Integrated Clinical Features with Plasma and Multi-modal Neuroimaging Biomarkers to Diagnose Mild Cognitive Impairment in Early Drug-Naive Parkinson’s Disease

Abstract

The pathogenesis of cognitive impairment in Parkinson's disease (PD) patients remains unclear, and there is no ideal diagnostic tool available at present. We assessed integrated clinical features with plasma and multi-modal neuroimaging biomarkers to identify mild cognitive impairment (MCI) in early drug-naive PD patients. 49 early drug-naive PD patients, including 26 with MCI (PD-MCI) and 23 with normal cognition (PD-NC), and 20 controls were recruited. Plasma markers [α-synuclein, betaamyloid 1-40 (Aβ40), beta-amyloid 1-42 (Aβ42), and phosphorylated Tau 181 (p-Tau181) levels], functional connectivity (FC) of the default mode network, and cortical thickness (CTh) were evaluated to identify PD-MCI. The PD-MCI group had significantly higher plasma p-Tau181 levels and p-Tau181/Aβ42 ratio and lower Aβ42/Aβ40 ratio compared to the PD-NC group. Compared to PD-NC, the PD-MCI group showed increased FC between left posterior cingulate cortex (pCC) and the left parahippocampal gyrus (PHG), and between the right hippocampal formation and the left anterior cingulate and paracingulate gyri, and the right middle temporal gyrus. Additionally, the PD-MCI group had thinner cortex thickness in the right lateral occipital and frontal pole compared to the PD-NC group. The final model combining clinical characteristics and several variables (age, sex, plasma p-Tau181 level, Aβ42/Aβ40 ratio, the right lateral occipital CTh, and the FC value between the left pCC and left PHG) had the highest diagnostic accuracy for PD-MCI (AUC = 0.987, 95% CI 0.903−1.000; p = 0.001 compared to age and sex alone). The combination of clinical features, plasma biomarkers, and multi-modal neuroimaging biomarkers can identify early cognitive decline in PD patients.

Drooling disrupts the brain functional connectivity network in Parkinson's disease

“…The anterior cingulate and paracingulate gyri (ACG) are mainly involved in cognitive and affective regulation, which has been implicated in cognitive impairment and depression 32–34 . Wang et al 33 found increased FC between the right hippocampal formation and the ACG.L in PD patients with mild cognitive impairment compared to those without mild cognitive impairment. However, Feng et al 34 discovered reduced FC of the ACG in Alzheimer's disease.…”

The Evolving Landscape of Parkinson's Disease Research: Current Challenges and Future Outlook

“…145,147,[149][150][151][152][153][154] Neuroimaging biomarkers: (i) Dopamine transporter (DAT) imaging with single-photon emission computed tomography (SPECT) or positron emission tomography (PET) can assess presynaptic dopaminergic function and differentiate PD from other parkinsonian syndromes; (ii) Functional MRI (fMRI) can evaluate changes in brain activity and connectivity patterns associated with PD, providing insights into disease pathophysiology and compensatory mechanisms; (iii) Structural MRI techniques, such as volumetric analysis and diffusion tensor imaging (DTI), can detect changes in brain morphology, white matter integrity, and gray matter density associated with PD. 45,145,[155][156][157] Cerebrospinal fluid (CSF) biomarkers: (i) Measurement of α-Synuclein levels or specific αsynuclein species (e.g., oligomeric forms) in CSF may reflect underlying pathology and serve as a diagnostic or prognostic biomarker for PD; (ii) Elevated levels of Tau and phosphorylated Tau (p-Tau) in CSF have been reported in PD patients and may indicate neurodegeneration and tau pathology. 151,153,[158][159][160] Blood-based biomarkers: (i) Blood-based assays for α-Synuclein levels and post-translational modifications are under investigation as potential biomarkers for PD.…”

“…However, blood-based αsynuclein assays have been challenging due to low concentrations and high variability; (ii) Biomarkers of neuroinflammation, such as cytokines, chemokines, and inflammatory mediators, have been proposed as potential indicators of disease activity and progression in PD. 153,157,159,161 Genetic biomarkers: (i) Genetic variants associated with PD risk identified through genomewide association studies (GWAS) and next-generation sequencing may serve as genetic biomarkers for disease susceptibility and progression; (ii) Pathogenic monogenic mutations in genes such as SNCA, LRRK2, PARK2, and GBA are associated with familial forms of PD and may serve as biomarkers for genetic testing and personalized risk assessment. 147,[161][162][163] Peripheral biomarkers: (i) Olfactory dysfunction, commonly observed in PD patients, may serve as a peripheral biomarker for early disease detection and monitoring; (ii) Alterations in gut microbiota composition and metabolites have been reported in PD patients and may represent peripheral biomarkers of disease risk and progression.…”

Structural network topology mediated cognitive impairment in Parkinson’s disease

“…In addition, fMRI has also been widely utilized to decipher the functional and structural abnormalities causally associated with cognitive deficits in PD patients [32–36]. Brain network analysis was an important neuroimaging approach [37–41] and has revealed widespread changes of structural and functional networks in PD patients with CI [34, 42–44]. Consistently, aberrations in both structural networks and functional network were found to be correlated with cognitive decline in PD patients [25, 34, 45].…”

“…Moreover, we also showed that global network metrics, such as global efficiency and local efficiency in structural network, partially mediated the age-dependent CI in PD patients [25]. For functional network, it has been shown that increased functional connectivity between left posterior cingulate cortex and left parahippocampal gyrus in default mode network (DMN) was associated with early cognitive decline in PD patients [42]. In addition, functional connectivity between left and right hippocampus in DMN was also associated with global and domain-specific cognitive decline in PD patients [34].…”