Brain network centrality and connectivity are associated with clinical subtypes and disease progression in Parkinson's disease.

To investigate brain network centrality and connectivity alterations in different Parkinson's disease (PD) clinical subtypes using resting-state functional magnetic resonance imaging (RS-fMRI), and to explore the correlation between baseline connectivity changes and the clinical progression. Ninety-two PD patients were enrolled at baseline, alongside 38 age- and sex-matched healthy controls. Of these, 85 PD patients underwent longitudinal assessments with a mean of 2.75 ± 0.59 years. Two-step cluster analysis integrating comprehensive motor and non-motor manifestations was performed to define PD subtypes. Degree centrality (DC) and secondary seed-based functional connectivity (FC) were applied to identify brain network centrality and connectivity changes among groups. Regression analysis was used to explore the correlation between baseline connectivity changes and clinical progression. Cluster analysis identified two main PD subtypes: mild PD and moderate PD. Two different subtypes within the mild PD were further identified: mild motor-predominant PD and mild-diffuse PD. Accordingly, the disrupted DC and seed-based FC in the left inferior frontal orbital gyrus and left superior occipital gyrus were severe in moderate PD. The DC and seed-based FC alterations in the right gyrus rectus and right postcentral gyrus were more severe in mild-diffuse PD than in mild motor-predominant PD. Moreover, disrupted DC were associated with clinical manifestations at baseline in patients with PD and predicted motor aspects progression over time. Our study suggested that brain network centrality and connectivity changes were different among PD subtypes. RS-fMRI holds promise to provide an objective assessment of subtype-related connectivity changes and predict disease progression in PD.

Convergent and divergent intra- and internetwork connectivity in Parkinson's disease with wearing-off.

OBJECTIVE: Our study aimed to explore the functional connectivity alterations between cortical nodes of resting-state networks in Parkinson's disease (PD) patients with wearing-off (WO) at different levels. METHODS: Resting-state functional magnetic resonance imaging was performed on 36 PD patients without wearing-off (PD-nWO), 30 PD patients with wearing-off (PD-WO), and 35 healthy controls (HCs) to extract functional networks. Integrity, network, and edge levels were calculated for comparison between groups. UPDRS-III, MMSE, MOCA, HAMA, and HAMD scores were collected for further regression analysis. RESULTS: We observed significantly reduced connectivity strength in the dorsal attention network and limbic network in the PD-WO group compared with the HC group. The PD-WO group showed a decreased degree of functional connectivity at 12 nodes, including the bilateral orbital part of the superior frontal gyrus, right olfactory cortex, left medial orbital part of the superior frontal gyrus, bilateral gyrus rectus, right parahippocampal gyrus, right thalamus, left Heschl's gyrus, right superior temporal gyrus part of the temporal pole, left middle temporal gyrus part of the temporal pole, and right inferior temporal gyrus. Furthermore, the PD-WO group showed a significantly lower degree of functional connectivity in the left orbital part of the superior frontal gyrus and right gyrus rectus than the PD-nWO group. Internetwork analysis indicated reduced functional connectivity in five pairs of resting-state networks. CONCLUSION: Our results demonstrated altered intra- and internetwork connections in PD patients with WO. These findings will facilitate a better understanding of the distinction between the network changes in PD pathophysiology.

Voxel-based morphometry of grey matter structures in Parkinson's Disease with wearing-off.

Our study aimed to investigate the grey matter (GM) changes using voxel-based morphometry (VBM) in Parkinson's disease (PD) patients with wearing-off (WO). 3D-T1-weighted imaging was performed on 48 PD patients without wearing-off (PD-nWO), 39 PD patients with wearing-off (PD-WO) and 47 age and sex-matched healthy controls (HCs). 3D structural images were analyzed by VBM procedure with Statistical Parametric Mapping (SPM12) to detect grey matter volume. Widespread areas of grey matter changes were found in patients among three groups (in bilateral frontal, temporal lobes, lingual gyrus, inferior occipital gyrus, right precuneus, right superior parietal gyrus and right cerebellum). Grey matter reductions were found in frontal lobe (right middle frontal gyrus, superior frontal gyrus and precentral gyrus), right parietal lobe (precuneus, superior parietal gyrus, postcentral gyrus), right temporal lobe (superior temporal gyrus, middle temporal gyrus), bilateral lingual gyrus and inferior occipital gyrus in PD-WO group compared with the PD-nWO group. Our results suggesting that wearing-off may be associated with grey matter atrophy in the cortical areas. These findings may aid in a better understanding of the brain degeneration process in PD with wearing-off.

Cortical connectivity of cholinergic basal forebrain in Parkinson's disease with mild cognitive impairment.

Background: Cholinergic basal forebrain (BF) pathology is a hallmark of Parkinson's disease (PD) with mild cognitive impairment (PD-MCI). Assessment of functional connectivity (FC) of different cholinergic BF nuclei may deepen the understanding of PD-MCI pathogenesis. Methods: Seed-based FC analysis was performed with bilateral medial septal nucleus, the nucleus of the vertical limb of the diagonal band, nucleus of the horizontal limb of the diagonal band (Ch1-3), and the nucleus basalis of Meynert (NBM/Ch4) to explore the BF functional alterations in different frequency bands. Correlations between FC values of abnormal regions and scores of cognitive domains and depression in the PD group were also assessed. Results: For the right Ch4, in the conventional frequency band, the PD-MCI group exhibited lower FC values in the right middle cingulate and paracingulate gyri, middle frontal gyrus, left inferior parietal gyrus, and superior frontal gyrus compared with healthy controls (HC), and in the left calcarine fissure and surrounding cortex compared with PD with normal cognition (PD-NC). For the slow 4 subbands, the PD-MCI group showed significantly lower FC values in the left putamen, middle frontal gyrus, right middle frontal gyrus, and precuneus compared with HC, and in right middle frontal gyrus cingulate and paracingulate gyri compared with the PD-NC group. For the slow 5 subbands, the PD-MCI group showed increased FC values in the right calcarine fissure and surrounding cortex, and left cerebellum. For the left Ch1-3, FC values in the right middle cingulate and paracingulate gyri were lower in patients with PD-MCI than in the PD-NC group in slow 4 subbands. Furthermore, altered FC values in the cortical regions for Ch4 seed were possibly correlated with depression and different cognitive domain scores. Conclusions: The study identified an imbalanced association between different cholinergic BF nuclei and cortical regions in patients with PD-MCI, and showed that FC changes are frequency-specific, which may provide new insights into functional alterations within the cholinergic system in cognitive impairment associated with PD.

Abnormal cerebellum connectivity patterns related to motor subtypes of Parkinson's disease.

Cerebellar dysfunction may substantially contribute to the clinical symptoms of Parkinson's disease (PD). The role of cerebellar subregions in tremors and gait disturbances in PD remains unknown. To investigate alterations in cerebellar subregion volumes and functional connectivity (FC), as well as FC between the dentate nucleus (DN) and ventral lateral posterior nucleus (VLp) of the thalamus, which are potentially involved in different PD motor subtypes. We conducted morphometric and resting-state functional connectivity analyses in various cerebellar subregions in 22 tremor-dominant (TD)-PD and 35 postural instability gait difficulty dominant (PIGD)-PD patients and 38 sex- and age-matched healthy controls (HCs). The volume and FC alterations in various cerebellar subregions and the neural correlates of these changes with the clinical severity scores were investigated. The PIGD-PD group showed greater FC between the right motor cerebellum (CBMm) and left postcentral gyrus than the HC group, and a higher FC was associated with less severe PIGD symptoms. In contrast, the TD-PD group had decreased FC between the right DN and left VLp compared with the PIGD-PD and HC groups, and lower FC was associated with worse TD symptoms. Furthermore, the PIGD-PD group had higher FC between the left DN and left inferior temporal gyrus than the TD-PD group. Morphometric analysis revealed that the TD-PD group showed a significantly higher volume of left CBMm than the HC group. Our findings point to differential alteration patterns in cerebellar subregions and offer a new perspective on the pathophysiology of motor subtypes of PD.

Diffusion along perivascular spaces provides evidence interlinking compromised glymphatic function with aging in Parkinson's disease.

AIMS: The aim of the study was to evaluate the glymphatic function and its related factors in patients with Parkinson's disease (PD) and patients with PD of different ages using the diffusion tensor image analysis along the perivascular space (DTI-ALPS) method. METHODS: Medical records and imaging data of 93 patients with idiopathic PD and 42 age- and sex-matched healthy controls (HCs) were retrospectively reviewed and analyzed. The diffusivity along the perivascular spaces, projection fibers, and association fibers were calculated on diffusion tensor imaging (DTI) to acquire the analysis along the perivascular space (ALPS) index. RESULTS: PD patients exhibited a reduced ALPS index compared with the HCs. Negative correlations between the ALPS index and clinical information including age, age at disease onset, Parkinson's disease sleep scale 2nd version (PDSS-2) scores, and history of diabetes mellitus were revealed in the PD group. Besides, a negative correlation between the ALPS index and the severity of motor symptoms was identified in the subgroup aged 65 and above, rather than in the younger ones. CONCLUSIONS: The results demonstrate that reduced ALPS index, a potential noninvasive measure of compromised glymphatic activity, is involved in the pathophysiology of PD, especially in the aged ones and those with sleep disorders.

Quantitative susceptibility mapping and blood neurofilament light chain differentiate between parkinsonian disorders.

Objectives: We employed quantitative susceptibility mapping (QSM) to assess iron deposition in parkinsonian disorders and explored whether combining QSM values and neurofilament light (NfL) chain levels can improve the accuracy of distinguishing Parkinson's disease (PD) from multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). Materials and methods: Forty-seven patients with PD, 28 patients with MSA, 18 patients with PSP, and 28 healthy controls (HC) were enrolled, and QSM data were reconstructed. Susceptibility values in the bilateral globus pallidus (GP), putamen (PUT), caudate nucleus (CN), red nucleus (RN), substantia nigra (SN), and dentate nucleus (DN) were obtained. Plasma NfL levels of 47 PD, 18 MSA, and 14 PSP patients and 22 HC were measured by ultrasensitive Simoa technology. Results: The highest diagnostic accuracy distinguishing MSA from PD patients was observed with increased susceptibility values in CN (AUC: 0.740). The susceptibility values in RN yielded the highest diagnostic performance for distinguishing PSP from PD patients (AUC: 0.829). Plasma NfL levels were significantly higher in the MSA and PSP groups than in PD and HC groups. Combining the susceptibility values in the RN and plasma NfL levels improved the diagnostic performance for PSP vs. PD (AUC: 0.904), whereas plasma NfL levels had higher diagnostic accuracy for MSA vs. PD (AUC: 0.877). Conclusion: The exploratory study indicates different patterns of iron accumulation in deep gray matter nuclei in Parkinsonian disorders. Combining QSM values with NfL levels may be a promising biomarker for distinguishing PSP from PD, whereas plasma NfL may be a reliable biomarker for differentiating MSA from PD. QSM and NfL measures appeared to have low accuracy for separating PD from controls.

Metabolite changes in prefrontal lobes and the anterior cingulate cortex correlate with processing speed and executive function in Parkinson disease patients.

Background: Processing speed and executive function can be impaired in patients with Parkinson disease (PD). However, the neural factors related to the slowdown in processing speed and dysexecutive function in PD are not completely understood. The objective of this study is to investigate the metabolic changes of the frontal and anterior cingulate cortex (ACC) through the use of 1H magnetic resonance spectroscopy and to explore the association between cognitive function and metabolic ratios. Methods: In this retrospective case-control study, we conducted neuropsychological assessments of executive function and information processing speed in healthy controls (HCs) and in patients with PD. Chemical information was obtained for the of N-acetyl-aspartate (NAA):creatine (Cr) ratio and the choline-containing compounds (Cho):Cr ratio within the bilateral prefrontal cortex and ACC. Using hierarchical multiple regression analysis, we analyzed the relationship between cognitive function and metabolic ratios in the bilateral prefrontal lobe and ACC in patients with PD. Results: In all, 59 patients with PD and 30 HCs were recruited. Patients with PD showed worse performance in executive function and processing speed compared with HCs (P<0.001). In patients with PD, the Cho:Cr ratios in the ACC (Z=2.20, P=0.028) and the right prefrontal cortex (t=2.16, P=0.034) were significantly increased. The hierarchical multiple regressions in patients with PD showed that the NAA:Cr ratio in the ACC correlated with the Stroop A completion times (P<0.05) and that the NAA:Cr ratio of the right prefrontal cortex correlated with the scores of the Wechsler Adult Intelligence Scale (WAIS)-Digit symbol test (P<0.05). Conclusions: Information processing speed and executive function are impaired in patients with PD. Neuronal integrity and membrane turnover in the ACC and the right prefrontal cortex may be important factors in the slowdown of the information processing speed in patients with PD.

Retinal microvascular impairment in Parkinson's disease with cognitive dysfunction.

BACKGROUND: Parkinson's disease (PD) is associated with structural alterations of the retina. However, it remains unknown whether these changes are present in PD with mild cognitive impairment (MCI). The purpose of the study was to evaluate the retinal microvasculature using optical coherence tomography angiography (OCTA) to assess possible retinal microvascular impairments associated with PD and PD with MCI. METHODS: This study included 83 eyes of 45 PD patients and 83 eyes of 42 healthy controls. All subjects underwent complete neurological and ophthalmological examinations before measurements. Cognitive function was also measured in PD patients. Retinal microvasculature was evaluated with OCTA. Vessel density in the superficial capillary plexus (SRCP), deep capillary plexus (DRCP), and radial peripapillary capillaries (RPC) and intraretinal layer thickness in the peripapillary retinal nerve fibre layer (RNFL) and ganglion cell complex (GCC) were analysed. Correlations between vessel density and cognitive function were analysed in the PD group. RESULTS: Parafoveal vessel density in the SRCP and DRCP were lower in the eyes of PD patients than healthy controls (P < 0.05). However, there were no significant differences in the RPC (P = 0.120), RNFL (P = 0.303) or GCC (P = 0.375) between PD patients and healthy controls. Lower executive function scores were associated with lower vessel density in the DRCP of PD patients (P < 0.05, 95% CI [0.133,1.342]). CONCLUSION: OCTA revealed lower macular microvascular density in PD patients and microvascular impairments in the deep retinal capillary layer in PD patients with executive dysfunction. These parameters might have potential utility as early disease diagnostic biomarkers.

Abnormal Neural Activity in Different Frequency Bands in Parkinson's Disease With Mild Cognitive Impairment.

Background: Abnormal spontaneous neural activity is often found in patients with Parkinson's disease with mild cognitive impairment (PD-MCI). However, the frequency dependence of neuronal interaction activities, especially the fractional amplitude of low-frequency fluctuation (fALFF) and degree centrality (DC), in PD-MCI is still unclear. Thus, this study aimed to explore the frequency dependence of PD-MCI based on fALFF and DC maps. Methods: Twenty-four patients with PD-MCI, 42 PD patients with normal cognition (PD-NC), and 33 healthy controls (HCs) were enrolled. Neuropsychological assessments and resting-state functional MRI (rs-fMRI) were performed. The fALFF and DC values in the conventional, slow4 and slow5 frequency bands were compared among the groups. Results: In the conventional frequency band, the DC value in the left precentral area was decreased in PD-MCI patients, while that in the right fusiform area was increased in PD-NC patients compared with HCs. Regarding fALFFs, both the PD-MCI and PD-NC patients had decreased values in the right precentral area compared with those of the HCs. The fALFFs did not differ between PD-MCI and PD-NC patients. The fALFF results in the slow4 subfrequency band were consistent with those in the conventional frequency band. In the slow5 band, the DC value in the left middle temporal lobe was higher in PD-MCI patients than in PD-NC patients and was positively correlated with the performance of the PD-MCI patients on the Montreal Cognitive Assessment (MoCA). Additionally, both PD-MCI and PD-NC patients showed lower fALFF values in the bilateral putamen than the HCs, and the fALFF in the bilateral putamen was negatively correlated with the Hoehn and Yahr stages of PD-MCI. The fALFF in the left putamen was negatively correlated with the scores of PD-MCI patients on the Movement Disorder Society-Unified Parkinson Disease Rating Scale Part III (MDS-UPRDS-III). Conclusion: Our results suggested that abnormal neuronal activities, such as fALFF and DC, are dependent on frequency in PD-MCI. Some subfrequency bands could distinguish PD-MCI from PD. Our findings may be helpful for further revealing the frequency-dependent resting functional disruption in PD-MCI.

Different iron deposition patterns in Parkinson's disease subtypes: a quantitative susceptibility mapping study.

BACKGROUND: Parkinson's disease (PD) is a heterogeneous neurodegenerative disorder with various subtypes and uncertain pathogenesis. Iron deposition is considered to be involved in the pathological mechanisms of PD. The present study aimed to investigate the iron deposition in deep gray matter in patients with different PD subtypes using quantitative susceptibility mapping (QSM). METHODS: Forty-six PD patients and 22 healthy controls (HCs) were recruited for the study. PD patients were allocated to the tremor-dominant (TD) group (n=22), postural instability and gait disorder-dominant (PIGD) group (n=19), and intermediate group (n=5). Susceptibility values in deep gray matter nuclei measured by QSM among the PD-TD and PD-PIGD groups and the HCs, as well as the relationship between iron accumulation and clinical motor features, were investigated. RESULTS: Susceptibility values in the dentate nucleus (DN) were greater in the PD-TD (118.73±70.45) group than in the PD-PIGD (72.14±39.85, P=0.02) group and HCs (78.26±41.38, P=0.042). Further, a significant positive correlation was observed between the DN susceptibility values and tremor scores (r=0.324, P=0.028). Compared with the HCs (182.60±85.35), both the PD-TD (282.00±102.49, P=0.006) and PD-PIGD groups (284.91±118.54, P=0.007) exhibited greater susceptibility values in the substantia nigra (SN) pars reticulata. The susceptibility values in the SN pars compacta were also greater in the PD-PIGD group (164.51±89.44) than in the HCs (107.78±63.11, P=0.048). CONCLUSIONS: The present study demonstrated various iron deposition patterns in different PD phenotypes. These findings give insight into the pathophysiology underlying different PD phenotypes, and potentially illustrate the involvement of iron deposition in the PD-TD and PD-PIGD subtypes.

Hemiparkinsonism or Hemidystonia With Hemiatrophy Syndrome: A Case Series With Follow-Up.

Hemiparkinsonism-hemiatrophy syndrome (HPHA) and hemidystonia-hemiatrophy syndrome (HDHA) are rare movement disorders composed of hemidystonia or hemiparkinsonism that present with unilateral limb, face, trunk, or cerebral hemiatrophy and mostly occur following head trauma or postanoxic events. However, relatively little is known about the pathogenesis of these conditions. In our case series, we present three HPHA patients and one HDHA patient who underwent detailed neuropsychological, radiological, motor, and non-motor functional assessments with a mean follow-up of 2 years. We followed two patients who showed differences in their progression for more than 2 years: one barely progressed with no treatment, and the other exhibited levodopa-induce dyskinesia (LID) and definitive progression while receiving multiple adjunctive therapies. In addition, we performed positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) and 18F-dihydroxyphenylalanine (DOPA) in one HPHA patient who showed bilaterally symmetrical uptake of FDG with no significant increase or decrease in the cerebral hemispheres, including the striatum, but exhibited a significant reduction in the uptake of 18F-DOPA in the contralateral posterior striatum. In this study, we followed HPHA patients who showed different disease courses to explore the clinical characteristics and pathogenesis of HPHA and HDHA and illustrate the clinical heterogeneity of these diseases.