MOTOR SYMPTOMS IN FAMILIAL ALZHEIMER’S DISEASE: FREQUENCY, SEVERITY AND PREDICTIVE VALUE

Abstract

To evaluate motor dysfunction as a potential symptom of autosomal dominant Alzheimer's disease (ADAD). We utilized data from the Dominantly Inherited Alzheimer's Network (DIAN) observational study to assess motor dysfunction as determined by the Unified Parkinson Disease Rating Scale part-three (UPDRS-III). We analyzed UPDRS-III scores (0 (best) to 108 (worst)) at baseline for all 433 participants at data freeze 10. We compared the frequency (UPDRS-III 0 vs. >0) and severity (UPDRS-III scores) of motor symptoms between mutation carriers (MC) and non-carriers (NC). In MC, correlations of UPDRS-III scores with estimated years to symptom onset (EYO) and Clinical Dementia Rating Scale - Sum of Boxes (CDR-SOB) were analyzed. Fisher's exact test, Mann-Whitney U test, Spearman correlation and Holm-Bonferroni correction were used. MC exhibited a higher frequency (28.4% vs. 12.8%; p=0.0001) and severity (mean UPDRS-III scores 2.0 vs. 0.4; p=0.00007) of motor symptoms compared to NC. 13 out of 27 symptoms assessed in UPDRS-III were statistically more frequent in MC, with 7 symptoms surviving Holm-Bonferroni correction: finger taps right hand (6.9% vs. 0%; p=0.001), hand movements right hand (5.7% vs. 0%; p=0.0076) and left hand (6.1% vs. 0.6%; p=0.039), rapid alternating movements right hand (7.7% vs. 0%; p=0.0008) and left hand (9.6% vs. 0.6%; p=0.0005), leg agility right leg (4.6% vs. 0%; p=0.026), and gait (4.2% vs. 0%; p=0.039). In cognitively asymptomatic MC (CDR Global=0) rapid alternating movements right hand (3.8% vs. 0%; p=0.02) and left hand (4.4% vs. 0.6%; p=0.03) were more frequently impaired compared to NC after Holm-Bonferroni correction. The positive predictive value to predict MC status in cognitively asymptomatic persons with 50% a priori risk was 100% for right hand and 87.5% for left hand rapid alternating movements. In MC, highly significant positive correlations between UPDRS-III scores and EYO (rs=0.409; p=6.7597E-12) (increasing scores with disease duration) and CDR-SOB (rs=0.420; p=1.3918E-12) were found. In ADAD, motor symptoms occur more frequently and to a larger extend. Furthermore, their degree increases with disease progression and cognitive decline. Impairment in rapid alternating hand movements is a very strong predictor of mutation carrier status in cognitively asymptomatic ADAD family members.