Premanifest Carriers Research Articles

Cognitive-affective manifestations since premanifest phases of Spinocerebellar Ataxia Type 3/Machado-Joseph Disease

BackgroundCognitive deficits were related to Spinocerebellar Ataxia type 3/Machado-Joseph Disease (SCA3/MJD), but the Cerebellar Cognitive Affective Syndrome (CCAS) needs further investigation in this disorder. We aimed to characterize cognitive-affective deficits in manifest and premanifest SCA3/MJD carriers. MethodsSubjects at 50% risk, manifest carriers and unrelated controls were evaluated in-person or in virtual settings with CCAS Scale (CCAS-S), Stroop Color-Word Test (SCWT), Trail-Making Test (TMT), and Reading the Mind in the Eyes Test (RMET). Scale for Assessment and Rating of Ataxia (SARA) >2.5 or Friedreich Ataxia Rating Scale/Activities of Daily Living (FARS-adl) >4 divided carriers into manifest and premanifest. Time after onset or time left to gait ataxia onset (TimeToAfterOnset) were estimated. Differences between groups and correlations with TimeToAfterOnset, SARA and FARS-adl were checked. ResultsAfter random selection to balance groups, 23 manifest and 35 premanifest carriers, and 58 controls were included. CCAS-S, semantic fluency, phonemic fluency, category switching, affect, SCWT, and RMET showed significant differences between manifest carriers and controls; premanifest carriers mostly displayed intermediate values between controls and manifest carriers. These variables correlated with TimeToAfterOnset and SARA scores of the carriers. Correlations with SARA were stronger in the pre-ataxic group. CCAS-S had the strongest correlations with time and SARA. DiscussionCognitive-affective deficits in SCA3/MJD involve executive function, language, affect, and social cognition, which seem to be altered prior to the ataxia onset, and correlate with markers of motor progression. CCAS-S was the most promising biomarker and should be evaluated in longitudinal studies.

Huntington's Disease with Small CAG Repeat Expansions.

Carriers of small cytosine-adenine-guanine (CAG) repeats below 39 in the HTT gene are traditionally associated with milder Huntington's disease, but their clinical profile has not been extensively studied. To study the phenotype of CAG36-38 repeat carriers. We included 35 patients and premanifest carriers of CAG36-38 repeats. We compared clinical and neuropsychological profiles of 11 CAG36-38 patients with 11 matched CAG40-42 patients. In addition, we analyzed 243 CAG36-38 individuals from the ENROLL study to complete the phenotype description. Global cognitive efficiency and performance in different cognitive subdomains were similar in small CAG36-38 and typically CAG40-42 expanded individuals. Chorea as the first symptom was significantly less frequent for CAG36-38 patients (P = 0.04) despite similar total motor scores at first visit. Total motor score at last visit was significantly lower in CAG36-38 carriers (P = 0.003). The similar cognitive and different motor profile of CAG36-38 (n = 243) and CAG40-42 (n = 4675) carriers was confirmed in the ENROLL database. Additionally, clinicians were significantly less confident in diagnosing Huntington's disease (P = 2.4e-8) and diagnosis happened significantly later in CAG36-38 (P = 2.2e-6) despite a similar age at symptom onset (P = 0.29). We showed that small CAG36-38 expansion carriers had a similar cognitive profile to those with the more common CAG40-42 expansions. These individuals may evade molecular diagnosis because of the absence of chorea rather than because of a low penetrance of symptoms. This finding should encourage neurologists to consider Huntington's disease in cognitively impaired elderly patients without typical chorea and anticipate consequences for genetic counseling in their offspring. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Extending the Spectrum of Nonmotor Symptoms with Olfaction in Premotor Huntington’s Disease: A Pilot Study

Objective: The aim of this pilot study was to investigate change of olfactory functions in Huntington’s disease (HD). Background: HD is a neurodegenerative disease characterized by motor, cognitive, and behavioral abnormalities. There are several studies reporting olfactory dysfunction in manifest and some studies in premanifest HD carriers, and a recent neuropathological study demonstrated HD-specific protein aggregation in the anterior olfactory nucleus in HD patients. In this study, we wanted to assess olfactory functions as a possible early nonmotor symptom of HD mutation carriers without disease-specific motor symptoms and HD patients. Methods: All participants had genetic confirmed HD and were prospectively recruited during their routine control in a specialized outpatient clinic of the Medical University of Innsbruck, Department of Neurology, Austria. Healthy controls (HCs) were caregivers from patients. They were only included if they were younger than 70 years, scored more than 24/30 points on the Mini Mental State Examination, and had no other disease compromising olfactory function. Furthermore, all participants were tested on the Sniffin’ sticks 16-items identification test. Results: We included 23 patients with manifest HD, 13 HD mutation carriers, and 19 HCs. Mutation carriers showed significant impaired odor identification compared to HCs (p < 0.001), as well as Huntington’s patients compared with both mutation carriers (p = 0.003) and HCs (p < 0.001). Conclusions: The results of this pilot study suggest that olfactory dysfunction may be an early nonmotor symptom of HD and could be a potential marker to assess disease progression.

Genetic and Environmental Contributors to Neurodegeneration: An Exploration of the Effects of Alcohol on Clinical Features of Huntington's Disease Using the Enroll-HD Global Platform.

Huntington’s disease (HD) is a neurodegenerative dementia with a well recognised genetic cause. Alcohol misuse is a major environmental factor relevant to numerous neurological presentations, including HD. We explored the effects of alcohol intake on clinical features of HD by means of data from the Enroll-HD, which is a global registry study. A retrospective observational study making use of the Enroll-HD periodic dataset up to 2020 (in accordance with the Enroll-HD guidelines, encompassing 16,120 subjects with the HD gene (CAG expansion > 36), was carried out. This included 180 sites in 21 countries. The study looked at the association of alcohol use with the clinical presentation of HD, specifically looking into the age of first symptoms and HD severity. We also describe a specific case with manifest HD, a participant in the Enroll-HD study, whereby the patient’s obsessionality was central to her pattern of high alcohol intake and to her successful avoidance of alcohol thereafter. A record of past problems with high alcohol intake was more common in the group with manifest HD (9.0%, n = 1121) when compared with the pre-manifest carriers of the HD genetic abnormality (2.3%, n = 339). Age at onset of symptoms was not significantly influenced by current alcohol misuse, or past misuse. The severity of clinical impairments in HD was influenced by alcohol. Patients who reported high alcohol intake in the past had a statistically significant increase in motor impairments, by the Unified Huntington’s Disease Rating Scale total motor score (Kruskal–Wallis, post hoc Dunn’s, p < 0.001), and a significantly higher burden of psychiatric symptoms by the Problem Behaviours Assessment score (Kruskal–Wallis, post hoc Dunn’s, p < 0.01) compared with those not reporting high alcohol use. However, the past alcohol group did not have a lower Mini Mental State Examination score (Kruskal–Wallis, post hoc Dunn’s, p > 0.05) The first symptom of HD, as determined by the assessing clinician, was more likely to be psychiatric disturbance in patients currently misusing alcohol or those with prior history of alcohol misuse (55% and 31% respectively) when compared with controls (5%). Individual case experience, such as that presented in this study, shows that HD and alcohol, two major genetic and environmental contributors to neurodegeneration, interact in producing clinical problems. However, the complexities of these interactions are difficult to define, and may require larger studies dedicated to exploring the various factors in this interaction.

Plasma neurofilament light chain predicts cerebellar atrophy and clinical progression in spinocerebellar ataxia

Neurofilament light chain (NfL) is a marker of brain atrophy and predictor of disease progression in rare diseases such as Huntington Disease, but also in more common neurological disorders such as Alzheimer's disease. The aim of this study was to measure NfL longitudinally in autosomal dominant spinocerebellar ataxias (SCAs) and establish correlation with clinical and imaging parameters. We enrolled 62 pathological expansions carriers (17 SCA1, 13 SCA2, 19 SCA3, and 13 SCA7) and 19 age-matched controls in a prospective biomarker study between 2011 and 2015 and followed for 24 months at the Paris Brain Institute. We performed neurological examination, brain 3 T MRI and plasma NfL measurements using an ultrasensitive single-molecule array at baseline and at the two-year follow-up visit. We evaluated NfL correlations with ages, CAG repeat sizes, clinical scores and volumetric brain MRIs. NfL levels were significantly higher in SCAs than controls at both time points (p < 0.001). Age-adjusted NfL levels were significantly correlated at baseline with clinical scores (p < 0.01). We identified optimal NfL cut-off concentrations to differentiate controls from carriers for each genotype (SCA1 16.87 pg/mL, SCA2, 19.1 pg/mL, SCA3 16.04 pg/mL, SCA7 16.67 pg/mL). For all SCAs, NfL concentration was stable over two years (p = 0.95) despite a clinical progression (p < 0.0001). Clinical progression between baseline and follow-up was associated with higher NfL concentrations at baseline (p = 0.04). Of note, all premanifest carriers with NfL levels close to cut off concentrations had signs of the disease at follow-up. For all SCAs, the higher the observed NfL, the lower the pons volume at baseline (p < 0.01) and follow-up (p = 0.02). Higher NfL levels at baseline in all SCAs predicted a decrease in cerebellar volume (p = 0.03). This result remained significant for SCA2 only among all genotypes (p = 0.02). Overall, plasma NfL levels at baseline in SCA expansion carriers predict cerebellar volume change and clinical score progression. NfL levels might help refine inclusion criteria for clinical trials in carriers with very subtle signs.

Clinical, Imaging, and Laboratory Markers of Premanifest Spinocerebellar Ataxia 1, 2, 3, and 6: A Systematic Review

Background and PurposePremanifest mutation carriers with spinocerebellar ataxia (SCA) can exhibit subtle abnormalities before developing ataxia. We summarized the preataxic manifestations of SCA1, -2, -3, and -6, and their associations with ataxia onset.MethodsWe included studies of the premanifest carriers of SCA published between January 1998 and December 2019 identified in Scopus and PubMed by searching for terms including ‘spinocerebellar ataxia’ and several synonyms of ‘preataxic manifestation’. We systematically reviewed the results obtained in studies categorized based on clinical, imaging, and laboratory markers.ResultsWe finally performed a qualitative analysis of 48 papers. Common preataxic manifestations appearing in multiple SCA subtypes were muscle cramps, abnormal muscle reflexes, instability in gait and posture, lower Composite Cerebellar Functional Severity scores, abnormalities in video-oculography and transcranial magnetic stimulation, and gray-matter loss and volume reduction in the brainstem and cerebellar structures. Also, decreased sensory amplitudes in nerve conduction studies were observed in SCA2. Eotaxin and neurofilament light-chain levels were revealed as sensitive blood biomarkers in SCA3. Concerning potential predictive markers, hyporeflexia and abnormalities of somatosensory evoked potentials showed correlations with the time to ataxia onset in SCA2 carriers. However, no longitudinal data were found for the other SCA gene carriers.ConclusionsOur results suggest that preataxic manifestations vary among SCA1, -2, -3, and -6, with some subtypes sharing specific features. Combining various markers into a standardized index for premanifest carriers may be useful for early screening and assessing the risk of disease progression in SCA carriers.

Alterations in the tyrosine and phenylalanine pathways revealed by biochemical profiling in cerebrospinal fluid of Huntington\u2019s disease subjects

Huntington’s disease (HD) is a severe neurological disease leading to psychiatric symptoms, motor impairment and cognitive decline. The disease is caused by a CAG expansion in the huntingtin (HTT) gene, but how this translates into the clinical phenotype of HD remains elusive. Using liquid chromatography mass spectrometry, we analyzed the metabolome of cerebrospinal fluid (CSF) from premanifest and manifest HD subjects as well as control subjects. Inter-group differences revealed that the tyrosine metabolism, including tyrosine, thyroxine, L-DOPA and dopamine, was significantly altered in manifest compared with premanifest HD. These metabolites demonstrated moderate to strong associations to measures of disease severity and symptoms. Thyroxine and dopamine also correlated with the five year risk of onset in premanifest HD subjects. The phenylalanine and the purine metabolisms were also significantly altered, but associated less to disease severity. Decreased levels of lumichrome were commonly found in mutated HTT carriers and the levels correlated with the five year risk of disease onset in premanifest carriers. These biochemical findings demonstrates that the CSF metabolome can be used to characterize molecular pathogenesis occurring in HD, which may be essential for future development of novel HD therapies.

Regional subcortical shape analysis in premanifest Huntington's disease.

Huntington's disease (HD) involves preferential and progressive degeneration of striatum and other subcortical regions as well as regional cortical atrophy. It is caused by a CAG repeat expansion in the Huntingtin gene, and the longer the expansion the earlier the age of onset. Atrophy begins prior to manifest clinical signs and symptoms, and brain atrophy in premanifest expansion carriers can be studied. We employed a diffeomorphometric pipeline to contrast subcortical structures' morphological properties in a control group with three disease groups representing different phases of premanifest HD (far, intermediate, and near to onset) as defined by the length of the CAG expansion and the participant's age (CAG-Age-Product). A total of 1,428 magnetic resonance image scans from 694 participants from the PREDICT-HD cohort were used. We found significant region-specific atrophies in all subcortical structures studied, with the estimated abnormality onset time varying from structure to structure. Heterogeneous shape abnormalities of caudate nuclei were present in premanifest HD participants estimated furthest from onset and putaminal shape abnormalities were present in participants intermediate to onset. Thalamic, hippocampal, and amygdalar shape abnormalities were present in participants nearest to onset. We assessed whether the estimated progression of subcortical pathology in premanifest HD tracked specific pathways. This is plausible for changes in basal ganglia circuits but probably not for changes in hippocampus and amygdala. The regional shape analyses conducted in this study provide useful insights into the effects of HD pathology in subcortical structures.

Gray Matter Volume of a Region in the Thalamic Pulvinar Is Specifically Associated with Novelty Seeking.

Personality reflects the set of psychological traits and mechanisms characteristic for an individual. Geno-neuro-biologically inspired personality accounts have proposed a set of temperaments and characters that jointly compose personality profiles. The present study addresses the link between neurobiology and personality and investigates the association between temperament traits and regional gray matter volume. Furthermore, the specificity of these associations as well as the underlying components that drive the association are addressed. One hundred and four participants completed the Temperament and Character Inventory (TCI) and underwent structural magnetic resonance brain imaging. The participants included premanifest carriers of Huntington's disease, as this population is associated with temperament-related neuropsychiatric symptoms. Whole brain voxel-based multiple regression analyses on gray matter volume revealed a significant specific positive correlation between a region in the left thalamic pulvinar and novelty seeking score, controlled for the other traits (Pheight < 0.05, FWE-corrected). No significant associations were observed for the other temperament traits. Region of interest analyses showed that this association is driven by the subscale NS2: impulsiveness. The results increase the knowledge of the structural neurobiology of personality and indicate that individual differences in novelty seeking reflect the structural differences observed in the brain in an area that is widely and densely connected, which is in line with the typically domain-general behavioral influence of personality traits on a wide range of affective, perceptual, mnemotic, executive, and other cognitive functions.

Quantification of the Light Subunit of Neurofilament Protein in Cerebrospinal Fluid of Huntington's Disease Patients.

Neurofilament light proteins (NFL) are a structural element of the neuronal cytoskeleton and are released with neuronal damage. Its levels are increased in cerebrospinal fluid (CSF) in the setting of neurodegenerative diseases. We investigated the CSF-NFL levels of Huntington´s disease (HD) patients (participating in a clinical trial SAT-HD) as well as of premanifest carriers and compared their results with a sample of healthy controls and correlated CSF-NFL levels with demographic and clinical variables (baseline demographic characteristics and HD measures of disease severity). CSF levels were significantly higher in all HD subjects [5014.4 (1557.3) ng/l] and pre-manifest carriers [1050 (212.13) ng/l as compared to controls [331.4 (200.2) ng/l] (p<0.00) and were correlated with age (correlation coefficient -0.37, p<0.01) and CAG triplet number (0,51, p<0.05) in the subset of HD patients. NFL levels were not correlated with age in the control group. We did not find any correlation with the remaining variables. These results indicate, as in previous studies, that CSF-NFL levels are a marker of neuronal damage in HD. It seems to be a highly sensitive, but non-specific marker of axonal damage. One of the limitations of our study is a very small number of patients in pre-symptomatic group and lack of individuals with very advanced HD. Further investigations should focus on study of CSF-NFL levels in advanced patients, tracking prospectively CSF-NFL levels and analysing its correlation with the clinical course and usefulness to monitor disease progression, validation and quantification of NFL levels in more accessible biofluids.

Tau or neurofilament light-Which is the more suitable biomarker for Huntington's disease?

IntroductionPrevious studies have suggested cerebrospinal fluid (CSF) levels of neurofilament light (NFL) and total tau are elevated in Huntington’s disease (HD) and may be used as markers of disease stage. Biomarkers are needed due to the slow disease progression and the limitations of clinical assessment. This study aims to validate the role of NFL and tau as biomarkers in HD.MethodsCSF was obtained from a cohort of HD patients and premanifest HD-mutation carriers. Unified Huntington’s Disease Rating Scale (UHDRS) testing was performed on all subjects at the time of sampling. NFL and tau concentrations were determined by ELISA. Spearman correlations were calculated with R version 3.2.3.Results11 premanifest HD and 12 manifest HD subjects were enrolled. NFL and tau levels were correlated. NFL showed strong correlations with all items included in the clinical assessment (for example the total functional capacity (TFC) (r = - 0.70 p < 0.01) and total motor score (TMS) (r = 0.83p < 0.01). Tau showed slightly weaker correlations (eg. TMS (r = 0.67 p < 0.01); TFC (r = - 0.59 p < 0.01)). NFL was significantly correlated with 5-year probability of disease onset, whereas tau was not.ConclusionThis study strengthens the case for NFL as a useful biomarker of disease stage. NFL was strongly correlated to all evaluated items in the UHDRS assessment. Tau also has a potential for use as a biomarker but correlations to clinical tests are weaker in this study. We suggest that NFL and possibly tau be used in clinical drug trials as biomarkers of disease progression that are potentially influenced by future disease-modifying therapies.

A liminal stage after predictive testing for Huntington disease

BackgroundFollowing predictive testing for Huntington disease (HD), knowledge of one's carrier status may have consequences on disease onset. Our study aimed to address two questions. First, does knowledge of being...

Current status of PET imaging in Huntington's disease.

PurposeTo review the developments of recent decades and the current status of PET molecular imaging in Huntington’s disease (HD).MethodsA systematic review of PET studies in HD was performed. The MEDLINE, Web of Science, Cochrane and Scopus databases were searched for articles in all languages published up to 19 August 2015 using the major medical subject heading “Huntington Disease” combined with text and key words “Huntington Disease”, “Neuroimaging” and “PET”. Only peer-reviewed, primary research studies in HD patients and premanifest HD carriers, and studies in which clinical features were described in association with PET neuroimaging results, were included in this review. Reviews, case reports and nonhuman studies were excluded.ResultsA total of 54 PET studies were identified and analysed in this review. Brain metabolism ([18F]FDG and [15O]H2O), presynaptic ([18F]fluorodopa, [11C]β-CIT and [11C]DTBZ) and postsynaptic ([11C]SCH22390, [11C]FLB457 and [11C]raclopride) dopaminergic function, phosphodiesterases ([18F]JNJ42259152, [18F]MNI-659 and [11C]IMA107), and adenosine ([18F]CPFPX), cannabinoid ([18F]MK-9470), opioid ([11C]diprenorphine) and GABA ([11C]flumazenil) receptors were evaluated as potential biomarkers for monitoring disease progression and for assessing the development and efficacy of novel disease-modifying drugs in premanifest HD carriers and HD patients. PET studies evaluating brain restoration and neuroprotection were also identified and described in detail.ConclusionBrain metabolism, postsynaptic dopaminergic function and phosphodiesterase 10A levels were proven to be powerful in assessing disease progression. However, no single technique may be currently considered an optimal biomarker and an integrative multimodal imaging approach combining different techniques should be developed for monitoring potential neuroprotective and preventive treatment in HD.

A clinical classification acknowledging neuropsychiatric and cognitive impairment in Huntington's disease.

BackgroundInvoluntary movements, neuropsychiatric symptoms, and cognitive impairment are all part of the symptom triad in Huntington’s disease (HD). Despite the fact that neuropsychiatric symptoms and cognitive decline may be early manifestations of HD, the clinical diagnosis is conventionally based on the presence of involuntary movements and a positive genetic test for the HD CAG repeat expansion. After investigating the frequencies of the triad manifestations in a large outpatient clinical cohort of HD gene-expansion carriers, we propose a new clinical classification.MethodsIn this cross-sectional study, 107 gene-expansion carriers from a Danish outpatient clinic were recruited. All participants underwent neurological examination, psychiatric evaluation and neuropsychological testing. Participants were categorised according to motor symptoms, neuropsychiatric symptoms, the use of psychotropic medication, and cognitive impairment.ResultsAmong the motor manifest HD gene-expansion carriers, 51.8% presented with the full symptom triad, 25.0% were defined as cognitively impaired in addition to motor symptoms, and 14.3% had neuropsychiatric symptoms along with motor symptoms. Only 8.9% had isolated motor symptoms. Among gene-expansion carriers without motor symptoms, 39.2% had neuropsychiatric symptoms, were cognitively impaired, or had a combination of the two.ConclusionThis is the first study to report the frequencies of both motor symptoms, cognitive impairment, and neuropsychiatric symptoms in HD gene-expansion carriers in a national outpatient HD clinical cohort. We found that almost 40% of the gene-expansion carriers without motor symptoms had either neuropsychiatric symptoms, cognitive impairment or both, emphasising that these patients are not premanifest in psychiatric and cognitive terms, suggesting that the current clinical classification is neither necessarily suitable nor helpful for this patient group. Some premanifest gene-expansion carriers may have psychiatric and/or cognitive symptoms caused by reactive stress or other pathology than HD. Acknowledging this fact we, however, suggest classifying all HD gene-expansion carriers into three clinical categories: premanifest, non-motor manifest, and motor manifest.

Impaired brain energy metabolism in the BACHD mouse model of Huntington's disease: critical role of astrocyte-neuron interactions.

Huntington's disease (HD) is caused by cytosine-adenine-guanine (CAG) repeat expansions in the huntingtin (Htt) gene. Although early energy metabolic alterations in HD are likely to contribute to later neurodegenerative processes, the cellular and molecular mechanisms responsible for these metabolic alterations are not well characterized. Using the BACHD mice that express the full-length mutant huntingtin (mHtt) protein with 97 glutamine repeats, we first demonstrated localized in vivo changes in brain glucose use reminiscent of what is observed in premanifest HD carriers. Using biochemical, molecular, and functional analyses on different primary cell culture models from BACHD mice, we observed that mHtt does not directly affect metabolic activity in a cell autonomous manner. However, coculture of neurons with astrocytes from wild-type or BACHD mice identified mutant astrocytes as a source of adverse non-cell autonomous effects on neuron energy metabolism possibly by increasing oxidative stress. These results suggest that astrocyte-to-neuron signaling is involved in early energy metabolic alterations in HD.

Relationship of Mediterranean Diet and Caloric Intake to Phenoconversion in Huntington Disease

Adherence to Mediterranean-type diet (MeDi) may delay onset of Alzheimer and Parkinson diseases. Whether adherence to MeDi affects time to phenoconversion in Huntington disease (HD), a highly penetrant, single-gene disorder, is unknown. To determine if MeDi modifies the time to clinical onset of HD (phenoconversion) in premanifest carriers participating in Prospective Huntington at Risk Observational Study (PHAROS), and to examine the effects of body mass index and caloric intake on time to phenoconversion. A prospective cohort study of 41 Huntington study group sites in the United States and Canada involving 1001 participants enrolled in PHAROS between July 1999 and January 2004 who were followed up every 9 months until 2010. A total of 211 participants aged 26 to 57 years had an expanded CAG repeat length (≥ 37). A semiquantitative food frequency questionnaire was administered 33 months after baseline. We calculated daily gram intake for dairy, meat, fruit, vegetables, legumes, cereals, fish, monounsaturated and saturated fatty acids, and alcohol and constructed MeDi scores (0-9); higher scores indicate higher adherence. Demographics, medical history, body mass index, and Unified Huntington's Disease Rating Scale (UHDRS) score were collected. Cox proportional hazards regression models to determine the association of MeDi and phenoconversion. RESULTS Age, sex, caloric intake, education status, and UHDRS motor scores did not differ among MeDi tertiles (0-3, 4-5, and 6-9). The highest body mass index was associated with the lowest adherence to MeDi. Thirty-one participants phenoconverted. In a model adjusted for age, CAG repeat length, and caloric intake, MeDi was not associated with phenoconversion (P for trend = 0.14 for tertile of MeDi, and P = .22 for continuous MeDi). When individual components of MeDi were analyzed, higher dairy consumption (hazard ratio, 2.36; 95% CI, 1.0-5.57; P = .05) and higher caloric intake (P = .04) were associated with risk of phenoconversion. MeDi was not associated with phenoconversion; however, higher consumption of dairy products had a 2-fold increased risk and may be a surrogate for lower urate levels (associated with faster progression in manifest HD). Studies of diet and energy expenditure in premanifest HD may provide data for interventions to modify specific components of diet that may delay the onset of HD.

Lessons from preclinical disease

Identifying individuals at risk of developing neurodegenerative conditions prior to clinical manifestation of disease, has become a popular subject for recent neurological research. It is well established that by the time patients present with these disorders, a significant degree of irreversible neuronal loss has already occurred. Understanding the evolution of preclinical disease may, therefore, highlight methods by which the pathological processes can be slowed or curtailed; either through modifying environmental factors or by the use of novel disease modifying agents. Encouragingly this approach already has a number of successful precedents and is widely employed in the prevention of heart disease and indeed in many other branches of medicine. An important first step in this process will be the ability to screen individuals at risk for predictive biomarkers of disease, but identifying the population at risk for sporadic neurodegenerative conditions has proved problematic. However, the study of fully penetrant autosomal dominant disorders, in which a reliable genetic test is currently available, offers an opportunity to identify specific predefined cohorts. These very specific cohorts can then be assessed in detail, if necessary over prolonged time periods, for a large range of potential clinical, biological and radiological biomarkers. Although the numbers of individuals at risk of these relatively rare genetic disorders are commonly limited, the hope is that studies of this important group of individuals may offer important insights into more common sporadic conditions. In this month’s journal club, we examine three articles; each one addressing these issues in seperate neurodegenerative disorders, all of which are autosomal dominant and fully penetrant conditions and in which the age at onset can be predicted with varying degrees of accuracy: Huntington’s disease (HD), autosomal dominant cerebellar ataxias (SCA) and presenilin 1 autosomal dominant Alzheimer’s disease. In the first paper Tabrizi et al., examine premanifest carriers of HD and early HD patients in a 36-month longitudinal study. The second paper by Jacobi et al., examines carriers of the SCA1, SCA2, SCA3 and SCA6 mutations prior to disease onset. The final paper describes a cross sectional analysis of a Colombian cohort of Presenilin 1 mutation carriers. All three studies have employed different methodologies in search of a common goal; to identify informative clinical, biological or radiological biomarkers for these diseases.

Learning fast accurate movements requires intact frontostriatal circuits

The basal ganglia are known to play a crucial role in movement execution, but their importance for motor skill learning remains unclear. Obstacles to our understanding include the lack of a universally accepted definition of motor skill learning (definition confound), and difficulties in distinguishing learning deficits from execution impairments (performance confound). We studied how healthy subjects and subjects with a basal ganglia disorder learn fast accurate reaching movements. We addressed the definition and performance confounds by: (1) focusing on an operationally defined core element of motor skill learning (speed-accuracy learning), and (2) using normal variation in initial performance to separate movement execution impairment from motor learning abnormalities. We measured motor skill learning as performance improvement in a reaching task with a speed-accuracy trade-off. We compared the performance of subjects with Huntington's disease (HD), a neurodegenerative basal ganglia disorder, to that of premanifest carriers of the HD mutation and of control subjects. The initial movements of HD subjects were less skilled (slower and/or less accurate) than those of control subjects. To factor out these differences in initial execution, we modeled the relationship between learning and baseline performance in control subjects. Subjects with HD exhibited a clear learning impairment that was not explained by differences in initial performance. These results support a role for the basal ganglia in both movement execution and motor skill learning.

Is non-recognition of choreic movements in Huntington disease always pathological?

Clinical experience and prior studies suggest that Huntington disease (HD) patients have low insight into their motor disturbances and poor real-time awareness (concurrent awareness) of chorea. This has been attributed to sensory deficits but, until now, concurrent awareness of choreic movements has not been compared to the degree of insight that presymptomatic carriers of the HD gene and healthy control subjects have into non-pathological involuntary movements. To further investigate loss of insight into motor dysfunction in HD patients, we administered a video-recorded interview and 4experimental tasks to 68 subjects from the TRACK-HD cohort, including 28 high-functioning patients in early stages of HD, 28 premanifest mutation carriers and 12 controls. All underwent full neurological and neuropsychological evaluations and 3T MRI examinations. Subjects were asked to assess the presence, body location, frequency, practical consequences and probable causes of motor impairments, as well as the presence and body location of involuntary movements during 4experimental tasks. The accuracy of their judgments, assessed by comparison with objective criteria, was used as a measure of their insight into motor disturbances and of their concurrent awareness of involuntary movements.Insight was poor in early HD patients: motor symptoms were nearly always underestimated. In contrast, concurrent awareness of involuntary movements, although also poor, was essentially indistinguishable across the 3groups of subjects: non-pathological involuntary movements were as difficult to perceive by controls and premanifest carriers as was chorea for early HD patients. GLM analysis suggested that both concurrent awareness and perception of practical consequences of movement disorder had a positive effect on intellectual insight, and that mental flexibility is involved in concurrent awareness.Our results suggest that low insight into motor dysfunction in early HD, although marginally modulated by cognitive factors, is mainly non-pathological, and parallels a general tendency, shared by healthy subjects, to neglect self-generated involuntary movements in real time. This tendency, combined with the paucity of functional consequences of incipient chorea, could explain the difficulty of its discovery by the patients.

Altered brain mechanisms of emotion processing in pre-manifest Huntington's disease

Huntington's disease is an inherited neurodegenerative disease that causes motor, cognitive and psychiatric impairment, including an early decline in ability to recognize emotional states in others. The pathophysiology underlying the earliest manifestations of the disease is not fully understood; the objective of our study was to clarify this. We used functional magnetic resonance imaging to investigate changes in brain mechanisms of emotion recognition in pre-manifest carriers of the abnormal Huntington's disease gene (subjects with pre-manifest Huntington's disease): 16 subjects with pre-manifest Huntington's disease and 14 control subjects underwent 1.5 tesla magnetic resonance scanning while viewing pictures of facial expressions from the Ekman and Friesen series. Disgust, anger and happiness were chosen as emotions of interest. Disgust is the emotion in which recognition deficits have most commonly been detected in Huntington's disease; anger is the emotion in which impaired recognition was detected in the largest behavioural study of emotion recognition in pre-manifest Huntington's disease to date; and happiness is a positive emotion to contrast with disgust and anger. Ekman facial expressions were also used to quantify emotion recognition accuracy outside the scanner and structural magnetic resonance imaging with voxel-based morphometry was used to assess the relationship between emotion recognition accuracy and regional grey matter volume. Emotion processing in pre-manifest Huntington's disease was associated with reduced neural activity for all three emotions in partially separable functional networks. Furthermore, the Huntington's disease-associated modulation of disgust and happiness processing was negatively correlated with genetic markers of pre-manifest disease progression in distributed, largely extrastriatal networks. The modulated disgust network included insulae, cingulate cortices, pre- and postcentral gyri, precunei, cunei, bilateral putamena, right pallidum, right thalamus, cerebellum, middle frontal, middle occipital, right superior and left inferior temporal gyri, and left superior parietal lobule. The modulated happiness network included postcentral gyri, left caudate, right cingulate cortex, right superior and inferior parietal lobules, and right superior frontal, middle temporal, middle occipital and precentral gyri. These effects were not driven merely by striatal dysfunction. We did not find equivalent associations between brain structure and emotion recognition, and the pre-manifest Huntington's disease cohort did not have a behavioural deficit in out-of-scanner emotion recognition relative to controls. In addition, we found increased neural activity in the pre-manifest subjects in response to all three emotions in frontal regions, predominantly in the middle frontal gyri. Overall, these findings suggest that pathophysiological effects of Huntington's disease may precede the development of overt clinical symptoms and detectable cerebral atrophy.