Assessment of Early Evidence of Multiple Sclerosis in a Prospective Study of Asymptomatic High-Risk Family Members

Abstract

Importance  Subclinical inflammatory demyelination and neurodegeneration often precede symptom onset in multiple sclerosis (MS).

Objective  To investigate the prevalence of brain magnetic resonance imaging (MRI) and subclinical abnormalities among asymptomatic individuals at risk for MS.

Design, Setting, and Participants  The Genes and Environment in Multiple Sclerosis (GEMS) project is a prospective cohort study of first-degree relatives of people with MS. Each participant’s risk for MS was assessed using a weighted score (Genetic and Environmental Risk Score for Multiple Sclerosis Susceptibility [GERS_MS]) comprising an individual’s genetic burden and environmental exposures. The study dates were August 2012 to July 2015.

Main Outcomes and Measures  Participants in the top and bottom 10% of the risk distribution underwent standard and quantitative neurological examination, including disability status, visual, cognitive, motor, and sensory testing, as well as qualitative and quantitative neuroimaging with 3-T brain MRI and optical coherence tomography.

Results  This study included 100 participants at risk for MS, with 41 at higher risk (40 women [98%]) and 59 at lower risk (25 women [42%]), at a mean (SD) age of 35.1 (8.7) years. Given the unequal sex distribution between the 2 groups, the analyses were restricted to women (n = 65). When considering all measured outcomes, higher-risk women differed from lower-risk women (P = .01 by omnibus test). Detailed testing with a vibration sensitivity testing device in a subgroup of 47 women showed that higher-risk women exhibited significantly poorer vibration perception in the distal lower extremities (P = .008, adjusting for age, height, and testing date). Furthermore, 5 of 65 women (8%) (4 at higher risk and 1 at lower risk) met the primary neuroimaging outcome of having T2-weighted hyperintense brain lesions consistent with the 2010 McDonald MRI criteria for dissemination in space. A subset of participants harbor many different neuroimaging features associated with MS, including perivenous T2-weighted hyperintense lesions and focal leptomeningeal enhancement, consistent with the hypothesis that these individuals are at higher risk of developing clinical symptoms of MS than the general population.

Conclusions and Relevance  Higher-risk asymptomatic family members of patients with MS are more likely to have early subclinical manifestations of MS. These findings underscore the importance of early detection in high-risk individuals.

JAMA Neurology 2017

Duration and Pathologic Correlates of Lewy Body Disease

Abstract

Importance  Although patients with dementia with Lewy bodies (DLB) have shorter disease duration than patients with Alzheimer disease dementia, little is known about which factors influence disease duration among patients with DLB.

Objective  To identify pathologic correlates of disease duration in participants with Lewy body disease (LBD).

Design, Setting, and Participants  This observational study, performed from September 1, 2005, to June 1, 2015, using the National Alzheimer’s Coordinating Center database included 807 participants with transitional or diffuse LBD.

Main Outcomes and Measures  The study used Braak neurofibrillary tangle (NFT) stage, frequency of neuritic plaques, and LBD stage to determine whether pathologic variables are associated with disease duration.

Results  This study included 807 participants with transitional or diffuse LBD (mean [SD] age, 70.0 [9.9] at the onset of cognitive decline and 79.2 [9.8] years at death; 509 male [63.1%]). Shorter disease duration from cognitive symptom onset to death was observed in men (β, −0.73; 95% CI, −1.33 to −0.14; P = .02) and in those with a later age at onset (β, −0.11; 95% CI, −0.14 to −0.08; P < .001). Diffuse (neocortical) LBD was associated with shorter disease duration compared with transitional LBD (β, −1.52; 95% CI, −2.11 to −0.93; P < .001). Braak NFT stage and the presence of neuritic plaques were not significantly associated with differences in disease duration.

Conclusions and Relevance  Diffuse LBD was associated with shorter disease duration compared with transitional LBD, and this effect is independent of Braak NFT stage or extent of neuritic plaque disease. Identifying antemortem biomarkers of LBD stage may provide important prognostic information to patients with DLB.

JAMA Neurology 2017

Quantitative assessment of white matter injury in preterm neonates

ABSTRACT

Objective: To quantitatively assess white matter injury (WMI) volume and location in very preterm neonates, and to examine the association of lesion volume and location with 18-month neurodevelopmental outcomes.

Methods: Volume and location of WMI was quantified on MRI in 216 neonates (median gestational age 27.9 weeks) who had motor, cognitive, and language assessments at 18 months corrected age (CA). Neonates were scanned at 32.1 postmenstrual weeks (median) and 68 (31.5%) had WMI; of 66 survivors, 58 (87.9%) had MRI and 18-month outcomes. WMI was manually segmented and transformed into a common image space, accounting for intersubject anatomical variability. Probability maps describing the likelihood of a lesion predicting adverse 18-month outcomes were developed.

Results: WMI occurs in a characteristic topology, with most lesions occurring in the periventricular central region, followed by posterior and frontal regions. Irrespective of lesion location, greater WMI volumes predicted poor motor outcomes (p = 0.001). Lobar regional analysis revealed that greater WMI volumes in frontal, parietal, and temporal lobes have adverse motor outcomes (all, p < 0.05), but only frontal WMI volumes predicted adverse cognitive outcomes (p = 0.002). To account for lesion location and volume, voxel-wise odds ratio (OR) maps demonstrate that frontal lobe lesions predict adverse cognitive and language development, with maximum odds ratios (ORs) of 78.9 and 17.5, respectively, while adverse motor outcomes are predicted by widespread injury, with maximum OR of 63.8.

Conclusions: The predictive value of frontal lobe WMI volume highlights the importance of lesion location when considering the neurodevelopmental significance of WMI. Frontal lobe lesions are of particular concern

Neurology 2017

Genome-wide association study identifies MAPT locus influencing human plasma tau levels

ABSTRACT

Objective: To identify genetic loci associated with plasma tau concentrations in healthy elders and individuals with Alzheimer disease.

Methods: Four hundred sixty-three non-Hispanic white individuals exceeding quality control criteria were included from the Alzheimer's Disease Neuroimaging Initiative (ADNI-1) cohort. Association of plasma tau with genetic polymorphisms was performed with a linear regression model. Significant associations were validated in an independent replication cohort consisting of 431 healthy elders or individuals with mild cognitive impairment recruited from the University of California, San Francisco Memory and Aging Center.

Results: The minor allele (A) of rs242557 in the microtubule-associated protein tau gene (MAPT) was associated with higher plasma tau levels at genome-wide significance (p = 4.85 × 10⁻⁹, empiric family-wise error corrected p = 0.0024) in a dose-dependent fashion. This association was also observed in the replication cohort (p = 1.0 × 10⁻⁵; joint analysis p = 1.2 × 10⁻¹²). Single nucleotide polymorphisms near PARK2 (rs2187213) (p = 6.15 × 10⁻⁶), IL2RA (rs7072793, rs7073236) (p = 7.89 × 10⁻⁶), and an intergenic locus on 9p21.3 (rs7047280) (p = 8.13 × 10⁻⁶) were identified as suggestive loci associated with plasma tau levels.

Conclusions: MAPT H1c haplotype (rs242557) has previously been identified as a genetic risk factor for progressive supranuclear palsy and corticobasal degeneration. The current findings suggest that plasma tau concentration could be an endophenotype for identifying risk for 4-repeat tauopathies in older individuals.

Neurology 2017

TOMM40′523 variant and cognitive decline in older persons with APOE ε3/3 genotype

ABSTRACT

Objective: To interrogate a poly-T variant (rs10524523, ′523) in TOMM40, a gene adjacent to the APOE gene on chromosome 19, in older persons with APOE ε3/3 homozygosity for association with cognitive decline, the clinical hallmark of Alzheimer disease (AD).

Methods: Data came from participants in 2 cohort studies of aging and dementia who underwent annual clinical evaluations for up to 21 years. APOE and TOMM40′523 genotypes were determined from DNA from blood or brain samples. Linear mixed models compared the rates of decline in cognition among APOE ε3/3 carriers with different ′523 genotypes.

Results: The 1,170 APOE ε3/3 homozygotes were of European ancestry, were free of dementia at baseline, and had an average age of 78.5 years at baseline. Three major genotypes at the ′523 variant were linked to APOE ε3/3; 26.5% had 2 short poly-Ts (S/S), 48.5% had 1 short and 1 very long poly-T (S/VL), and 24.0% had 2 very long poly-Ts (VL/VL). Participants with '523-S/S had faster decline in global cognition than participants with '523-S/VL or VL/VL (p = 0.002). The same association was observed for episodic memory (p < 0.001) and semantic memory (p = 0.003) but not for working memory, perceptual speed, or visuospatial ability.

Conclusions: Our data reveal an association of APOE ε3/3-TOMM40′523 haplotypes with cognitive decline in community-based older persons such that the S/S poly-T genotype is related to faster cognitive decline, primarily in the domains of episodic and semantic memory.

Neurology 2017

Natural course of mild cognitive impairment in Parkinson disease A 5-year population-based study

ABSTRACT

Objective: To examine the incidence, progression, and reversion of mild cognitive impairment in patients with Parkinson disease (PD-MCI) over 5 years.

Methods: A population-based cohort of patients with incident PD underwent repeated neuropsychological testing of attention, executive function, memory, and visuospatial abilities at baseline (n = 178), 1 year (n = 175), 3 years (n = 163), and 5 years (n = 150). Patients were classified as PD-MCI and diagnosed with dementia according to published criteria.

Results: Thirty-six patients (20.2%) fulfilled criteria for PD-MCI at baseline. Among those with normal cognition at baseline (n = 142), the cumulative incidence of PD-MCI was 9.9% after 1 year, 23.2% after 3 years, and 28.9% after 5 years of follow-up. Overall, 39.1% of patients with baseline or incident PD-MCI progressed to dementia during the 5-year study period. The conversion rate to dementia was 59.1% in patients with persistent PD-MCI at 1 year vs 7.2% in those with normal cognition during the first year (adjusted odds ratio 16.6, 95% confidence interval 5.1–54.7, p < 0.001). A total of 27.8% of patients with baseline PD-MCI and 24.2% of those with incident PD-MCI had reverted to normal cognition at study end, but the reversion rate decreased to 9.4% in those with persistent PD-MCI at 2 consecutive visits. Compared with cognitively normal patients, PD-MCI reverters within the first 3 years of follow-up were at increased risk of subsequently developing dementia (adjusted odds ratio 10.7, 95% confidence interval 1.5–78.5, p = 0.019).

Conclusions: Early PD-MCI, regardless of persistence or reversion to normal cognition, has prognostic value for predicting dementia in patients with PD.

Neurology 2017

Treatment decisions in multiple sclerosis — insights from real-world observational studies

The complexity of multiple sclerosis (MS) treatment means that doctors and decision-makers need the best available evidence to make the best decisions for patient care. Randomized controlled trials (RCTs) are accepted as the gold standard for assessing the efficacy and safety of any new drug, but conclusions of these trials do not always aid in daily decision-making processes. Indeed, RCTs are usually conducted in ideal conditions, so can measure efficacy only in restricted and unrepresentative populations. In the past decade, a growing number of MS databases and registries have started to produce long-term outcome data from large cohorts of patients with MS treated with disease-modifying therapies in real-world settings. Such observational studies are addressing issues that are otherwise difficult or impossible to study. In this Review, we focus on the most recently published observational studies designed to identify predictors of poor outcome and treatment response or failure, and to evaluate the relative and long-term effectiveness of currently used MS treatments. We also outline the statistical approaches that are most commonly used to reduce bias and limitations in these studies, and the challenges associated with the use of 'big MS data' to facilitate the implementation of personalized medicine in MS.

Nature Review Neurology 2017