Involvement of specific striatal subregion contributes to executive deficits in Alzheimer disease

Abstract

Background: There is growing evidence that the striatum plays a central role in cognitive dysfunction. However, it remains unclear whether and how the striatum contributes specifically to executive deficits in Alzheimer disease (AD). We sought to elucidate aberrations in the striatal subregion associated with executive function and its metabolic connectivity with the cortical regions to investigate its role in the pathogenesis of executive deficits in patients with AD.

Methods: Patients with AD and healthy controls underwent a neuropsychological assessment battery, including assessment of executive function, and a hybrid positron emission tomography/magnetic resonance imaging (PET/MRI) scan. We performed voxel-wise analyses of cerebral metabolism between patients and controls, focusing on the executive subregion of the striatum according to the Oxford-GSK-Imanova Striatal Connectivity Atlas. We assessed the correlation between the [¹⁸F]-fluorodeoxyglucose standardized uptake value ratio of the striatal executive subregion and clinical variables, and we analyzed seed-based metabolic connectivity of the striatal executive subregion with the dorsolateral prefrontal cortex (DLPFC) using [¹⁸F]-fluorodeoxyglucose PET.

Results: We included 50 patients with AD and 33 controls in our analyses. The patterns of striatal hypometabolism in patients with AD were specific to executive and caudal motor subregions. Metabolic activity in the executive subregion of the striatum correlated negatively with the severity of executive dysfunction, as measured with the Trial-Making Test (TMT) part B and the difference score TMT B-A, and correlated positively with Digit Span (backward) and Verbal Fluency Test scales, particularly on the left side. Compared with controls, patients with AD showed reduced metabolic connectivity between striatal executive subregions and the dorsolateral prefrontal cortex (DLPFC).

Limitations: Our study was limited by small sample sizes and cross-sectional findings.

Conclusion: Our findings show that patients with AD have impairments in the executive subregion of the striatum, and these deficits may be associated with a disconnection between the executive striatum and DLPFC, providing valuable insight into the pathogenesis of this disease.

Figure 1

The hypometabolism pattern of the striatal executive subregion in the Alzheimer disease (AD) group. (A) Striatal parcellations based on intrinsic functional connectivity with the cerebral cortex. (B) Projections of areas with relative hypometabolism of the striatal executive subregion in patients with AD compared to healthy controls (HC). T values are colour-coded in a red–yellow colour gradient to highlight the differences for AD < controls. Data were analyzed at a height threshold of p < 0.001 and were family-wise error–corrected at the cluster level at p < 0.05. Compared with controls, patients with AD had hypometabolism in bilateral executive subregions of the striatum. Notably, the involvement of the executive striatum appeared to be specific to the caudate portion.

Figure 2

The metabolism in the striatal executive subregion and its association with executive performance in patients with Alzheimer disease (AD). (A) Compared with controls, patients with AD had lower [¹⁸F]-fluorodeoxyglucose (FDG) uptake in the bilateral executive subregions of the striatum. Data were analyzed using the Student t test, **p < 0.01, ***p < 0.001, ****p < 0.0001. (B) Significant correlations existed between the striatal executive subregion and executive performance in patients with AD. Scatter plots show that standardized uptake value ratios (SUVRs) of the striatal left executive subregion correlated significantly with neuropsychological scores of executive functions assessed using the Digit Span (backward), Trail-Making Test part B (TMT-B), difference score TMT B–A and Verbal Fluency Test. Pearson correlation analysis showed that SUVRs of the right striatal executive subregion were negatively correlated with TMT B–A, but not with the Digit Span (backward), TMT-B or Verbal Fluency Test. Region and scatterplot colours: blue: Digit Span (backward); purple: TMT-B; green: TMT B–A; red: Verbal Fluency Test.

Figure 3

Metabolic connectivity of the striatal executive subregion. Compared with controls, patients with Alzheimer disease (AD) showed decreased metabolic connectivity between executive subregions of the striatum and dorsolateral prefrontal cortex (DLPFC). Weakened metabolic connections are represented by blue lines.