Preclinical Mutation Carriers Research Articles

Quantitative Evaluation of Stance as a Sensitive Biomarker of Postural Ataxia Development in Preclinical SCA1 Mutation Carriers.

The aim of this study was to determine the time between the first detection of postural control impairments and the evident manifestation of ataxia in preclinical SCA1 individuals. Twenty five preclinical SCA1 mutation carriers: 13 with estimated disease onset ≤ 6years (SCA1 +) aged 27.8 ± 8.1years; 12 with expected disease onset > 6years (SCA1-) aged 26.6 ± 3.1years and 26 age and sex matched healthy controls (HCs) underwent static posturography during 5years of observation. The movements of the centre of feet pressure (COP) during quiet standing with eyes open (EO) and closed (EC) were quantified by calculating the mean radius (R), developed surface area (A) and mean COP movement velocity (V). Ataxia was evaluated by use of the Scale for Assessment and Rating of Ataxia (SARA).SCA1 + exhibited significantly worse quality of stance with EC vs. SCA1- (p < 0.05 for V) and HCs (p < 0.001) even 5 to 6years before estimated disease onset. There were no statistically significant differences between SCA1- and HCs. A slow increase in Cohen's d effect size was observed for VEO up to the clinical manifestation of ataxia. VEO and AEC recorded in preclinical SCA1 individuals correlated slightly but statistically significantly with SARA (r = 0.47).The study confirms that static posturography detects COP sway changes in SCA1 preclinical gene carriers even 5 to 6years before estimated disease onset. The quantitative evaluation of stance in preclinical SCA is a sensitive biomarker for the monitoring of the disease progression and may be useful in clinical trials.

Functional and structural changes of cholinergic basal forebrain in asymptomatic PSEN1 E280A mutation carriers compared with non‐mutation carriers from the API ADAD Colombia cohort

AbstractBackgroundImaging studies showed early atrophy of the cholinergic basal forebrain in prodromal sporadic Alzheimer’s disease (AD) and alterations of the posterior basal forebrain functional connectivity in amyloid positive, but cognitively normal people. Similar investigations in familial cases of AD are still lacking. Here we investigated whether basal forebrain volume, metabolism, and posterior connectivity were already reduced in preclinical stages of autosomal dominant AD.MethodWe analyzed baseline data from 242 cognitively unimpaired subjects (69% PSEN1 E280A mutation carriers; mean age = 38 years; 62% female; mean education = 9 years) enrolled in the API ADAD Colombia Trial including available MRI, FDG‐PET and cognitive measures. We determined volume and metabolism of the basal forebrain, and of the hippocampus as a comparison region. In addition, we created connectivity maps from resting state fMRI data using anterior and posterior BF seed regions. We carried out Bayesian ANCOVA to determine evidence in favor or against an effect of carriers’ status on volumes, metabolism, functional connectivity and cognitive scores.ResultWe found inconclusive to moderate evidence in favor of no effect of carrier status on basal forebrain (BF10 = 0.884) and hippocampal volumes (BF10 = 0.964) or metabolism (BF10 = 0.187) (see Figure) in preclinical (CDR = 0) and prodromal (CDR = 0.5) subjects. However, we found extreme evidence that delayed memory was decreased already in preclinical mutation carriers (BF10 = 4066.73). Yet, we found no conclusive evidence that this subtle memory impairment was associated with basal forebrain (BF10 = 0.582) or hippocampal (BF10 = 0.906) atrophy.ConclusionOur findings indicate absence of basal forebrain and hippocampus atrophy or metabolic impairment in preclinical mutation carriers. Interestingly, memory impairment was already present in preclinical mutation carriers. This is consistent with results of the Dominantly Inherited Alzheimer Network (DIAN) cohort showing early cognitive impairment in mutation carriers, but no significant group differences in hippocampal volume until later stages of the disease. These previous and our findings may suggest that different brain regions and networks are affected in preclinical stages of familial AD than in preclinical sporadic AD, which should be investigated in future studies.

Plasma metabolomics indexes time to clinical dementia in autosomal dominant Alzheimer’s disease mutation carriers

AbstractBackgroundMetabolic dysregulation has been implicated in the pathobiology of Alzheimer’s disease (AD), including familial autosomal dominant AD (ADAD). Recent metabolic neuroimaging of preclinical ADAD mutation carriers has suggested that levels of the reactive glial marker myo‐inositol increase with proximity to expected age at dementia onset. It remains unclear, however, if similar metabolic change related to anticipated phenoconversion can be observed at network‐scale in the peripheral plasma metabolome of ADAD mutation carriers.MethodWe collected peripheral blood plasma from ADAD mutation carriers with and without objective cognitive decline (ncarrier = 55) who participated in a longitudinal kindred study. We used untargeted liquid chromatography‐ mass spectrometry (LC‐MS) metabolomics to infer putative metabolic pathway and protein disruptions associated with impending dementia diagnosis at whole‐genome scale. Spearman 𝝆 correlation coefficients were determined for each identified mass feature in relation to clinical, family‐wise estimated years to diagnosis prior to the submission of these summary statistics to metabolomic modeling.ResultA total of 91 LC‐MS mass features were significantly correlated with estimated years to dementia onset, nominal p’s &lt; .05. Pathway‐based, genome‐scale metabolomic modeling analysis revealed a de novo plasma metabolomic activity network composed of interconnected lipid and small, polar metabolite hubs. These same correlations were also submitted to gene‐inferring, whole‐genome metabolomic modeling using PIUmet. Intriguingly, mRNA expression of prioritized genes was not limited to the brain and involved multiple peripheral tissues. In the CNS itself, however, genes prioritized by PIUMet metabolomic modeling frequently demonstrated expression in glia.ConclusionConsistent with prior metabolic findings in ADAD mutation carriers, network alterations to the peripheral plasma metabolome correspond with increasing proximity to expected age of dementia onset. Because neuroinflammation has been previously described as an immunometabolic process in pathological aging, emerging metabolic network disintegrity in ADAD may index reactive glial pathobiology previously suggested by prior metabolic investigations of this population. These perturbed networks inferred from participant blood plasma suggest targetable CNS‐peripheral metabolic dyshomeostases which otherwise precipitate pathobiological “failures of compensation” and concomitant cognitive decline in carriers of Mendelian ADAD mutations.

Use of advanced echocardiographic modalities to discriminate preclinical HCM mutation carriers from non-carriers

Abstract Background It is a challenging goal to identify which family members of patients with hypertrophic cardiomyopathy (HCM) will subsequently develop HCM. Previous studies evaluating the utility of two-dimensional conventional Doppler echocardiography in HCM families with a known pathogenic variant identified on genetic testing have been unable to reliably distinguish preclinical genotype-positive, phenotype-negative (G+P−) individuals from their healthy genotype-negative, phenotype-negative (G−P−) relatives. Purpose To determine if advanced echocardiographic modalities can discriminate preclinical HCM mutation carriers (G+P−) from non-carriers (G−P−). Methods A total of 199 participants who had undergone genetic testing from HCM families with a known pathogenic variant were included in the study: 39 G−P−; 58 G+P− and 102 overt HCM patients (G+P+). Speckle tracking echocardiography (STE) and colour M-mode were performed on all participants and longitudinal, circumferential and radial strain, and torsion were compared. Results Patients with overt HCM had the highest septal, posterior wall thickness, septum/posterior wall (Sep/PW) thickness ratio and left ventricular outflow tract (LVOT) gradient and lowest global longitudinal, circumferential and radial strain, and tissue Doppler-derived myocardial systolic and diastolic velocities. Comparing G−P− and G+P− individuals, there were no significant differences in LV cavity size, wall thickness, LVOT gradient, LVEF and tissue Doppler-derived myocardial systolic and diastolic velocities. However, G+P− individuals had significantly higher peak apical rotation, peak twist and colour M-mode flow propagation velocity (Vp). Multivariate linear regression identified two independent predictors (peak apical rotation and Vp), and a regression equation (using multivariate linear regression) {Mutation carrier prediction value = (0.210×peak apical rotation) − (0.002×Vp) + 0.156; r=0.655)} was derived which allowed reliable discrimination of G+P- individuals with a sensitivity of 95.2% and specificity of 94.1% at the optimal cut-off. Conclusion In HCM family members without overt HCM, peak apical rotation and Vp provide good sensitivity and specificity for identifying mutation carriers and may be a clinically useful early marker of HCM before the onset of hypertrophy. Future longitudinal studies involving larger cohorts are required to validate these findings. Funding Acknowledgement Type of funding sources: None.

Use of Advanced Echocardiographic Modalities to Discriminate Preclinical HCM Mutation Carriers From Non-Carriers

It is a challenging goal to identify which family members of patients with hypertrophic cardiomyopathy (HCM) will subsequently develop HCM. Conventional and tissue Doppler echocardiography are unable to reliably detect preclinical mutation carriers (G+P−).

Association of serum neurofilament light and disease severity in patients with spinocerebellar ataxia type 3.

To investigate serum neurofilament light protein (sNfL) levels in patients with spinocerebellar ataxia type 3 (SCA3) and to determine whether they are associated with disease severity. This cross-sectional study enrolled 185 healthy controls and 235 ATXN3 mutation carriers (17 asymptomatic stage, 20 preclinical stage, and 198 ataxic stage). We measured sNfL levels with the single molecule array (Simoa) platform. Clinical disease severity was assessed using the Scale of Assessment and Rating of Ataxia (SARA) and the Inventory of Nonataxia Signs (INAS). In a subgroup of 50 ataxic stage patients, we further evaluated the gray matter volume and the integrity of white matter fibers by MRI. sNfL concentrations were elevated in asymptomatic, preclinical, and ataxic ATXN3 mutation carriers compared to controls (12.18 [10.20-13.92], 21.84 [18.37-23.45], 36.06 [30.04-45.90], and 8.24 [5.92-10.84] pg/mL, median [interquartile range], respectively, p < 0.001). sNfL correlated with SARA (r = 0.406, 95% confidence interval [CI] 0.284-0.515, p < 0.0001) and INAS (r = 0.375, 95% CI 0.250-0.487, p < 0.0001), and remained significant after adjustment for age and CAG repeats. In addition, we observed negative correlations of the sNfL with gray matter volume in the left precentral gyrus and the left paracentral lobule as well as with the mean diffusivity in widespread white matter tracts. Our results demonstrate that sNfL levels are increased in SCA3 and are associated with clinical disease severity, which supports sNfL as a biomarker for disease severity in SCA3. This study provides Class II evidence that in patients with SCA3, sNfL elevations are associated with clinical disease severity.

Early symptoms in symptomatic and preclinical genetic frontotemporal lobar degeneration

ObjectivesThe clinical heterogeneity of frontotemporal dementia (FTD) complicates identification of biomarkers for clinical trials that may be sensitive during the prediagnostic stage. It is not known whether cognitive or behavioural...

Abnormal eyeblink conditioning is an early marker of cerebellar dysfunction in preclinical SCA3 mutation carriers

BackgroundSpinocerebellar ataxias (SCAs) are a group of autosomal dominantly inherited degenerative diseases. As the pathological process probably commences years before the first appearance of clinical symptoms, preclinical carriers of a SCA mutation offer the opportunity to study the earliest stages of cerebellar dysfunction and degeneration. Eyeblink classical conditioning (EBCC) is a motor learning paradigm, crucially dependent on the integrity of the olivocerebellar circuit, and has been shown to be able to detect subtle alterations of cerebellar function, which might already be present in preclinical carriers.MethodsIn order to acquire conditioned responses, we performed EBCC, delay paradigm, in 18 preclinical carriers of a SCA3 mutation and 16 healthy, age-matched controls by presenting repeated pairings of an auditory tone with a supraorbital nerve stimulus with a delay interval of 400 ms.ResultsPreclinical carriers acquired significantly less conditioned eyeblink responses than controls and learning rates were significantly reduced. This motor learning defect was, however, not associated with the predicted time to onset.ConclusionsEBCC is impaired in preclinical carriers of a SCA3 mutation, as a result of impaired motor learning capacities of the cerebellum and is thus suggestive of cerebellar dysfunction. EBCC can be used to detect but probably not monitor preclinical cerebellar dysfunction in genetic ataxias, such as SCA3.

Impairment of memory generalization in preclinical autosomal dominant Alzheimer's disease mutation carriers

Fast, inexpensive, and noninvasive identification of Alzheimer's disease (AD) before clinical symptoms emerge would augment our ability to intervene early in the disease. Individuals with fully penetrant genetic mutations causing autosomal dominant Alzheimer's disease (ADAD) are essentially certain to develop the disease, providing a unique opportunity to examine biomarkers during the preclinical stage. Using a generalization task that has previously shown to be sensitive to medial temporal lobe pathology, we compared preclinical individuals carrying ADAD mutations to noncarrying kin to determine whether generalization (the ability to transfer previous learning to novel but familiar recombinations) is vulnerable early, before overt cognitive decline. As predicted, results revealed that preclinical ADAD mutation carriers made significantly more errors during generalization than noncarrying kin, despite no differences between groups during learning or retention. This impairment correlated with the left hippocampal volume, particularly in mutation carriers. Such identification of generalization deficits in early ADAD may provide an easily implementable and potentially linguistically and culturally neutral way to identify and track cognition in ADAD.

Brain atrophy measures in preclinical and manifest spinocerebellar ataxia type 2.

ObjectiveSpinocerebellar ataxia type 2 (SCA2) is an autosomal dominantly inherited neurodegenerative disease mainly affecting the cerebellum and brainstem. In this Cuban‐German research collaboration, we aimed to characterize atrophy patterns and associations with clinical measures in preclinical and manifest SCA2.MethodsIn this study, 16 nonmanifest SCA2 mutation carriers, 26 manifest patients with SCA2, and 18 healthy control subjects underwent magnetic resonance imaging, as well as genetic and clinical characterization including assessment of ataxia (Scale for the Assessment and Rating of Ataxia) and saccade velocity in Cuba were enrolled. Semiautomated quantitative volumetry of the cerebellum and brainstem, subdivided into the medulla oblongata, the pontine brainstem, and mesencephalon was performed. Additionally, the anteroposterior diameter of the pontine brainstem was measured.ResultsAnalysis of volumetric data revealed degeneration of the cerebellum and brainstem, in particular of pontine volumes and the anteroposterior diameter of the pons, in both manifest SCA2 patients and individuals at risk for SCA2 compared to controls. Comparing patients with nonataxic preclinical SCA2 mutation carriers, we found more pronounced reductions of the pontine brainstem and cerebellum in manifest SCA2. Volumetric data further showed associations with CAG repeat length and predicted age of onset in preclinical SCA2 individuals, and by trend with ataxia signs in patients. Although saccade velocity was associated with reduction in the pontine brainstem in preclinical and manifest SCA2, reduced ability to suppress interfering stimuli measured by the Stroop task was related to cerebellar volume loss in patients.InterpretationPreclinical SCA2 mutation carriers exhibit brain abnormalities, which could be targeted as surrogate parameters for disease progression and in future preventive trials.

The Alzheimer's Prevention Initiative Autosomal-Dominant Alzheimer's Disease Trial: A study of crenezumab versus placebo in preclinical PSEN1 E280A mutation carriers to evaluate efficacy and safety in the treatment of autosomal-dominant Alzheimer's disease, including a placebo-treated noncarrier cohort

IntroductionAutosomal-dominant Alzheimer's disease (ADAD) represents a crucial population for identifying prevention strategies that might modify disease course for cognitively unimpaired individuals at high imminent risk for developing symptoms due to Alzheimer's disease (AD), that is, who have “preclinical” AD. Crenezumab is an antiamyloid monoclonal antibody that binds monomeric and aggregated forms of amyloid β, with highest affinity for oligomers; it is in development for early stages of sporadic AD and for ADAD. MethodsThis is a prospective, randomized, double-blind, placebo-controlled phase 2 study of the efficacy of crenezumab versus placebo in asymptomatic PSEN1 E280A mutation carriers from family kindreds with ADAD in Colombia. Participants were randomized to receive either crenezumab or placebo for 260 weeks. The study was designed to enroll a planned total of 300 participants, including 200 preclinical mutation carriers (approximately 100 treatment, 100 placebo) and an additional control group of mutation noncarriers from the same family kindreds included to mask mutation carrier status (100 placebo only). The primary outcome is change in the Alzheimer's Prevention Initiative ADAD Composite Cognitive Test Score from baseline to week 260. Secondary outcomes include time to progression to mild cognitive impairment due to AD or dementia due to AD; changes in dementia severity, memory, and overall neurocognitive functioning; and changes in amyloid–positron emission tomography, fluorodeoxyglucose–positron emission tomography, magnetic resonance imaging volumes, and cerebrospinal fluid levels of β amyloid, tau, and p-tau. Safety and tolerability are assessed. ResultsTwo hundred fifty-two participants were enrolled between December 2013 and February 2017. DiscussionWe describe the first large-scale, potentially label-enabling clinical trial of a preclinical treatment for ADAD. Results from this trial will inform on the efficacy of crenezumab for delaying onset of, slowing decline in, or preventing cognitive impairment in individuals with preclinical ADAD and will foster an improved understanding of AD biomarkers and their relationship to clinical outcomes.

BDNF VAL66MET INCREASES RATE OF MEMORY DECLINE, HIPPOCAMPAL VOLUME LOSS AND TAU ACCUMULATION IN AUTOSOMAL DOMINANT ALZHEIMER’S DISEASE

The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism (rs6265) is implicated in synaptic excitation and neuronal integrity. In autosomal dominant Alzheimer's disease (ADAD), mutation carriers (MC) who also carry the Met66 allele show worse memory and higher levels of cerebrospinal fluid (CSF) tau, but equivalent amyloid levels compared to MC Val66 homozygotes at baseline. The aim of this study was to determine the extent to which the BDNF Val66Met polymorphism affects changes in memory, brain volume, tau and Aβ in ADAD prospectively. Prospective neuropsychological, biomarker and neuroimaging data collected from the Dominantly Inherited Alzheimer Network (DIAN) over ∼2 years were analyzed in 81 preclinical mutation carriers (MC), all with a clinical dementia rating (CDR) score of 0 and estimated to be 11 years prior to clinical symptom onset, and 78 matched mutation non-carriers (NC). BDNF genotype was obtained for MCs (58 Val66 homozygotes, 23 Met66 carriers). Compared to MC Val66 homozygotes, MC Met66 carriers showed greater decline in episodic memory (p<.001), loss of hippocampal volume (p=.005), and increase of CSF tau (p<.001) (Figure 1). Cortical Aβ accumulation was equivalent between MC Val66 homozygotes and MC Met66 carriers (p=.427) (Figure 1). Compared to NCs, MC Val66 homozygotes showed greater increase in cortical Aβ accumulation (p<.001) but equivalent rates of change in episodic memory decline (p=.700), loss of hippocampal volume (p=.215), and accumulation of CSF tau (p=.266) (Figure 1). ADAD is associated with pathologically increased rates of Aβ and tau accumulation, loss of hippocampal volume and decline in episodic memory. The results of the current study show that for MCs who also carry the BDNF Met66 allele, decline in episodic memory, loss of hippocampal volume and increase in CSF tau is substantially greater than for MCs who are Val66 homozygotes, despite equivalent rates of Aβ accumulation. This is consistent with findings in preclinical sporadic AD, where amyloid positive Met66 carriers also show faster deterioration in episodic memory and hippocampal volume, but not Aβ accumulation, when compared to Aβ+ Val66 homozygotes. Together, these data suggest that the BDNF Val66Met polymorphism modifies the contributions to the neurodegenerative process in ADAD. Episodic memory performance, hippocampal volume, Aβ, and tau in preclinical MC Val66 homozygotes (blue lines) and preclinical MC Met66 carriers (red lines) when compared to mutation non-carriers (black lines).

Stance instability in preclinical SCA1 mutation carriers: A 4-year prospective posturography study

ObjectiveWe aimed to study postural balance in preclinical Spinocerebellar ataxia type 1 (SCA1) mutation carriers to identify and observe specific motor functional deficit before evident clinical manifestation. MethodsParticipants were 9 asymptomatic SCA1 mutation carriers (6M/3F), aged 31.8±7years (range 22–44), and 17 age-matched non-carrier controls (5M/12F) (age 18–42). Subjects underwent postural tests on a force platform (Tetrax®-IBS, Sunlight Medical Ltd.) with and without visual feedback. Amount of body sway was represented by stability index (ST). Tests were repeated after 2- and 4-years. Estimated years to onset were calculated. ResultsIn controls, ST was unchanged from baseline to 4-year evaluations in all standing conditions. SCA1 mutation carriers performed similarly to controls in the postural tasks with open eyes, whereas in conditions without visual feedback SCA1 carriers had significantly higher ST than controls at all longitudinal evaluations. Close-to-disease onset carriers (≤7years) showed more prominent time-dependent stance abnormalities (p<0.0001 for all comparisons). ConclusionsTraceable and progressive postural abnormalities can be observed in preclinical close-to-onset SCA1 carriers. Quantitative analysis of stance could represent a promising outcome measure in clinical trials including preclinical subjects.

Decreased body mass index in the preclinical stage of autosomal dominant Alzheimer\u2019s disease

The relationship between body-mass index (BMI) and Alzheimer´s disease (AD) has been extensively investigated. However, BMI alterations in preclinical individuals with autosomal dominant AD (ADAD) have not yet been investigated. We analyzed cross-sectional data from 230 asymptomatic members of families with ADAD participating in the Dominantly Inherited Alzheimer Network (DIAN) study including 120 preclinical mutation carriers (MCs) and 110 asymptomatic non-carriers (NCs). Differences in BMI and their relation with cerebral amyloid load and episodic memory as a function of estimated years to symptom onset (EYO) were analyzed. Preclinical MCs showed significantly lower BMIs compared to NCs, starting 11.2 years before expected symptom onset. However, the BMI curves begun to diverge already at 17.8 years before expected symptom onset. Lower BMI in preclinical MCs was significantly associated with less years before estimated symptom onset, higher global Aβ brain burden, and with lower delayed total recall scores in the logical memory test. The study provides cross-sectional evidence that weight loss starts one to two decades before expected symptom onset of ADAD. Our findings point toward a link between the pathophysiology of ADAD and disturbance of weight control mechanisms. Longitudinal follow-up studies are warranted to investigate BMI changes over time.

Left Atrial structure and function in hypertrophic cardiomyopathy sarcomere mutation carriers with and without left ventricular hypertrophy

BackgroundImpaired left atrial (LA) function is an early marker of cardiac dysfunction and predictor of adverse cardiac events. Herein, we assess LA structure and function in hypertrophy in hypertrophic cardiomyopathy (HCM) sarcomere mutation carriers with and without left ventricular hypertrophy (LVH).MethodSeventy-three participants of the HCMNet study who underwent cardiovascular magnetic resonance (CMR) imaging were studied, including mutation carriers with overt HCM (n = 34), preclinical mutation carriers without HCM (n = 24) and healthy, familial controls (n = 15).ResultsLA volumes were similar between preclinical, control and overt HCM cohorts after covariate adjustment. However, there was evidence of impaired LA function with decreased LA total emptying function in both preclinical (64 ± 8%) and overt HCM (59 ± 10%), compared with controls (70 ± 7%; p = 0.002 and p = 0.005, respectively). LA passive emptying function was also decreased in overt HCM (35 ± 11%) compared with controls (47 ± 10%; p = 0.006). Both LAtotal emptying function and LA passive emptying function were inversely correlated with the extent of late gadolinium enhancement (LGE; p = 0.005 and p < 0.05, respectively), LV mass (p = 0.02 and p < 0.001) and interventricular septal thickness (p < 0.001 for both) and serum NT-proBNP levels (p < 0.001 for both).ConclusionLA dysfunction is detectable by CMR in preclinical HCM mutation carriers despite non-distinguishable LV wall thickness and LA volume. LA function appears most impaired in subjects with overt HCM and a greater extent of LV fibrosis.

Individual changes in preclinical spinocerebellar ataxia identified via increased motor complexity.

Movement changes in autosomal-dominant spinocerebellar ataxias are suggested to occur many years before clinical manifestation. Detecting and quantifying these changes in the preclinical phase offers a window for future treatment interventions and allows the clinician to decipher the earliest dysfunctions starting the evolution of spinocerebellar ataxia. We hypothesized that quantitative movement analysis of complex stance and gait tasks allows to (i) reveal movement changes already at early stages of the preclinical phase when clinical ataxia signs are still absent and to (ii) quantify motor progression in this phase. A total of 46 participants (14 preclinical spinocerebellar ataxia mutation carriers [spinocerebellar ataxias 1,2,3,6], 9 spinocerebellar ataxia patients at an early stage; 23 healthy controls) were assessed by quantitative movement analyses of increasingly complex stance and walking tasks in a cross-sectional design. Body sway in stance and spatiotemporal variability in tandem walking differentiated between preclinical mutation carriers and healthy controls (P < .01). Complex movement conditions allowed one to discriminate even those mutation carriers without any clinical signs in posture and gait (SARAposture&gait = 0; P < .04). Multivariate regression analysis categorized preclinical mutation carriers on a single-subject level with 100% accuracy within a range of 10 years to the estimated onset. Movement features in stance and gait correlated significantly with genetically estimated time to onset, indicating a gradual increase of motor changes with increasing proximity to disease manifestation. Our results provide evidence for subclinical motor changes in spinocerebellar ataxia, which allow to discriminate patients without clinical signs even on a single-subject basis and may help capture disease progression in the preclinical phase. © 2016 International Parkinson and Movement Disorder Society.

Evolution of hypertrophic cardiomyopathy in sarcomere mutation carriers

ObjectiveThe early natural history of sarcomere mutations and the evolution to hypertrophic cardiomyopathy (HCM) are poorly characterised. To describe phenotypic progression, we compared mutation carriers who developed HCM to those...

BDNF Val66Met moderates memory impairment, hippocampal function and tau in preclinical autosomal dominant Alzheimer's disease.

SEE ROGAEVA AND SCHMITT-ULMS DOI101093/AWW201 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is implicated in synaptic excitation and neuronal integrity, and has previously been shown to moderate amyloid-β-related memory decline and hippocampal atrophy in preclinical sporadic Alzheimer's disease. However, the effect of BDNF in autosomal dominant Alzheimer's disease is unknown. We aimed to determine the effect of BDNF Val66Met on cognitive function, hippocampal function, tau and amyloid-β in preclinical autosomal dominant Alzheimer's disease. We explored effects of apolipoprotein E (APOE) ε4 on these relationships. The Dominantly Inherited Alzheimer Network conducted clinical, neuropsychological, genetic, biomarker and neuroimaging measures at baseline in 131 mutation non-carriers and 143 preclinical autosomal dominant Alzheimer's disease mutation carriers on average 12 years before clinical symptom onset. BDNF genotype data were obtained for mutation carriers (95 Val66 homozygotes, 48 Met66 carriers). Among preclinical mutation carriers, Met66 carriers had worse memory performance, lower hippocampal glucose metabolism and increased levels of cerebrospinal fluid tau and phosphorylated tau (p-tau) than Val66 homozygotes. Cortical amyloid-β and cerebrospinal fluid amyloid-β42 levels were significantly different from non-carriers but did not differ between preclinical mutation carrier Val66 homozygotes and Met66 carriers. There was an effect of APOE on amyloid-β levels, but not cognitive function, glucose metabolism or tau. As in sporadic Alzheimer's disease, the deleterious effects of amyloid-β on memory, hippocampal function, and tau in preclinical autosomal dominant Alzheimer's disease mutation carriers are greater in Met66 carriers. To date, this is the only genetic factor found to moderate downstream effects of amyloid-β in autosomal dominant Alzheimer's disease.

Three-dimensional speckle tracking echocardiography for left atrial and left ventricular function in hypertrophic cardiomyopathy mutation carriers

Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiac disorder and is the leading cause of sudden cardiac death in young individuals and athletes. It is caused by mutations in genes that encode for sarcomere proteins and is characterized by unexplained left ventricular (LV) hypertrophy (LVH). However, the penetrance of LVH is incomplete, highly variable, and age dependent. Recent reports have suggested that HCM mutation carriers without overt LVH frequently have risk factors for sudden cardiac death. Genetic testing provides a certain diagnosis for HCM mutation carriers before development of LVH, though it is hampered by being complex and unfeasible in up to 50% of HCM family members as genetic mutations are only identified in 40–60% of HCM patients. Therefore, an alternative family screening approach for early diagnosis of HCM patients is required. LV diastolic dysfunction as the first marker of disease in preclinical HCM mutation carriers has been previously detected by tissue Doppler imaging (TDI). However, the reported sensitivity and specificity were highly variable. Other imaging tools for the early identification of myocardial systolic dysfunction and myocardial structural alteration such as two–dimensional speckle tracking echocardiography (2DSTE) and integrated backscatter echocardiography, respectively were also investigated albeit with mixed results. Recently, cardiac magnetic resonance (CMR) imaging with its high spatial resolution has displayed subtle myocardial structural changes but also intramyocardial crypts in these mainly asymptomatic patients. However the availability of CMR is limited and the analysis is time consuming. Quantification of LA size and function is a good diagnostic tool for LV diastolic function as well as a predictor of therapy response and major cardiovascular outcomes in various cardiac patients including HCM patients. The assessment of left atrial (LA) longitudinal strain using 2DSTE has recently been shown as a feasible and reproducible marker of LA function. Three–dimensional speckle tracking echocardiography (3DSTE) is an emerging tool building on the strengths of 2DSTE for better quantification of myocardial volumes and mechanics including assessment of dyssynchrony in one fast analysis. In this study, we tested the ability of 3DSTE to distinguish HCM mutation carriers from normal subjects primarily by detecting subtle abnormalities in LA size and longitudinal strain as surrogate markers of early LV dysfunction. Likewise, we evaluated the magnitude and timing of systolic myocardial deformation to detect any abnormalities that can define early systolic dysfunction in these subjects. A total of 80 subjects with normal LV ejection fraction (EF) were divided into 3 groups: HCM mutation carriers ( n = 23), manifest HCM patients ( n = 28), and normal controls ( n = 29). They prospectively underwent 3DSTE for left atrial (LA) and LV strain analysis. HCM mutation carriers showed significantly higher LA minimum volume (ml/m 2 ) (17 ± 6 vs. 14 ± 4, respectively, P = 0.03) and a significantly lower peak atrial longitudinal strain (PALS) (%), (27 ± 5 vs. 31 ± 7, respectively, P = 0.02) when compared to controls. However, no differences were found in global or regional LV systolic myocardial deformation between carriers and normal controls. Manifest HCM patients, compared to carriers showed significantly higher LA minimum (27 ± 10 vs. 17 ± 6, respectively, P < 0.001) and maximum volume (42 ± 14 vs. 32 ± 8, respectively, P = 0.007) as well as lower LA EF (%) (35 ± 8 vs. 47 ± 9, respectively, P < 0.001) and PALS (17 ± 5 vs. 27 ± 5, respectively, P < 0.001). Comparing LV strain, HCM patients showed reduced global longitudinal (−11 ± 4 vs. −16 ± 3, respectively, P < 0.001) and area strain (−35 ± 6 vs. −40 ± 5, respectively, P = 0.005). In addition, there was higher mechanical dyssynchrony (SDI) in the long-axis motion (13.6 ± 10 vs. 8.3 ± 4, respectively, P = 0.007). HCM mutation carriers could be distinguished from healthy subjects using 3DSTE through detection of LA dysfunction that might indicate subtle LV dysfunction. No differences were found in LV systolic myocardial deformation between both groups. The exact clinical value of 3DSTE in family screening for HCM needs to be further evaluated.

Biological and clinical characteristics of individuals at risk for spinocerebellar ataxia types 1, 2, 3, and 6 in the longitudinal RISCA study: analysis of baseline data

Spinocerebellar ataxias (SCAs) are autosomal, dominantly inherited, fully penetrant neurodegenerative diseases. Our aim was to study the preclinical stage of the most common SCAs: SCA1, SCA2, SCA3, and SCA6. Between Sept 13, 2008, and Dec 1, 2011, offspring or siblings of patients with SCA1, SCA2, SCA3, or SCA6 were enrolled into a prospective, longitudinal observational study at 14 European centres. To be eligible for inclusion in our study, individuals had to have no ataxia and be aged 18-50 years if directly related to individuals with SCA1, SCA2, or SCA3, or 35-70 years if directly related to individuals with SCA6. We did anonymous genetic testing to identify mutation carriers. We assessed participants with clinical scales, questionnaires, and performance-based coordination tests. In eight of the 14 centres, participants underwent MRI. We analysed relations between outcome variables and time from onset (defined as the difference between present age and estimated age at ataxia onset). This study is registered with ClinicalTrials.gov, number NCT01037777. 276 participants met inclusion criteria and agreed to participate, of whom 12 (4%) were excluded from final analysis because DNA samples were missing or genotyping failed. Estimated time from onset was -9 years (IQR -13 to -6) in 50 carriers of the SCA1 mutation, -12 years (-15 to -9) in 31 SCA2 mutation carriers, -8 years (-11 to -6) in 26 SCA3 mutation carriers, and -18 years (-22 to -16) in 16 SCA6 mutation carriers. Compared with non-carriers of each mutation, SCA1 mutation carriers had higher median scores on the scale for the assessment and rating of ataxia (SARA; 0·5 [IQR 0-1·0] vs 0 [0-0]; p=0·0052), as did SCA2 mutation carriers (0·5 [0-2·0] vs 0 [0-0·5]; p=0·0037). SCA2 mutation carriers had lower SCA functional index scores than did non-carriers (-0·43 [-0·91 to -0·07] vs 0·09 [-0·30 to 0·56]; p=0·0007). SCA2 mutation carriers had worse composite cerebellar functional scores than did their non-carrier counterparts (0·915 [0·861-0·959] vs 0·849 [0·764-0·886]; p=0·0039). All other differences between carriers and non-carriers were non-significant. In SCA1 and SCA2 mutation carriers, SARA scores were increased in participants who were closer to the estimated age at onset (SCA1: r=0·36, p=0·0112; SCA2: r=0·50, p=0·0038). 83 individuals (30%) underwent MRI. Voxel-based morphometry showed grey-matter loss in the brainstem and cerebellum in SCA1 and SCA2 mutation carriers, and normalised brainstem volume was lower in SCA2 mutation carriers (median 0·015, range 0·012-0·016) than in non-carriers (0·019, 0·017-0·021; p=0·0107). Preclinical SCA1 and SCA2 mutation carriers seem to have mild coordination deficits and abnormalities in the brain that are more common in carriers who are closer to the estimated onset of ataxia. Individuals in this early disease stage could be targeted in future preventive trials. ERA-Net E-Rare and Polish Ministry of Science and Higher Education.