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Foundation models pretrained on large-scale datasets via self-supervised learning demonstrate exceptional versatility across various tasks. Due to the heterogeneity and hard-to-collect medical data, this approach is especially beneficial for medical image analysis and neuroscience research, as it streamlines broad downstream tasks without the need for numerous costly annotations. However, there has been limited investigation into brain network foundation models, limiting their adaptability and generalizability for broad neuroscience studies. In this study, we aim to bridge this gap. In particular, 1) we curated a comprehensive dataset by collating images from 30 datasets, which comprises 70,781 samples of 46,686 participants. Moreover, we introduce pseudo-functional connectivity (pFC) to further generates millions of augmented brain networks by randomly dropping certain timepoints of the BOLD signal; 2) we propose the BrainMass framework for brain network self-supervised learning via mask modeling and feature alignment. BrainMass employs Mask-ROI Modeling (MRM) to bolster intra-network dependencies and regional specificity. Furthermore, Latent Representation Alignment (LRA) module is utilized to regularize augmented brain networks of the same participant with similar topological properties to yield similar latent representations by aligning their latent embeddings. Extensive experiments on eight internal tasks and seven external brain disorder diagnosis tasks show BrainMass's superior performance, highlighting its significant generalizability and adaptability. Nonetheless, BrainMass demonstrates powerful few/zero-shot learning abilities and exhibits meaningful interpretation to various diseases, showcasing its potential use for clinical applications.

Brain connectivity networks based on functional magnetic resonance imaging (fMRI) have expanded our understanding of brain functions in both healthy and diseased states. However, most current studies construct connectivity networks using averaged regional time courses with the strong assumption that the activities of voxels contained in each brain region are similar, ignoring their possible variations. Additionally, pairwise correlation analysis is often adopted with more attention to positive relationships, while joint interactions at the network level as well as anti-correlations are less investigated. In this paper, to provide a new strategy for regional activity representation and brain connectivity modeling, a novel homogeneous multiset canonical correlation analysis (HMCCA) model is proposed, which enforces sign constraints on the weights of voxels to guarantee homogeneity within each brain region. It is capable of obtaining regional representative signals and constructing covariation and contravariance networks simultaneously, at both group and subject levels. Validations on two sessions of fMRI data verified its reproducibility and reliability when dealing with brain connectivity networks. Further experiments on subjects with and without Parkinson's disease (PD) revealed significant alterations in brain connectivity patterns, which were further associated with clinical scores and demonstrated superior prediction ability, indicating its potential in clinical practice.

Dementia affects millions of elderly worldwide causing remarkable costs to society, but effective treatment is still lacking. Acupuncture is one of the complementary therapies that has been applied to cognitive deficits such as Alzheimer's disease (AD) and vascular cognitive impairment (VCI), while the underlying mechanisms of its therapeutic efficiency remain elusive. Neuroplasticity is defined as the ability of the nervous system to adapt to internal and external environmental changes, which may support some data to clarify mechanisms how acupuncture improves cognitive impairments. This review summarizes the up-to-date and comprehensive information on the effectiveness of acupuncture treatment on neurogenesis and gliogenesis, synaptic plasticity, related regulatory factors, and signaling pathways, as well as brain network connectivity, to lay ground for fully elucidating the potential mechanism of acupuncture on the regulation of neuroplasticity and promoting its clinical application as a complementary therapy for AD and VCI., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Shaozhen Ji et al.)

Whole-exome sequencing has been successful in identifying genetic factors contributing to familial or sporadic Parkinson's disease (PD). However, this approach has not been applied to explore the impact of de novo mutations on PD pathogenesis. Here, we sequenced the exomes of 39 early onset patients, their parents, and 20 unaffected siblings to investigate the effects of de novo mutations on PD. We identified 12 genes with de novo mutations ( MAD1L1 , NUP98 , PPP2CB , PKMYT1 , TRIM24 , CEP131 , CTTNBP2 , NUS1 , SMPD3 , MGRN1 , IFI35 , and RUSC2 ), which could be functionally relevant to PD pathogenesis. Further analyses of two independent case-control cohorts (1,852 patients and 1,565 controls in one cohort and 3,237 patients and 2,858 controls in the other) revealed that NUS1 harbors significantly more rare nonsynonymous variants ( P = 1.01E-5, odds ratio = 11.3) in PD patients than in controls. Functional studies in Drosophila demonstrated that the loss of NUS1 could reduce the climbing ability, dopamine level, and number of dopaminergic neurons in 30-day-old flies and could induce apoptosis in fly brain. Together, our data suggest that de novo mutations could contribute to early onset PD pathogenesis and identify NUS1 as a candidate gene for PD., Competing Interests: The authors declare no conflict of interest.

Background and Purpose: Patients with Parkinson's disease (PD) have difficulty performing self-initiated movements. The neural mechanism of this deficiency remains unclear. In the present study, we used functional magnetic resonance imaging (fMRI) to investigate the functional connectivity of the subthalamic nucleus (STN) during self-initiated movement in patients with PD., Materials and Methods: fMRI were acquired from patients with PD and age- and sex-matched healthy control subjects during a self-initiated right hand tapping task. We selected the bilateral sensorimotor subregions of the STN as regions of interest for our connectivity analysis., Results and Conclusions: We found that the STN contralateral to voluntary hand movement exhibited enhanced connectivity with the midbrain, thalamus, putamen, and so on in patients with PD compared to control subjects. In contrast, the STN ipsilateral to the hand movement exhibited enhanced connectivity with the midbrain and insula in PD patients compared to control subjects. Connectivity between the STN contralateral to the hand movement and the primary motor cortex and supplementary motor area was positively correlated with the severity of bradykinesia. Our findings suggest that STN-related connectivity in the hyperdirect and indirect basal ganglia pathways is strengthened during self-initiated movement in patients with PD. These disrupted network connections may contribute to bradykinesia., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Background: Markers of neuroinflammation are increased in some patients with LRRK2 Parkinson's disease compared with individuals with idiopathic Parkinson's disease, suggesting possible differences in disease pathogenesis. Previous PET studies have suggested amplified dopamine turnover and preserved serotonergic innervation in LRRK2 mutation carriers. We postulated that patients with LRRK2 mutations might show abnormalities of central cholinergic activity, even before the diagnosis of Parkinson's disease., Methods: Between June, 2009, and December, 2015, we recruited participants from four movement disorder clinics in Canada, Norway, and the USA. Patients with Parkinson's disease were diagnosed by movement disorder neurologists on the basis of the UK Parkinson's Disease Society Brain Bank criteria. LRRK2 carrier status was confirmed by bidirectional Sanger sequencing. We used the PET tracer N- 11 C-methyl-piperidin-4-yl propionate to scan for acetylcholinesterase activity. The primary outcome measure was rate of acetylcholinesterase hydrolysis, calculated using the striatal input method. We compared acetylcholinesterase hydrolysis rates between groups using ANCOVA, with adjustment for age based on the results of linear regression analysis., Findings: We recruited 14 patients with LRRK2 Parkinson's disease, 16 LRRK2 mutation carriers without Parkinson's disease, eight patients with idiopathic Parkinson's disease, and 11 healthy controls. We noted significant between-group differences in rates of acetylcholinesterase hydrolysis in cortical regions (average cortex p=0·009, default mode network-related regions p=0·006, limbic network-related regions p=0·020) and the thalamus (p=0·008). LRRK2 mutation carriers without Parkinson's disease had increased acetylcholinesterase hydrolysis rates compared with healthy controls in the cortex (average cortex, p=0·046). Patients with LRRK2 Parkinson's disease had significantly higher acetylcholinesterase activity in some cortical regions (average cortex p=0·043, default mode network-related regions p=0·021) and the thalamus (thalamus p=0·004) compared with individuals with idiopathic disease. Acetylcholinesterase hydrolysis rates in healthy controls were correlated inversely with age., Interpretation: LRRK2 mutations are associated with significantly increased cholinergic activity in the brain in mutation carriers without Parkinson's disease compared with healthy controls and in LRRK2 mutation carriers with Parkinson's disease compared with individuals with idiopathic disease. Changes in cholinergic activity might represent early and sustained attempts to compensate for LRRK2-related dysfunction, or alteration of acetylcholinesterase in non-neuronal cells., Funding: Michael J Fox Foundation, National Institutes of Health, and Pacific Alzheimer Research Foundation., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Asymptomatic, nonmanifesting carriers of leucine-rich repeat kinase 2 mutations are at increased risk of developing PD. Clinical and neuroimaging features may be associated with gene carriage and/or may demarcate individuals at greater risk for phenoconversion to PD., Objectives: To investigate clinical and dopamine transporter single-photon emission computed tomography imaging characteristics of leucine-rich repeat kinase 2 asymptomatic carriers., Methods: A total of 342 carriers' and 259 noncarriers' relatives of G2019S leucine-rich repeat kinase 2/PD patients and 39 carriers' and 31 noncarriers' relatives of R1441G leucine-rich repeat kinase 2/PD patients were evaluated. Motor and nonmotor symptoms were assessed using specific scales and questionnaires. Neuroimaging quantitative data were obtained in 81 carriers and compared with 41 noncarriers., Results: G2019S carriers scored higher in motor scores and had lower radioligand uptake compared to noncarriers, but no differences in nonmotor symptoms scores were observed. R1441G carriers scored higher in motor scores, had lower radioligand uptake, and had higher scores in depression, dysautonomia, and Rapid Eye Movements Sleep Behavior Disorder Screening Questionnaire scores, but had better cognition scores than noncarriers. Among G2019S carriers, a group with "mild motor signs" was identified, and was significantly older, with worse olfaction and lower radioligand uptake., Conclusions: G2019S and R1441G carriers differ from their noncarriers' relatives in higher motor scores and slightly lower radioligand uptake. Nonmotor symptoms were mild, and different nonmotor profiles were observed in G2019S carriers compared to R1441G carriers. A group of G2019S carriers with known prodromal features was identified. Longitudinal studies are required to determine whether such individuals are at short-term risk of developing overt parkinsonism. © 2017 International Parkinson and Movement Disorder Society., (© 2017 International Parkinson and Movement Disorder Society.)

Aberrant α-synuclein (α-syn) accumulation has been shown to impair mitochondrial function by reducing mitochondrial membrane potential (MMP). However, the underlying mechanisms remain elusive. Transient receptor potential canonical (TRPC) channels are a diverse group of non-selective Ca 2+ channels, among which TRPC3 is the only one that is localized in mitochondria and plays a role in maintaining the normal MMP. This raises a possibility that altered TRPC3 expression may play a role in the mitochondrial dysfunction induced by α-syn accumulation. To demonstrate this possibility, we first examined the expressions of mitochondrial TRPC3 in the brains of aging monkeys and α-syn transgenic and wild-type mice. We showed that α-syn levels increased in mitochondria in an age-dependent manner that was positively correlated to an elevation of mitochondrial TRPC3. This correlation was more prominent in the striatum than in the cerebellum, possibly due to the greater age-dependent α-syn accumulation in the striatum than in the cerebellum. We then used primary neurons overexpressing α-syn to investigate the effect of the α-syn-induced elevation of mitochondrial TRPC3 on the MMP and apoptotic cell death. We found that neurons with overexpressed α-syn had increased mitochondrial TRPC3 and decreased MMP, which were accompanied by increased number of apoptotic neurons. Suppressing TRPC3 expression partially reversed the reduction of MMP and alleviated the apoptotic cell death, indicating that the mitochondrial TRPC3 may play a role in the mitochondrial dysfunction in neurons with α-syn accumulation that may occur in not only the aged brain but also the brain with PD.

Dual-mode, multielectrode recordings have become routine in rodent neuroscience research and have recently been adapted to the non-human primate. However, robust and reliable application of acute, multielectrode recording methods in monkeys especially for deep brain nucleus research remains a challenge. In this paper, We described a low cost silicon based 16-site implantable microelectrode array (MEA) chip fabricated by standard lithography technology for in vivo test. The array was 25mm long and designed to use in non-human primate models, for electrophysiological and electrochemical recording. We presented a detailed protocol for array fabrication, then showed that the device can record Spikes, LFPs and dopamine (DA) variation continuously from cortex to striatum in an esthetized monkey. Though our experiment, high-quality electrophysiological signals were obtained from the animal. Across any given microelectrode, spike amplitudes ranged from 70 to 300μV peak to peak, with a mean signal-to-noise ratio of better than 5:1. Calibration results showed the MEA probe had high sensitivity and good selectivity for DA. The DA concentration changed from 42.8 to 481.6μM when the MEA probe inserted from cortex into deep brain nucleus of striatum, which reflected the inhomogeneous distribution of DA in brains. Compared with existing methods allowing single mode (electrophysiology or electrochemistry) recording. This system is designed explicitly for dual-mode recording to meet the challenges of recording in non-human primates., (Copyright © 2016 Elsevier B.V. All rights reserved.)

We previously reported that the levels of α-syn oligomers, which play pivotal pathogenic roles in age-related Parkinson's disease (PD) and dementia with Lewy bodies, increase heterogeneously in the aging brain. Here, we show that exogenous α-syn incubated with brain extracts from older cynomolgus monkeys and in Lewy body pathology (LBP)-susceptible brain regions (striatum and hippocampus) forms higher amounts of phosphorylated and oligomeric α-syn than that in extracts from younger monkeys and LBP-insusceptible brain regions (cerebellum and occipital cortex). The increased α-syn phosphorylation and oligomerization in the brain extracts from older monkeys and in LBP-susceptible brain regions were associated with higher levels of polo-like kinase 2 (PLK2), an enzyme promoting α-syn phosphorylation, and lower activity of protein phosphatase 2A (PP2A), an enzyme inhibiting α-syn phosphorylation, in these brain extracts. Further, the extent of the age- and brain-dependent increase in α-syn phosphorylation and oligomerization was reduced by inhibition of PLK2 and activation of PP2A. Inversely, phosphorylated α-syn oligomers reduced the activity of PP2A and showed potent cytotoxicity. In addition, the activity of GCase and the levels of ceramide, a product of GCase shown to activate PP2A, were lower in brain extracts from older monkeys and in LBP-susceptible brain regions. Our results suggest a role for altered intrinsic metabolic enzymes in age- and brain region-dependent α-syn oligomerization in aging brains.

In this study, we sought to identify a disease-related spatial covariance pattern of spontaneous neural activity in Parkinson's disease using resting-state functional magnetic resonance imaging (MRI). Time-series data were acquired in 58 patients with early to moderate stage Parkinson's disease and 54 healthy controls, and analyzed by Scaled Subprofile Model Principal Component Analysis toolbox. A split-sample analysis was also performed in a derivation sample of 28 patients and 28 control subjects and validated in a prospective testing sample of 30 patients and 26 control subjects. The topographic pattern of neural activity in Parkinson's disease was characterized by decreased activity in the striatum, supplementary motor area, middle frontal gyrus, and occipital cortex, and increased activity in the thalamus, cerebellum, precuneus, superior parietal lobule, and temporal cortex. Pattern expression was elevated in the patients compared with the controls, with a high accuracy (90%) to discriminate the patients from the controls. The split-sample analysis produced a similar pattern but with a lower accuracy for group discrimination in both the derivation (80%) and the validation (73%) samples. Our results showed that resting-state functional MRI can be potentially useful for identification of Parkinson's disease-related spatial covariance patterns, and for differentiation of Parkinson's disease patients from healthy controls at an individual level.

Aging is associated with an increased risk for Parkinson's disease and dementia with Lewy bodies, in which α-synuclein (α-syn) oligomerization plays key pathogenic roles. Here, we show that oligomeric α-syn levels increase with age in the brain of cynomolgus monkeys and are accompanied by a decrease in the expression and activity of glucocerebrosidase (GCase), a lysosomal enzyme whose dysfunction is linked to accumulation of oligomeric α-syn. Besides, levels of α-syn phosphorylated at serine 129 (pS129 α-syn), a modification that promotes α-syn oligomerization also increase with age in the brain and is associated with a reduction in the activity of protein phosphatase 2A (PP2A), an enzyme that facilitates α-syn dephosphorylation. The inverse relationship between levels of oligomeric α-syn and pS129 α-syn and activity of GCase and PP2A was more evident in brain regions susceptible to neurodegeneration (i.e., the striatum and hippocampus) than those that are less vulnerable (i.e., cerebellum and occipital cortex). In vitro experiments showed that GCase activity was more potently inhibited by oligomeric than by monomeric α-syn in the lysosome-enriched fractions isolated from brain tissues and cultured neuronal cells. Inhibition of GCase activity induced an elevation of oligomeric α-syn levels, which was shown to increase pS129 α-syn levels and reduce PP2A activity in cultured neuronal cells. The alterations in oligomeric and pS129 α-syns and their association with GCase and PP2A in aging brains may explain the vulnerability of certain brain regions to neurodegeneration in Parkinson's disease and dementia with Lewy bodies., (Copyright © 2015 Elsevier Inc. All rights reserved.)

We investigated the lateralization of brain activity pattern during performance of unilateral movement in drug-naïve Parkinson's disease (PD) patients with only right hemiparkinsonian symptoms. Functional MRI was obtained when the subjects performed strictly unilateral right hand movement. A laterality index was calculated to examine the lateralization. Patients had decreased activity in the left putamen and left supplementary motor area, but had increased activity in the right primary motor cortex, right premotor cortex, left postcentral gyrus, and bilateral cerebellum. The laterality index was significantly decreased in PD patients compared with controls (0.41 ± 0.14 vs. 0.84 ± 0.09). The connectivity from the left putamen to cortical motor regions and cerebellum was decreased, while the interactions between the cortical motor regions, cerebellum, and right putamen were increased. Our study demonstrates that in early PD, the lateralization of brain activity during unilateral movement is significantly reduced. The dysfunction of the striatum-cortical circuit, decreased transcallosal inhibition, and compensatory efforts from cortical motor regions, cerebellum, and the less affected striatum are likely reasons contributing to the reduced motor lateralization. The disruption of the lateralized brain activity pattern might be a reason underlying some motor deficits in PD, like mirror movements or impaired bilateral motor coordination., (© 2015 Wiley Periodicals, Inc.)

The brainstem and basal ganglia are important in the pathophysiology of Parkinson's disease (PD). Reliable and sensitive detection of neural activity changes in these regions should be helpful in scientific and clinical research on PD. In this study, we used resting state functional MRI and amplitude of low frequency fluctuation (ALFF) methods to examine spontaneous neural activity in 109 patients with PD. We examined activity in two frequency bands, slow-4 (between 0.027 and 0.073 Hz) and slow-5 (0.010-0.027 Hz). Patients had decreased ALFF in the striatum and increased ALFF in the midbrain, and changes were more significant in slow-4. Additionally, changes in slow-4 in both basal ganglia and midbrain correlated with the severity of the parkinsonism. The ALFF in the caudate nucleus positively correlated with the dose of levodopa, while the ALFF in the putamen negatively correlated with the disease duration in both slow-4 and slow-5 bands. In addition, the ALFF in the rostral supplementary motor area negatively correlated with bradykinesia subscale scores. Our findings show that with a large cohort of patients and distinguishing frequency bands, neural modulations in the brainstem and striatum in PD can be detected and may have clinical relevance. The physiological interpretation of these changes needs to be determined., (© 2014 Wiley Periodicals, Inc.)

Background: The pathophysiological changes before the presentation of clinical symptoms in parkinsonism are unclear. In this study, we investigated neural network modulations in persons in the preclinical stage of familial parkinsonism, and how the network interactions change at the clinical stage., Methods: We performed functional MRI in a family with SCA2 mutation, including 9 asymptomatic carriers and 10 mutation carriers with parkinsonian symptoms. Functional connectivity from the posterior putamen bilaterally and rostral supplementary motor area was used to explore network interactions in the subjects., Results: Both the asymptomatic carriers and patients had decreased connectivity within the basal ganglia-thalamus-cortical motor loop compared to controls. The asymptomatic carriers showed extensively increased connectivity compared to controls, including the cortico-cortical motor, cortico-cerebellar, cortico-brainstem, and part of the basal ganglia-thalamus-cortical motor circuits. In contrast, the connectivity of most of these networks was decreased in the patients. These abnormalities were relatively normalized after levodopa administration., Conclusions: In the preclinical stage of SCA2 parkinsonism, the connectivity of a part of the basal ganglia motor loop is weakened as a consequence of dopaminergic deficits; meanwhile, the connectivity of other large-scale brain networks is strengthened presumably to compensate for the dysfunction of the basal ganglia to maintain brain function in the early stage of dopaminergic deficits. The simultaneous effects of progressive disruption of basal ganglia motor circuits and failure of compensatory mechanisms as dopaminergic dysfunction progresses may contribute to the onset of clinical symptoms., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objectives: Recently, 9-[(18)F]fluoropropyl-(+)-dihydrotetrabenazine ((18)F-AV-133) was reported as a new vesicular monoamine transporter (VMAT2) imaging agent for diagnosis of Parkinson's disease (PD). To shorten the preparation of (18)F-AV-133 and to make it more widely available, we evaluated a simple, rapid purification with a solid-phase extraction method (SPE) using an Oasis HLB cartridge instead of high pressure liquid chromatography (HPLC). The SPE method produced doses containing a pseudo-carrier, 9-hydroxypropyl-(+)-dihydrotetrabenazine (AV-149)., Methods: To test the possible side effects of this pseudo-carrier, comparative dynamic PET scans of the brains of normal monkeys (2 each) and uni-laterally 6-OH-dopamine-lesioned PD monkeys (2 each) were performed using (18)F-AV-133 doses prepared by either SPE (containing pseudo-carrier) or HPLC (containing no pseudo-carrier). Autoradiographs of post mortem monkey brain sections were evaluated to confirm the relative (18)F-AV-133 uptake in the PD monkey brains and the effects of the pseudo-carrier on VMAT2 binding., Results: The radiochemical purity of the (18)F-AV-133, whether prepared by SPE or by HPLC, was excellent (>99%). PET scans of normal and PD monkey brains showed an expected reduction of VMAT2 in the lesioned areas of the striatum. It was not affected by the presence of the pseudo-carrier, AV-149 (maximally 250 μg/dose). The reduced uptake in the striatum of the lesioned monkey brains was confirmed by autoradiography. Ex vivo inhibition studies of (18)F-AV-133 binding in rat brains, conducted with increasing amounts of AV-149, suggested that at the highest concentration (3.5mg/kg) the VMAT2 binding in the striatum was only moderately blocked (20% reduction)., Conclusions: The pseudo-carrier, AV-149, did not affect the (18)F-AV-133/PET imaging of VMAT2 binding sites in normal or uni-laterally lesioned monkey brains. The new streamlined SPE purification method will enable (18)F-AV-133 to be widely available for routine clinical application in determining changes in monoamine neurons for patient with movement disorders or other psychiatric illnesses., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To investigate the abnormal diffusion in cerebral white matter and its relationship with the olfactory dysfunction in patients with Parkinson's disease (PD) through diffusion tensor imaging (DTI)., Materials and Methods: Diffusion tensor imaging of the cerebrum was performed in 25 patients with Parkinson's disease and 25 control subjects matched for age and sex. Differences in fractional anisotropy (FA) and mean diffusivity (MD) between these two groups were studied by voxel-based analysis of the DTI data. Correlations between diffusion indices and the olfactory function in PD patients were evaluated using the multiple regression model after controlling for the duration of the disease, Unified Parkinson's Disease Rating Sale (UPDRS), and age., Results: The damaged white and gray matter showed decreased FA or increased MD, localized bilaterally in the cerebellar and orbitofrontal cortex. In addition, in PD patients there was a positive correlation between FA values in the white matter of the left cerebellum and the thresholds of olfactory identification (TOI) and a negative correlation between MD values in the white matter of right cerebellum and the TOI., Conclusion: In patients with PD, there was disruption in the cerebellar white matter which may play an important role in the olfactory dysfunction in patients with Parkinson's disease., (Copyright © 2009 Elsevier Ireland Ltd. All rights reserved.)

Patients with Parkinson's disease have great difficulty in performing bimanual movements; this problem is more obvious when they perform bimanual anti-phase movements. The underlying mechanism of this problem remains unclear. In the current study, we used functional magnetic resonance imaging to study the bimanual coordination associated changes of brain activity and inter-regional interactions in Parkinson's disease. Subjects were asked to perform right-handed, bimanual in-phase and bimanual anti-phase movements. After practice, normal subjects performed all tasks correctly. Patients with Parkinson's disease performed in-phase movements correctly. However, some patients still made infrequent errors during anti-phase movements; they tended to revert to in-phase movement. Functional magnetic resonance imaging results showed that the supplementary motor area was more activated during anti-phase movement than in-phase movement in controls, but not in patients. In performing anti-phase movements, patients with Parkinson's disease showed less activity in the basal ganglia and supplementary motor area, and had more activation in the primary motor cortex, premotor cortex, inferior frontal gyrus, precuneus and cerebellum compared with normal subjects. The basal ganglia and dorsolateral prefrontal cortex were less connected with the supplementary motor area, whereas the primary motor cortex, parietal cortex, precuneus and cerebellum were more strongly connected with the supplementary motor area in patients with Parkinson's disease than in controls. Our findings suggest that dysfunction of the supplementary motor area and basal ganglia, abnormal interactions of brain networks and disrupted attentional networks are probably important reasons contributing to the difficulty of the patients in performing bimanual anti-phase movements. The patients require more brain activity and stronger connectivity in some brain regions to compensate for dysfunction of the supplementary motor area and basal ganglia in order to perform bimanual movements correctly.

Patients with Parkinson's disease (PD) have difficulty in performing learned movements automatically. The neural mechanism of this deficiency remains unclear. In the current study, we used functional MRI (fMRI) and psychophysiological interaction (PPI) methods to investigate the changes in effective connectivity of the brain networks when movements become automatic in PD patients and age-matched normal controls. We found that during automaticity, the rostral supplementary motor area, cerebellum, and cingulate motor area had increased effective connectivity with brain networks in PD patients. In controls, in addition to these regions, the putamen also had automaticity-related strengthened interactions with brain networks. The dorsal lateral prefrontal cortex had more connectivity at the novel stage than in the automatic stage in normal subjects, but not in PD patients. The comparison of the PPI results between the groups showed that the rostral supplementary motor area, cerebellum, and cingulate motor area had significantly more increased effective connectivity with several regions in normal subjects than in PD. The changes of effective connectivity in some areas negatively correlated with the Unified Parkinson's Disease Rating Scale (UPDRS). Our findings show that some of the factors related to PD patients having difficulty achieving automaticity are less efficient neural coding of movement and failure to shift execution of automatic movements more subcortically. The changes of effective connectivity become more abnormal as the disorder progresses. In addition, in PD, the connections of the attentional networks are altered., (Published by Elsevier Inc.)

Resting state brain activity in Parkinson's disease (PD) can give clues to the pathophysiology of the disorder, and might be helpful in diagnosis, but it has never been explored using functional MRI (fMRI). In the current study, we used a regional homogeneity (ReHo) method to investigate PD-related modulations of neural activity in the resting state. FMRIs were acquired in 22 patients with PD at both before and after levodopa administration, as well as in 22 age- and sex-matched normal controls. In the PD group compared with the healthy controls, we found ReHo decreased in extensive brain regions, including the putamen, thalamus, and supplementary motor area; and increased in some other areas, including the cerebellum, primary sensorimotor cortex, and premotor area. The ReHo off medication was negatively correlated with the Unified Parkinson's Disease Rating Scale (UPDRS) in the putamen and some other regions, and was positively correlated with the UPDRS in the cerebellum. Administration of levodopa relatively normalized ReHo. Our findings demonstrate that neural activity in the resting state is changed in patients with PD. This change is secondary to dopamine deficiency, and related to the severity of the disease. The different neuronal activity at the baseline state should be considered in explaining fMRI findings obtained during tasks., (. (c) 2008 Wiley-Liss, Inc.)

alpha-Synuclein (alpha-Syn) abnormality and mitochondrial deficiency are two major changes in the brain of patients with Parkinson's disease (PD). A link between alpha-Syn and mitochondria in PD has been demonstrated by a recent study showing that accumulation of alpha-Syn in the mitochondria from the PD-vulnerable brain regions was associated with decreased complex I activity of these mitochondria. In this study, we examined the normal expressions of alpha-Syn in mitochondria from different regions of the rat brain. We showed that alpha-Syn was highly expressed in the mitochondria in olfactory bulb, hippocampus, striatum, and thalamus, where the cytosolic alpha-Syn was also rich. However, the cerebral cortex and cerebellum were two exceptions, which contained rich cytosolic alpha-Syn but very low or even undetectable levels of mitochondrial alpha-Syn. The close quantitative association between mitochondrial and cytosolic alpha-Syn in most brain regions, suggests that the concentration of cytosolic alpha-Syn may determine the amount of alpha-Syn in mitochondria. This is partially supported by the in vitro experiment showing that incubation of alpha-Syn with endogenous alpha-Syn-undetectable cerebellar mitochondria caused a dose-dependent transport of alpha-Syn to the mitochondria. Moreover, we found that the inhibitory effect of alpha-Syn on complex I activity of mitochondrial respiratory chain was also dose-dependent. These results suggest that alpha-Syn in mitochondria is differentially expressed in different brain regions and the background levels of mitochondrial alpha-Syn may be a potential factor affecting mitochondrial function and predisposing some neurons to degeneration.

Alpha-synuclein (alpha-Syn) is a brain-enriched protein of 140 amino acids. Despite of strong evidence showing the implication of the protein in the pathogenesis of several neurodegenerative diseases, its physiological function remains poorly understood. To study the physiological function of alpha-Syn, a depiction of its precise subcellular localization is necessary. Although alpha-Syn expression in the brain has been extensively investigated using several different antibodies, its precise subcellular localization in neurons remains elusive. In this study, immunogold electron microscopy with a newly produced 3D5 monoclonal antibody recognizing the C-terminal 115-121 amino acids of alpha-Syn was used to examine its subcellular localization in rat brain neurons. In addition, the relative amount of the protein in different subcellular pools of the neurons in several brain regions was evaluated and compared. The results showed that alpha-Syn-positive gold particles were unevenly distributed in axons, presynaptic terminals, cytoplasm and nucleus in the neuron, with the density of gold particles being greater in presynaptic terminals and nucleus than in other subcellular pools. In the cytoplasmic region, relatively dense gold particles were seen in some mitochondria. In the same subcellular pools, the density of gold particles was varied among the neurons from different brain regions. Although the cortical neurons showed much higher density of gold particles in the presynaptic terminals and nuclei than in striatal, hippocampal and substantia nigral neurons, the density of gold particles in their mitochondria was much lower compared with the mitochondria of striatal, hippocampal and substantia nigral neurons. The relative high level of mitochondrial alpha-Syn in hippocampus, striatum and substantia nigral neurons may have special pathophysiological significance, which deserves further investigation.

Our knowledge about aging modulation of the central motor system remains sparse and contradictory. In the current study, we used functional MRI (fMRI) to study the aging influence on regional homogeneity of the motor-related brain areas in the resting state. We found that regional homogeneity in extensive motor regions, like the cingulate motor area, cerebellum, primary motor cortex, premotor area, supplementary motor area, thalamus, globus pallidus and putamen was significantly decreased in aged subjects. Our study indicates that normal aging process may disrupt the function of motor areas in the resting state, which may contribute to the declined motor ability in aged population.

There is a compelling body of evidence indicating an association between cholesterol and Alzheimer's disease (AD). Acyl-coenzyme A: cholesterol acyltransferase 1 (ACAT1), an endoplasmic-reticulum-resident enzyme that catalyses the formation of cholesteryl esters (CEs) from cholesterol and long-chain fatty acids, modulates the generation of beta amyloid peptide (Abeta). A single nucleotide polymorphism rs1044925 in the sterol O-acyltransferase 1 (SOAT1), the gene encoding ACAT1, has been reported to be association with an increased risk for sporadic AD (SAD) in European population. In the present study, we examined the association of the SOAT1 rs1044925 polymorphism with SAD in our northern Han-Chinese (107 cases, 118 age and gender-matched controls) sample using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. There was no genotypic (chi(2)=0.030, OR 0.942, 95% CI=0.478-1.857) or allelic (chi(2)=0.021, OR 0.955, 95% CI=0.508-1.794) association between SAD and controls, even when the data were stratified by APOEvarepsilon4 carrier status. Our results indicate that the polymorphism rs1044925 in the 3'UTR of SOAT1 gene does not affect the risk of SAD in the northern Han-Chinese.