrier group for 3 of the SCL-90-R symptom dimensions (anxiety, paranoid ideation, and psychoticism). A significant group effect was found on the Center for Epidemiological Studies Depression Scale (P = .04). The frequency of depressive symptoms was significantly higher in the manifest HD group and the preclinical mutation carrier group 2 as compared with the nonmutation carrier group. This study identified specific psychiatric symptom dimensions that differentiate nonmutation carriers from individuals in the early preclinical stages of HD who are either symptom free or have minor nonspecific motor abnormalities.

Endophenotyping

Neuroimaging-based endophenotyping is becoming popular. The aim is to discover markers for altered CNS gene expression in nonmanifesting gene carriers for illnesses with reduced penetrance, preclinical gene carriers for illnesses with a late onset, and even healthy subjects with allelic variants possibly related to an increased susceptibility for development of given personality traits or psychiatric disorders. As examples, using PET and fMRI, imaging biomarkers have been described for the gene responsible for primary torsion dystonia (DYT1),1 for the Parkin gene mutation responsible for early-onset parkinsonism,2 and for allelic variants in the promoter region of the serotonin transporter implicated in abnormal level of anxiety.3 Neuroimaging endophenotyping is made possible by using highly specialized expensive equipment with well-trained experimenters. These studies cannot determine, however, whether the abnormal activity network associated with the gene is directly gene-related or part of a compensatory mechanism. In this issue of Neurology , O’Dwyer et al.4 show that even relatively simple clinical testing is able to detect subclinical abnormal spatial discrimination capability (SDT) in unaffected relatives of patients with a genetic …

Striatal dopamine D2 receptors, metabolism, and volume in preclinical Huntington disease

Among 27 preclinical carriers of the Huntington disease mutation (PMC), the authors found normal striatal values for MRI volumetry in 88% and for fluorodesoxyglucose PET metabolic index in 67%. Raclopride PET binding potential (RAC-BP) was decreased in 50% and correlated with increases in the product of age and CAG repeat length (p < 0.0005). Dopamine D2 receptor availability measured by RAC-BP seems the most sensitive indicator of early neuronal impairment in PMC.