Yanbing Hou

Dysfunction of the Default Mode Network in Drug-Naïve Parkinson's Disease with Mild Cognitive Impairments: A Resting-State fMRI Study

Objective: Cognitive impairments are common in Parkinson’s disease (PD) and can even occur in the early stages. The default mode network (DMN) is highly relevant for cognitive processes; however, it remains largely unknown if changes in the DMN connectivity are related to the cognitive decline in drug-naïve early stage PD patients with a mild cognitive impairment (MCI). This study used resting-state functional MRI (fMRI) to explore the brain connectivity of the DMN in early stage drug-naïve PD patients with MCI. Method: We recruited 32 early stage drug-naïve PD patients and 22 matched healthy controls (HC). Among the PD patients, 14 were classified as having MCI (PD-MCI) and 18 were classified as having unimpaired cognition (PD-CU). The functional integration of the DMN was evaluated by a seed-based correlation approach. Results: The brain connectivity analysis revealed reduced functional connectivity (FC) in both PD subgroups compared with HC. The PD-MCI group showed a significant reduction in FC between the DMN and a set of regions, including the precentral gyrus, middle temporal gyrus, insula, anterior inferior parietal lobule and middle frontal gyrus. Compared to the PD-CU group, the PD-MCI group demonstrated a significantly decreased FC in the middle frontal and middle temporal gyri. Additionally, compared to HC, the PD-MCI group had a significantly decreased FC within the DMN, mainly in the FC between the hippocampal formation and inferior frontal gyrus, between the posterior cingulate cortex and posterior inferior parietal lobule, and between the anterior temporal lobe and inferior frontal gyrus. Compared to the PD-CU group, the only significantly decreased FC within the DMN in the PD-MCI group was between the anterior temporal lobe and inferior frontal gyrus. In all PD patients, the decreased FC between anterior temporal lobe and middle temporal gyrus was positively correlated with attention/working performance, and the reduced FC between the hippocampal formation and inferior frontal gyrus was also positively correlated with memory function. Conclusion: Our findings suggest that an altered DMN connectivity characterizes PD-MCI patients. These findings may be helpful for facilitating the further understanding of the potential mechanisms underlying MCI in PD. However, our results are preliminary, and further investigation is needed.

Default-mode network connectivity in cognitively unimpaired drug-naïve patients with rigidity-dominant Parkinson’s disease

Parkinson’s disease (PD) with akinetic rigidity (PDAR) is more likely to develop cognitive deficits compared to PD with tremor-dominant symptoms (PDTD). The default mode network (DMN) is highly relevant for cognitive processes, so this study tested the functional connectivity (FC) of DMN in cognitively unimpaired PDAR patients. Resting-state fMRI data were collected in 21 cognitively unimpaired early stage drug-naïve patients with PDAR and 21 healthy controls (HC). PD patients were matched closely to HCs for demographic and cognitive variables. FC of DMN was evaluated by seed-based correlation approach. Compared to HCs, despite comparable cognitive performance and no statistically discernible GM volume differences, a disruption in the DMN of PDAR subjects was detected. A decreased FC of DMN was found, specifically prominent in the posterior DMN. We also found a significantly increased FC of the anterior DMN. Three parts of left medial prefrontal regions (anterior, ventral, and dorsal) had significantly increased FC with the cerebellum. In addition, increased FC values of the anterior and ventral parts were negatively correlated with cognitive scores. An evident decline of FC of posterior DMN and enhanced compensatory FC of anterior DMN suggested an early functional disruption of DMN in PDAR prior to clinical evidence of cognitive impairment. It could be hypothesized that the dysfunction of DMN connectivity may have a role in the development of cognitive decline in PD. However, further longitudinal studies are warranted to understand the underlying neural mechanisms and their relevance to clinical and cognitive outcomes in PDAR subtype.

Characteristics of Nonmotor Symptoms in Progressive Supranuclear Palsy

Objectives. To explore the clinical correlates of nonmotor symptoms (NMS) in progressive supranuclear palsy (PSP) and their differences from healthy controls and patients with Parkinsons disease (PD). Methods. Twenty-seven PSP patients, 27 age- and gender-matched healthy controls (HC), and 27 age- and gender-matched PD patients were included for this case-control study. NMS were assessed using the Nonmotor Symptoms Scale (NMSS, including 9 domains). Results. All PSP patients reported NMS. The frequency and severity of “sleep/fatigue,” “mood/apathy,” “attention/memory,” “gastrointestinal,” “sexual dysfunction,” and “miscellaneous” domains in PSP group were significantly higher than those in HC group (P < 0.05). The frequency of “mood/apathy,” “attention/memory,” and “sexual dysfunction” domains and the severity of “attention/memory” and “gastrointestinal” domains in PSP group were significantly higher than those in PD group (P < 0.05). The “attention/memory” domain in PSP had a significant but weak-to-moderate correlation with age (R = 0.387, P = 0.046) and onset age (R = 0.406, P = 0.036). Conclusions. NMS are common in PSP patients. Patients with PSP seem to be subjected to more frequent and severe specific NMS compared to healthy aging subjects and PD patients. Older PSP patients and late-onset patients are likely to be subjected to cognitive decline.

Prediction of individual clinical scores in patients with Parkinson's disease using resting-state functional magnetic resonance imaging

Neuroimaging holds the promise that it may one day aid the clinical assessment. However, the vast majority of studies using resting-state functional magnetic resonance imaging (fMRI) have reported average differences between Parkinsons disease (PD) patients and healthy controls, which do not permit inferences at the level of individuals. This study was to develop a model for the prediction of PD illness severity ratings from individual fMRI brain scan. The resting-state fMRI scans were obtained from 84 patients with PD and the Unified Parkinsons Disease Rating Scale-III (UPDRS-III) scores were obtained before scanning. The RVR method was used to predict clinical scores (UPDRS-III) from fMRI scans. The application of RVR to whole-brain resting-state fMRI data allowed prediction of UPDRS-III scores with statistically significant accuracy (correlation=0.35, P-value=0.001; mean sum of squares=222.17, P-value=0.002). This prediction was informed strongly by negative weight areas including prefrontal lobe and medial occipital lobe, and positive weight areas including medial parietal lobe. It was suggested that fMRI scans contained sufficient information about neurobiological change in patients with PD to permit accurate prediction about illness severity, on an individual subject basis. Our results provided preliminary evidence, as proof-of-concept, to support that fMRI might be possible to be a clinically useful quantitative assessment aid in PD at individual level. This may enable clinicians to target those uncooperative patients and machines to replace human for a more efficient use of health care resources.

Executive dysfunctions and behavioral changes in early drug-naïve patients with Parkinson's disease

OBJECTIVES This study aims to explore the clinical profiles and onset age-related difference of executive dysfunctions and behavioral changes in early drug-naïve patients with Parkinsons disease (PD). METHODS A cross-sectional analysis on 419 early stage drug-naïve PD patients was conducted. The frontal assessment battery (FAB) was used to assess executive functions and the frontal behavioral inventory (FBI) was used to assess behavioral changes. RESULTS Executive dysfunctions were detected in 113 patients (27.0%), and 219 patients (52.3%) displayed varied degrees of behavioral changes. The most frequent affected domain for the FAB was lexical fluency (31.7%), while the three most frequent affected domains for the FBI were apathy (26.0%), irritability (24.3%) and inattention (20.8%). Compared to the early-onset PD (EOPD) patients, the late-onset PD (LOPD) patients exhibited significantly higher frequent damage in FAB especially similarities, motor series, and conflicting instructions as well as lower frequent damage in lexical fluency. The frequencies of FBI-abnormal were not different between the two groups. Multivariate analyses indicated that age at PD onset was independently associated with FAB total score and its subscores including lexical fluency, motor series, conflicting instructions and go-no go task, but it has no relationship with FBI total score and its subscores. CONCLUSIONS Executive deficits and behavioral changes are common in the early stage of PD. Age at PD onset is independently associated with the performance of executive functions. However, behavioral changes in PD may be not affected by onset age.

Impaired topographic organization in cognitively unimpaired drug-naïve patients with rigidity-dominant Parkinson's disease

BACKGROUND Resting-state functional magnetic resonance imaging (fMRI) and graph theory approaches have been combined to investigate the topographic organization in Parkinsons disease (PD). METHOD Twenty cognitively unimpaired drug-naïve patients with rigidity-dominant PD (PDAR) and 20 age-, sex-, and education-matched healthy controls were included. Small-world profile and topographic properties (clustering coefficient (Cp), characteristic path length (Lp), local efficiency (Eloc), global efficiency (Eglob), nodal efficiency (Enod), nodal degree (NDeg), and nodal betweenness (NBet)) were measured and compared between two groups, with age, gender and education as covariates. Correlation analyses between topographic features and the unified PD rating scale part-III (UPDRS-III) scores, cognitive scores were performed. RESULTS PDAR patients presented the small-world property, and abnormalities at the nodal level (Enod, NDeg, and NBet) but not at the global level (Cp, Lp, Eloc, and Eglob). Our results revealed lower nodal centralities mainly in the occipital lobe and areas of the limbic system (including amygdala nucleus), and higher nodal centralities in distributed frontal and temporal regions. Notably, the decreased nodal efficiency of occipital regions (including the calcarine area, lingual area and superior occipital gyrus (SOG)) was negatively correlated with UPDRS-III scores. And the nodal efficiency of the calcarine area was positively correlated with visuospatial scores. CONCLUSION Our results may provide insights into the underlying pathophysiology of PDAR and aid the development of potential biomarkers of the disease progression and cognitive decline in PDAR patients.

Altered intrinsic brain functional connectivity in drug-naïve Parkinson’s disease patients with LRRK2 mutations

BACKGROUND Leucine-rich repeat kinase 2 (LRRK2) has been recently identified as a causative gene of Parkinsons disease (PD), and the LRRK2 R1628P and G2385R mutations are common in ethnic Han-Chinese PD patients. However, the pathogenic mechanism of LRRK2 mutations in PD remains largely unknown. METHODS Resting-state functional MRI (fMRI) was used to assess the functional connectivity (FC) of the striatal subregions of 11 ethnic Han-Chinese drug-naïve PD patients with the LRRK2 R1628P or G2385R mutations, 11 ethnic Han-Chinese drug-naïve PD patients without such mutations, and 22 healthy control (HC) subjects. RESULTS Compared with the HC subjects, both subgroups of the PD patients showed alterations in the FC within the sensorimotor-striatal and posterior putamen-striatal circuits. In addition, relative to the subgroup of PD patients without the LRRK2 mutations, the subgroup of PD patients with the LRRK2 mutation exhibited decreased FC between the putamen and the bilateral superior frontal gyri, precuneus and calcarine gyri. The FC between the putamen and the bilateral superior frontal gyri decreased with age in the LRRK2 mutation carriers but not in the non-carriers. CONCLUSION Differences in the FC between ethnic Han-Chinese drug-naïve PD patients with and without the LRRK2 mutation may provide new insights into the understanding of the neural functional changes in ethnic Han-Chinese PD patients with LRRK2 mutations. However, our results are preliminary, and further investigations are needed.

Patterns of striatal and cerebellar functional connectivity in early-stage drug-naïve patients with Parkinson’s disease subtypes

PurposeBoth the striatal-thalamo-cortical (STC) circuit and cerebello-thalamo-cortical (CTC) circuit play a critical role in Parkinson’s disease (PD).MethodsResting-state functional MRI was used to assess functional connectivity (FC) focusing on the basal ganglia (BG) and cerebellum among early-stage drug-naïve PD patients with tremor-dominant (TD) PD patients with postural instability and gait dysfunction (PIGD) and healthy controls (HCs).ResultsCompared to HCs, both PD subgroups had higher FC between the cerebellum and paracentral lobule, sensorimotor areas; lower FC between the BG and superior frontal gyrus, and within the BG circuit; PD-TD patients showed higher FC between the BG and fusiform, paracentral lobule, cerebellum Lobule VI, and between the cerebellum and supplementary motor areas (SMA), insula; lower FC between the BG and rectus, sensorimotor areas, and within the cerebellum circuit; PD-PIGD patients showed higher FC between the cerebellum and middle frontal gyrus, precuneus; lower FC between the BG and cerebellum Crus II. Besides, compared to PD-PIGD patients and HCs, PD-TD patients had higher FC between the BG and calcarine region. In all PD patients, FC in paracentral lobule, SMA, and cerebellum Lobule VI positively correlated with tremor scores, and FC in calcarine area positively correlated with tremor scores, but negatively correlated with PIGD scores.ConclusionOur findings mainly suggested that the BG and cerebellum had hyper-connectivity with the cortical motor cortex, and the BG had prominent hyper-connectivity with the visual cortex in early-stage PD-TD patients. These findings may be helpful for facilitating the further understanding of potential mechanisms in the early-stage PD-TD. However, our results are preliminary, and further investigations are needed.

Clinical characteristics and quality of life in Chinese patients with Parkinson’s disease beyond 20 years

Abstract Background The number of Parkinson’s disease (PD) patients with disease duration of more than 20 years (long disease duration PD, LPD) is on the rise. Objectives This study aims to describe the clinical profiles and the quality of life (QoL) of LPD patients from a cohort of the Chinese population. Methods We compared 71 LPD subjects to 60 PD patients who died less than 20 years after the onset of PD (control PD, CPD). A regression model was constructed to assess the determinants for 20 years survival and the QoL of LPD patients. Results Compared to CPD patients, LPD patients exhibited a younger age at disease onset, higher total levodopa equivalent daily dose applications, more frequent motor complications, lower annual change in Unified PD Rating Scale (UPDRS) III score, as well as lower scores for ‘sleep/fatigue’ and ‘mood/apathy’ domains and higher score for ‘sexual dysfunction’ domain in the Non-Motor Symptom Scale (NMSS) (p < 0.05). Multivariate regression analyses indicated that a younger age at disease onset (OR = 0.520, 95%CI = 0.295–0.919, p = 0.024), lower annual change in UPDRS III score (OR = 0.009, 95%CI = 0.001–0.246, p = 0.005) and lower ‘cardiovascular’ score (OR = 0.552, 95%CI = 0.319–0.955, p = 0.034) were associated with 20-year survival, while UPDRS III (β = 0.320, p < 0.001) and NMSS (β = 0.549, p < 0.001) scores were associated with the PD Questionnaire 39 score in LPD. Conclusions The age at disease onset, rate of PD deterioration, and cardiovascular symptoms are the potential determinants for 20-year survival with PD. Both motor and non-motor disturbances contribute to the reduced QoL of LPD patients.

Resting-state network connectivity in cognitively unimpaired drug-naïve patients with rigidity-dominant Parkinson’s disease

BACKGROUND Parkinsons disease (PD) could be classified into akinetic-rigidity (PDAR), tremor-dominant (PDTD) and mixed subtypes. PDAR patients are more prone to develop cognitive deficits. The default mode network (DMN), fronto-parietal network (FPN) and dorsal attention network (DAN) play important roles in cognitive processing. Our aim was to evaluate changes in connectivity patterns of the DMN, and its interrelation with the FPN and DAN in cognitively unimpaired drug-naïve PDAR patients. METHOD Resting-state functional MRI (rs-fMRI) data was collected in 20 cognitively unimpaired early-stage drug-naïve PDAR patients and 20 age-, gender- and cognition- matched healthy controls (HCs). Group-level independent component analysis (ICA) was used to investigate changes in functional connectivity (FC) within the DMN between PDAR and HCs groups, and relationships between the DMN and FPN/DAN were evaluated by seed-based approach. RESULTS In PDAR patients, a significantly decreased FC, as compared with HCs, was observed in the left inferior parietal lobule (IPL) within the DMN. And the left IPL had a reduced FC with the left anterior cingulate cortex (ACC), left superior frontal gyrus (SFG), and left precuneus. However, no differences were detected in the FC between the left IPL and FPN/DAN. In addition, cognitive scores on the brief visuospatial memory test revised (BVMT-R), representing for cognitive memory domain, were positively correlated with the FC of the left IPL with bilateral SFG. CONCLUSIONS Our study mainly revealed altered within-DMN connectivity in cognitively unimpaired PDAR patients, which could provide further insights into the mechanism underlying cognitive decline evolution in the PD subtype.