Neural substrates underlying distinct dual cognitive syndromes in Parkinson's disease

A dual-syndrome hypothesis, which states the cognitive impairments in Parkinson's disease (PD) are attributable to frontostriatal dopaminergic dysregulation and cortical disturbance-each associated with attention/executive and memory/visuospatial dysfunction, respectively-has been widely accepted. This multisystem contribution also underlies highly heterogeneous progression rate to dementia.

Nondemented PD patients who underwent [¹²³I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) nortropane ([¹²³I]FP-CIT) SPECT and neuropsychological examinations were enrolled. Patients who agreed to participate and age- and sex-matched healthy controls (HCs) also underwent 7-T MRI. Patients were classified as cognitively normal (PD-CN) or mild cognitive impairment (PD-MCI) following the level II criteria of Movement Disorder Society Guideline.

A total of 155 patients (PD-CN/PD-MCI 74/81) were enrolled, whereas 76 patients (PD-CN/PD-MCI 35/41) and 56 HCs underwent 7 T-MRI. The caudate [¹²³I]FP-CIT uptake in PD was correlated with the performance of attention/working memory (trail-making test [TMT]-A and symbol digit modality test) and executive (TMT-B) domains. In contrast, the regional cortical thickness in the left frontotemporal and right frontal lobes in PD was correlated with performance of memory (Hopkins verbal learning test-revised delayed recall) and visuospatial (judgment of line orientation) domains. Moreover, compared to 37 HCs with a Montreal Cognitive Assessment score of >25, PD-CN patients showed broad occipitoparietal cortical thinning.

We demonstrated distinctive impairments of dopaminergic frontostriatal deficits and cortical degeneration as neural bases for the dual-syndrome hypothesis. Our findings suggest that occipitoparietal lobe thinning occurs at a cognitively normal stage, and additional frontotemporal lobe thinning underlies impairments in the memory and visuospatial domains at the PD-MCI stage.