Huntington disease (HD) is an autosomal dominant neurological disorder that is caused by a CAG repeat expansion, translated into polyglutamine, in the huntingtin (HTT) gene. Although the length of this repeat polymorphism is inversely correlated with age of onset (AOO), it does not fully explain the variability in AOO. Genomic studies have provided evidence for the involvement of DNA repair in modifying this trait, potentially through somatic repeat instability. We therefore assessed genetic variants within the 12bp interrupting sequence between the pathogenic CAG repeat and the polymorphic proline (CCG) tract in the HTT gene and identified variants that result in complete loss of interruption (LOI) between the adjacent CAG/CCG repeats.Analysis of multiple HD pedigrees showed that this variant is associated with dramatically earlier AOO and is particularly relevant to HD patients with reduced penetrance alleles. On average AOO of HD is hastened by an average of 25 years in LOI carriers. This finding indicates that the number of uninterrupted CAG repeats is the most significant contributor to AOO of HD and is more impactful than polyglutamine length, which is not altered in these patients. We show that the LOI variant is associated with increases in both somatic and germline repeat instability, demonstrating a potential mechanism for this effect. Screening individuals from the general population (n=2,674 alleles) suggests that the variant occurs only in expanded CAG repeat alleles. Identification of this modifier has important clinical implications for disease management of HD families, especially for those in the reduced penetrance ranges.3

Objective The ACE-III is a brief cognitive screener with high sensitivity and specificity in detecting neurocognitive disorders. We examined the utility of ACE-III subscale scores (Attention/Orientation, Memory, Fluency, Language, Visuospatial) to predict performance on expanded neuropsychological evaluation and detect diagnostic group differences. Data Selection 217 patients (Mag = 74.0, Medu = 15.78) with neurocognitive concerns completed the ACE-III followed by a comprehensive neuropsychological evaluation, including Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) Digit Span Backward (DSB), Trail Making Test Part B (TMT B), Boston Naming Test (BNT), Controlled Oral Word Association Test (COWAT), Category Fluency (Vegetables), Wechsler Memory Scale-IV (WMS-IV) Logical Memory (LM), and WAIS-IV Block Design (BD). Patients were diagnosed as having Normal Cognition (NC), Mild Cognitive Impairment (MCI), or Major Neurocognitive Disorder (MND) from clinical history and overall performance (67-NC, 105-MCI, 45-MND). Within-construct performances on comprehensive testing were regressed on ACE-III subscales. Group differences in ACE-III subscales and total scores were also examined. Data Synthesis Each ACE-III subscale score predicted within-construct performance on expanded testing with moderate-strong effects (p’s < .001): Attention/Orientation predictive of WAIS-IV DSB and TMT B; Memory predictive of WMS-IV LM immediate and delayed; Fluency predictive of COWAT and Category Fluency; Language predictive of BNT; Visuospatial predictive of WAIS-IV BD. ACE-III subscale and total scores also distinguished between groups (NC > MCI > MND; p’s < .001). Conclusions Across severity of cognitive impairment, ACE-III subscales are predictive of within-construct performance on expanded testing. The ACE-III may be a useful proxy for a comprehensive neuropsychological evaluation and demonstrates diagnostic utility in distinguishing different levels of cognitive impairment in older adults referred for neurocognitive concerns.

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