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Visuomotor integration deficits are common to familial and sporadic preclinical Alzheimer's disease.

ABSTRACT: We investigated whether subtle visuomotor deficits were detectable in familial and sporadic preclinical Alzheimer's disease. A circle-tracing task-with direct and indirect visual feedback, and dual-task subtraction-was completed by 31 individuals at 50% risk of familial Alzheimer's disease (19 presymptomatic mutation carriers; 12 non-carriers) and 390 cognitively normal older adults (members of the British 1946 Birth Cohort, all born during the same week; age range at assessment = 69-71?years), who also underwent ?-amyloid-PET/MRI to derive amyloid status (positive/negative), whole-brain volume and white matter hyperintensity volume. We compared preclinical Alzheimer's groups against controls cross-sectionally (mutation carriers versus non-carriers; amyloid-positive versus amyloid-negative) on speed and accuracy of circle-tracing and subtraction. Mutation carriers (mean 7?years before expected onset) and amyloid-positive older adults traced disproportionately less accurately than controls when visual feedback was indirect, and were slower at dual-task subtraction. In the older adults, the same pattern of associations was found when considering amyloid burden as a continuous variable (Standardized Uptake Value Ratio). The effect of amyloid was independent of white matter hyperintensity and brain volumes, which themselves were associated with different aspects of performance: greater white matter hyperintensity volume was also associated with disproportionately poorer tracing accuracy when visual feedback was indirect, whereas larger brain volume was associated with faster tracing and faster subtraction. Mutation carriers also showed evidence of poorer tracing accuracy when visual feedback was direct. This study provides the first evidence of visuomotor integration deficits common to familial and sporadic preclinical Alzheimer's disease, which may precede the onset of clinical symptoms by several years.

SUBMITTER: Lu K

PROVIDER: S-EPMC7882207 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Visuomotor integration deficits are common to familial and sporadic preclinical Alzheimer's disease.

Lu Kirsty K Nicholas Jennifer M JM Weston Philip S J PSJ Stout Julie C JC O'Regan Alison M AM James Sarah-Naomi SN Buchanan Sarah M SM Lane Christopher A CA Parker Thomas D TD Keuss Sarah E SE Keshavan Ashvini A Murray-Smith Heidi H Cash David M DM Sudre Carole H CH Malone Ian B IB Coath William W Wong Andrew A Richards Marcus M Henley Susie M D SMD Fox Nick C NC Schott Jonathan M JM Schott Jonathan M JM Crutch Sebastian J SJ

Brain communications 20210125 1

We investigated whether subtle visuomotor deficits were detectable in familial and sporadic preclinical Alzheimer's disease. A circle-tracing task-with direct and indirect visual feedback, and dual-task subtraction-was completed by 31 individuals at 50% risk of familial Alzheimer's disease (19 presymptomatic mutation carriers; 12 non-carriers) and 390 cognitively normal older adults (members of the British 1946 Birth Cohort, all born during the same week; age range at assessment = 69-71 years), ...[more]

PMID: 33615219

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Project description:Our understanding of Alzheimer's disease pathogenesis is currently limited by difficulties in obtaining live neurons from patients and the inability to model the sporadic form of the disease. It may be possible to overcome these challenges by reprogramming primary cells from patients into induced pluripotent stem cells (iPSCs). Here we reprogrammed primary fibroblasts from two patients with familial Alzheimer's disease, both caused by a duplication of the amyloid-? precursor protein gene (APP; termed APP(Dp)), two with sporadic Alzheimer's disease (termed sAD1, sAD2) and two non-demented control individuals into iPSC lines. Neurons from differentiated cultures were purified with fluorescence-activated cell sorting and characterized. Purified cultures contained more than 90% neurons, clustered with fetal brain messenger RNA samples by microarray criteria, and could form functional synaptic contacts. Virtually all cells exhibited normal electrophysiological activity. Relative to controls, iPSC-derived, purified neurons from the two APP(Dp) patients and patient sAD2 exhibited significantly higher levels of the pathological markers amyloid-?(1-40), phospho-tau(Thr?231) and active glycogen synthase kinase-3? (aGSK-3?). Neurons from APP(Dp) and sAD2 patients also accumulated large RAB5-positive early endosomes compared to controls. Treatment of purified neurons with ?-secretase inhibitors, but not ?-secretase inhibitors, caused significant reductions in phospho-Tau(Thr?231) and aGSK-3? levels. These results suggest a direct relationship between APP proteolytic processing, but not amyloid-?, in GSK-3? activation and tau phosphorylation in human neurons. Additionally, we observed that neurons with the genome of one sAD patient exhibited the phenotypes seen in familial Alzheimer's disease samples. More generally, we demonstrate that iPSC technology can be used to observe phenotypes relevant to Alzheimer's disease, even though it can take decades for overt disease to manifest in patients.

Dataset Information

Visuomotor integration deficits are common to familial and sporadic preclinical Alzheimer's disease.

Publications

Visuomotor integration deficits are common to familial and sporadic preclinical Alzheimer's disease.

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