The Phosphodiesterase 10 Positron Emission Tomography Tracer, [18F]MNI-659, as a Novel Biomarker for Early Huntington Disease

Importance  In Huntington disease (HD) striatal neuron loss precedes and predicts motor signs or symptoms. Current imaging biomarkers lack adequate sensitivity for assessing the early stages of HD. Developing an imaging biomarker for HD spanning the time of onset of motor signs remains a major unmet research need. Intracellular proteins whose expression is altered by the mutant huntingtin protein may be superior markers for early HD stages.

Objective  To evaluate whether [18F]MNI-659 (2-(2-(3-(4-(2-[18F]fluoroethoxy)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione), a novel phosphodiesterase 10 positron emission tomography (PET) ligand, is a sensitive marker for striatal changes in early HD.

Design, Setting, and Participants  A cohort of individuals with HD, including premanifest (pre-HD) or manifest with motor signs (mHD), underwent clinical assessments, genetic determination, [18F]MNI-659 PET imaging, and brain magnetic resonance imaging. Age-matched healthy volunteers (HVs) also received clinical assessments and PET and magnetic resonance imaging.

Main Outcomes and Measures  Binding potentials (BPnds) were estimated for brain regions of interest, specifically within the basal ganglia, and compared between participants with HD and the HVs and correlated with markers of HD severity and atrophy of basal ganglia nuclei.

Results  Eleven participants with HD (8 mHD and 3 pre-HD) and 9 HVs participated. Ten of 11 HD participants had known huntingtin CAG repeat length, allowing determination of a burden of pathology (BOP) score. One individual with HD declined CAG determination. All participants with mHD had relatively early-stage disease (4 with stage 1 and 4 with stage 2) and a Unified Huntington’s Disease Rating Scale (UHDRS) total Motor subscale score of less than 50. The HD cohort had significantly lower striatal [18F]MNI-659 uptake than did the HV cohort (mean, −48.4%; P < .001). The HD cohort as a whole had a reduction in the basal ganglia BPnd to approximately 50% of the level in the HVs (mean, −47.6%; P < .001). The 3 pre-HD participants had intermediate basal ganglia BPnds. Striatal [18F]MNI-659 uptake correlated strongly with the severity of disease measured by the clinical scale (UHDRS Motor subscale; R = 0.903; P < .001), the molecular marker (BOP; R = 0.908; P < .001), and regional atrophy (R = 0.667; P < .05).

Conclusions and Relevance  As a promising striatal imaging biomarker, [18F]MNI-659 is potentially capable of assessing the extent of disease in early mHD. Furthermore, [18F]MNI-659 may identify early changes in medium spiny neurons and serve as a marker to predict conversion to mHD. Additional studies with larger, stratified cohorts of patients with HD and prospective studies of individuals with pre-HD are warranted.

JAMA Neurology 2014

Common Genetic Variants on 6q24 Associated With Exceptional Episodic Memory Performance in the Elderly

Importance  There are genetic influences on memory ability as we age, but no specific genes have been identified.

Objective  To use a cognitive endophenotype, exceptional episodic memory (EEM) performance, derived from nondemented offspring from the Long Life Family Study (LLFS) to identify genetic variants that may be responsible for the high cognitive performance of LLFS participants and further replicate these variants using an additional 4006 nondemented individuals from 4 independent elderly cohorts.

Design, Setting, and Participants  A total of 467 LLFS participants from 18 families with 2 or more offspring that exhibited exceptional memory performance were used for genome-wide linkage analysis. Adjusted multivariate linear analyses in the 40-megabase region encompassing the linkage peak were conducted using 4 independent replication data sets that included 4006 nondemented elderly individuals. Results of the individual replication cohorts were combined by meta-analysis.

Main Outcome Measure  Episodic memory scores computed as the mean of the 2 standardized measures of Logical Memory IA and IIA.

Results  Heritability estimates indicated a significant genetic component for EEM (h2 = 0.21; SE = 0.09). Genome-wide linkage analysis revealed that EEM was linked to the 6q24 region (maximum logarithm of odds score, 3.64). Association analysis in LLFS families identified single-nucleotide polymorphisms (SNPs) nominally associated with EEM in the 40-megabase window encompassing the linkage peak. Replication in one cohort identified a set of 26 SNPs associated with episodic memory (P ≤ .05). Meta-analysis of the 26 SNPs using the 4 independent replication cohorts found SNPs rs9321334 and rs6902875 to be nominally significantly associated with episodic memory (P = .009 and P = .013, respectively). With meta-analysis restricted to individuals lacking an APOE ε4 allele, SNP rs6902875 became statistically significant (meta-analysis, P = 6.7 × 10−5). Haplotype analysis incorporating the 2 SNPs flanking rs6902875 (rs9321334 and rs4897574) revealed that the A-A-C haplotype was significantly associated with episodic memory performance (P = 2.4 × 10−5). This genomic region harbors monooxygenase dopamine β-hydroxylase-like 1 gene (MOXD1), implicated in the biosynthesis of norepinephrine, which is prominently involved in cognitive functions.

Conclusions and Relevance  The results provide strong evidence for potential candidate genes related to EEM on 6q24. Identifying the genes will help in understanding the biological basis of memory performance and allow interventions for enhancement of cognitive function.

Neurology 2014

Amyotrophic Lateral Sclerosis Risk for Spinocerebellar Ataxia Type 2 ATXN2 CAG Repeat Alleles A Meta-analysis

Importance  Repeats of CAG in the ataxin 2 gene (ATXN2) in the long-normal range (sometimes referred to as intermediate) have been identified as modifiers of amyotrophic lateral sclerosis (ALS) risk. Prior studies have used thresholding considering various cutoffs for ATXN2 repeat length.

Objective  To calculate association between ATXN2 CAG repeat alleles and increased risk of ALS across multiple ethnic groups.

Data Sources  The MEDLINE database was searched for studies published by December 29, 2013, reporting ATXN2 CAG repeat length in patients with ALS and controls.

Study Selection  Studies were included if they reported original data on relative risks or odds ratios (ORs) from ALS and control populations for individual ATXN2 alleles. Review articles that reported no new data were not included in the analysis.

Data Extraction and Synthesis  Analysis of allele distribution was performed to ensure that all studies followed identical allele sizing. The ORs, 95% confidence intervals, and population attributable risk percentages were calculated according to standard procedures.

Main Outcomes and Measures  Occurrence of ALS associated with ATXN2 repeat alleles, expressed as ORs.

Results  Nine studies were analyzed, including 7505 controls and 6151 sporadic ALS cases. The ALS and control cohorts were recruited from different geographical and ethnic regions including the United States, French Canada/Canada, Belgium and the Netherlands, Germany, Italy, mainland China, Turkey, and Flanders-Belgium. The ATXN2 CAG repeat lengths ranged from 13 to 39 in patients with ALS and from 13 to 34 in controls. The ORs were less than 1.00 for alleles with 25 to 28 repeats. The OR was 1.55 for 30 repeats, but this elevation was not statistically significant (95% CI, 0.88-2.73). The ORs were 2.70 (95% CI, 1.47-4.93) for 31 CAG repeats, 11.09 (95% CI, 4.16-29.57) for 32 repeats, and 5.76 (95% CI, 1.79-18.57) for 33 repeats.

Conclusions and Relevance  In contrast to prior studies with smaller numbers, risk for ALS associated with long-normal alleles is complex. Alleles with 27 and 28 repeats lower ALS risk slightly. The risk for ALS increases beginning with 29 repeats and reaches a maximum at 32 and 33 repeats. Of note, alleles with repeats of these lengths are known to be predisposed to meiotic expansion to full-penetrance mutant alleles. In patients with ALS, alleles with 31 to 33 repeats may have undergone preferential expansion in motor neurons during mitosis or DNA repair. Our meta-analysis provides a framework for counseling individuals with long-normal ATXN2 repeats.

Neurology 2014

C9orf72 and UNC13A are shared risk loci for amyotrophic lateral sclerosis and frontotemporal dementia: a genome-wide meta-analysis.

OBJECTIVE:

Substantial clinical, pathological, and genetic overlap exists between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 inclusions have been found in both ALS and FTD cases (FTD-TDP). Recently, a repeat expansion in C9orf72 was identified as the causal variant in a proportion of ALS and FTD cases. We sought to identify additional evidence for a common genetic basis for the spectrum of ALS-FTD.

METHODS:

We used published genome-wide association studies data for 4,377 ALS patients and 13,017 controls, and 435 pathology-proven FTD-TDP cases and 1,414 controls for genotype imputation. Data were analyzed in a joint meta-analysis, by replicating topmost associated hits of one disease in the other, and by using a conservative rank products analysis, allocating equal weight to ALS and FTD-TDP sample sizes.

RESULTS:

Meta-analysis identified 19 genome-wide significant single nucleotide polymorphisms (SNPs) in C9orf72 on chromosome 9p21.2 (lowest p = 2.6 × 10(-12) ) and 1 SNP in UNC13A on chromosome 19p13.11 (p = 1.0 × 10(-11) ) as shared susceptibility loci for ALS and FTD-TDP. Conditioning on the 9p21.2 genotype increased statistical significance at UNC13A. A third signal, on chromosome 8q24.13 at the SPG8 locus coding for strumpellin (p = 3.91 × 10(-7) ) was replicated in an independent cohort of 4,056 ALS patients and 3,958 controls (p = 0.026; combined analysis p = 1.01 × 10(-7) ).

INTERPRETATION:

We identified common genetic variants in C9orf72, but in addition in UNC13A that are shared between ALS and FTD. UNC13A provides a novel link between ALS and FTD-TDP, and identifies changes in neurotransmitter release and synaptic function as a converging mechanism in the pathogenesis of ALS and FTD-TDP.

Neurology 2014

Analysis of the KIFAP3 gene in amyotrophic lateral sclerosis: a multicenter survival study.

Sporadic amyotrophic lateral sclerosis is a multifactorial disease of environmental and genetic origin. In a previous large multicenter genome wide study, common genetic variation in the Kinesin-Associated Protein 3 (KIFAP3) gene (rs1541160) was reported to have a significant effect on survival in amyotrophic lateral sclerosis patients. However, this could not be replicated in 3 smaller independent cohorts. We conducted a large multicenter multivariate survival analysis (n = 2362) on the effect of genetic variation in rs1541160. The previously reported beneficial genotype did not show a significant improvement in survival in this patient group.

Neurobiol.aging 2014

Systemic metabolism in frontotemporal dementia

Objective: To document the metabolic changes in frontotemporal dementia, including serum cholesterol and insulin levels, and compare and contrast these changes to motor neuron disease, where metabolism is proposed to affect disease progression.

Methods: A cohort of 90 patients with dementia (31 behavioral-variant frontotemporal dementia [bvFTD], 30 semantic dementia [SD], and 29 Alzheimer disease [AD]) underwent fasting blood cholesterol, glucose, and peripheral insulin level analysis. Insulin resistance was calculated using the homeostasis model assessment of insulin resistance (HOMA-IR). These results were compared with a cohort of 19 control subjects.

Results: The bvFTD cohort had lower high-density lipoprotein (HDL) cholesterol levels compared with control and AD groups, and increased total cholesterol/HDL ratio and triglyceride levels compared with the control group. The SD cohort had increased triglyceride levels compared with control subjects. Both FTD groups had increased fasting insulin levels and HOMA-IR index compared with the control group, and this remained increased in the subjects with bvFTD compared to subjects with AD.

Conclusion: Both patients with bvFTD and those with SD have increased triglyceride and insulin levels and lower HDL cholesterol levels compared with controls, suggesting a state of peripheral insulin resistance. These factors have been found to affect prognosis in motor neuron disease favorably, although insulin resistance has been proposed as a mechanism promoting neurodegeneration. We discuss the potential role of metabolism in FTD pathophysiology and progression.

Neurology 2014

Status of neurology medical school education Results of 2005 and 2012 clerkship director survey

Objective: To survey all US medical school clerkship directors (CDs) in neurology and to compare results from a similar survey in 2005.

Methods: A survey was developed by a work group of the American Academy of Neurology Undergraduate Education Subcommittee, and sent to all neurology CDs listed in the American Academy of Neurology database. Comparisons were made to a similar 2005 survey.

Results: Survey response rate was 73%. Neurology was required in 93% of responding schools. Duration of clerkships was 4 weeks in 74% and 3 weeks in 11%. Clerkships were taken in the third year in 56%, third or fourth year in 19%, and fourth year in 12%. Clerkship duration in 2012 was slightly shorter than in 2005 (fewer clerkships of ≥4 weeks, p = 0.125), but more clerkships have moved into the third year (fewer neurology clerkships during the fourth year, p = 0.051). Simulation training in lumbar punctures was available at 44% of schools, but only 2% of students attempted lumbar punctures on patients. CDs averaged 20% protected time, but reported that they needed at least 32%. Secretarial full-time equivalent was 0.50 or less in 71% of clerkships. Eighty-five percent of CDs were “very satisfied” or “somewhat satisfied,” but more than half experienced “burnout” and 35% had considered relinquishing their role.

Conclusion: Trends in neurology undergraduate education since 2005 include shorter clerkships, migration into the third year, and increasing use of technology. CDs are generally satisfied, but report stressors, including inadequate protected time and departmental support.

Neurology 2014