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BACKGROUND: Pathologic perivascular spaces (PVS), the fluid-filled compartments surrounding brain vasculature, may underlie cognitive decline in Parkinson's disease (PD). However, whether this impacts specific cognitive domains has not been investigated. OBJECTIVES: This study examined the relationship of PVS volume at baseline with domain-specific and global cognitive change over 2 years in PD individuals. METHODS: A total of 39 individuals with PD underwent 3T T1w magnetic resonance imaging to determine PVS volume fraction (PVS volume normalized to total regional volume) within (i) centrum semiovale, (ii) prefrontal white matter (medial orbitofrontal, rostral middle frontal, and superior frontal), and (iii) basal ganglia. A neuropsychological battery included assessment of cognitive domains and global cognitive function at baseline and after 2 years. RESULTS: Higher basal ganglia PVS at baseline was associated with greater decline in attention, executive function, and global cognition scores. CONCLUSIONS: While previous reports have associated elevated PVS volume in the basal ganglia with decline in global cognition in PD, our findings show such decline may affect the attention and executive function domains.
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Atenção , Gânglios da Base , Disfunção Cognitiva , Função Executiva , Imageamento por Ressonância Magnética , Doença de Parkinson , Humanos , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/patologia , Doença de Parkinson/fisiopatologia , Gânglios da Base/diagnóstico por imagem , Gânglios da Base/patologia , Gânglios da Base/fisiopatologia , Função Executiva/fisiologia , Feminino , Masculino , Idoso , Pessoa de Meia-Idade , Atenção/fisiologia , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/patologia , Sistema Glinfático/diagnóstico por imagem , Sistema Glinfático/patologia , Sistema Glinfático/fisiopatologia , Testes Neuropsicológicos , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Substância Branca/fisiopatologiaRESUMO
BACKGROUND: Understanding the sequential progression of cognitive impairments in Parkinson's disease (PD) is crucial for elucidating neuropathological underpinnings, refining the assessment of PD-related cognitive decline stages and enhancing early identification for targeted interventions. The first aim of this study was to use an innovative event-based modeling (EBM) analytic approach to estimate the sequence of cognitive declines in PD. The second aim was to validate the EBM by examining associations with EBM-derived individual-specific estimates of cognitive decline severity and performance on independent cognitive screening measures. METHODS: This cross-sectional observational study included 99 people with PD who completed a neuropsychological battery. Individuals were classified as meeting the criteria for mild cognitive impairment (PD-MCI) or subtle cognitive decline by consensus. An EBM was constructed to compare cognitively healthy individuals with those with PD-MCI or subtle cognitive disturbances. Multivariable linear regression estimated associations between the EBM-derived stage of cognitive decline and performance on two independent cognitive screening tests. RESULTS: The EBM estimated that tests assessing executive function and visuospatial ability become abnormal early in the sequence of PD-related cognitive decline. Each higher estimated stage of cognitive decline was associated with approximately 0.24 worse performance on the Dementia Rating Scale (p<0.001) and 0.26 worse performance on the Montreal Cognitive Assessment (p<0.001) adjusting for demographic and clinical variables. CONCLUSION: Findings from this study will have important clinical implications for practitioners, on specific cognitive tests to prioritise, when conducting neuropsychological evaluations with people with PD. Results also highlight the importance of frontal-subcortical system disruption impacting executive and visuospatial abilities.
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Mitochondrial DNA single nucleotide polymorphisms (mtSNPs) have been associated with a reduced risk of developing Parkinson's disease (PD), yet the underlying mechanisms remain elusive. In this study, we investigate the functional role of a PD-associated mtSNP that impacts the mitochondrial-derived peptide (MDP) Small Humanin-like Peptide 2 (SHLP2). We identify m.2158 T > C, a mtSNP associated with reduced PD risk, within the small open reading frame encoding SHLP2. This mtSNP results in an alternative form of SHLP2 (lysine 4 replaced with arginine; K4R). Using targeted mass spectrometry, we detect specific tryptic fragments of SHLP2 in neuronal cells and demonstrate its binding to mitochondrial complex 1. Notably, we observe that the K4R variant, associated with reduced PD risk, exhibits increased stability compared to WT SHLP2. Additionally, both WT and K4R SHLP2 show enhanced protection against mitochondrial dysfunction in in vitro experiments and confer protection against a PD-inducing toxin, a mitochondrial complex 1 inhibitor, in a mouse model. This study sheds light on the functional consequences of the m.2158 T > C mtSNP on SHLP2 and provides insights into the potential mechanisms by which this mtSNP may reduce the risk of PD.
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Mitocôndrias , Doença de Parkinson , Polimorfismo de Nucleotídeo Único , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Animais , Camundongos , Humanos , Polimorfismo de Nucleotídeo Único/genética , Mitocôndrias/metabolismo , DNA Mitocondrial/genética , Fatores de Proteção , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Modelos Animais de Doenças , Masculino , Complexo I de Transporte de Elétrons/metabolismo , Complexo I de Transporte de Elétrons/genética , Peptídeos/genética , Peptídeos/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Peptídeos e Proteínas de Sinalização IntracelularRESUMO
Perivascular spaces (PVS), fluid-filled compartments surrounding brain vasculature, are an essential component of the glymphatic system responsible for transport of waste and nutrients. Glymphatic system impairment may underlie cognitive deficits in Parkinson's disease (PD). Studies have focused on the role of basal ganglia PVS with cognition in PD, but the role of white matter PVS is unknown. This study examined the relationship of white matter and basal ganglia PVS with domain-specific and global cognition in individuals with PD. Fifty individuals with PD underwent 3T T1w magnetic resonance imaging (MRI) to determine PVS volume fraction, defined as PVS volume normalized to total regional volume, within (i) centrum semiovale, (ii) prefrontal white matter (medial orbitofrontal, rostral middle frontal, superior frontal), and (iii) basal ganglia. A neuropsychological battery included assessment of global cognitive function (Montreal Cognitive Assessment, and global cognitive composite score), and cognitive-specific domains (executive function, memory, visuospatial function, attention, and language). Higher white matter rostral middle frontal PVS was associated with lower scores in both global cognitive and visuospatial function. In the basal ganglia higher PVS was associated with lower scores for memory with a trend towards lower global cognitive composite score. While previous reports have shown that greater amount of PVS in the basal ganglia is associated with decline in global cognition in PD, our findings suggest that increased white matter PVS volume may also underlie changes in cognition.
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Sistema Glinfático , Doença de Parkinson , Substância Branca , Humanos , Doença de Parkinson/complicações , Substância Branca/patologia , Sistema Glinfático/diagnóstico por imagem , Sistema Glinfático/patologia , Imageamento por Ressonância Magnética/métodos , Cognição , Gânglios da Base/diagnóstico por imagemRESUMO
The basal ganglia are important modulators of the cognitive and motor benefits of exercise. However, the neural networks underlying these benefits remain poorly understood. Our study systematically analyzed exercise-associated changes in metabolic connectivity in the cortico-basal ganglia-thalamic network during the performance of a new motor task, with regions-of-interest defined based on mesoscopic domains recently defined in the mouse brain structural connectome. Mice were trained on a motorized treadmill for six weeks or remained sedentary (control), thereafter undergoing [14C]-2-deoxyglucose metabolic brain mapping during wheel walking. Regional cerebral glucose uptake (rCGU) was analyzed in 3-dimensional brains reconstructed from autoradiographic brain sections using statistical parametric mapping. Metabolic connectivity was assessed by calculating inter-regional correlation of rCGU cross-sectionally across subjects within a group. Compared to controls, exercised animals showed broad decreases in rCGU in motor areas, but increases in limbic areas, as well as the visual and association cortices. In addition, exercised animals showed (i) increased positive metabolic connectivity within and between the motor cortex and caudoputamen (CP), (ii) newly emerged negative connectivity of the substantia nigra pars reticulata with the globus pallidus externus, and CP, and (iii) reduced connectivity of the prefrontal cortex (PFC). Increased metabolic connectivity in the motor circuit in the absence of increases in rCGU strongly suggests greater network efficiency, which is also supported by the reduced involvement of PFC-mediated cognitive control during the performance of a new motor task. Our study delineates exercise-associated changes in functional circuitry at the subregional level and provides a framework for understanding the effects of exercise on functions of the cortico-basal ganglia-thalamic network.
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Conectoma , Humanos , Camundongos , Animais , Gânglios da Base/metabolismo , Encéfalo , Globo Pálido , Córtex Pré-Frontal , Vias Neurais , Imageamento por Ressonância MagnéticaRESUMO
Cognitive impairment, particularly deficits in executive function (EF) is common in Parkinson's disease (PD) and may lead to dementia. There are currently no effective treatments for cognitive impairment. Work from our lab and others has shown that physical exercise may improve motor performance in PD but its role in cognitive function remains poorly eludicated. In this study in a rodent model of PD, we sought to examine whether exercise improves cognitive processing and flexibility, important features of EF. Rats received 6-hydroxydopamine lesions of the bilateral striatum (caudate-putamen, CPu), specifically the dorsomedial CPu, a brain region central to EF. Rats were exercised on motorized running wheels or horizontal treadmills for 6-12 weeks. EF-related behaviors including attention and processing, as well as flexibility (inhibition) were evaluated using either an operant 3-choice serial reaction time task (3-CSRT) with rule reversal (3-CSRT-R), or a T-maze task with reversal. Changes in striatal transcript expression of dopamine receptors (Drd1-4) and synaptic proteins (Synaptophysin, PSD-95) were separately examined following 4 weeks of exercise in a subset of rats. Exercise/Lesion rats showed a modest, yet significant improvement in processing-related response accuracy in the 3-CSRT-R and T-maze, as well as a significant improvement in cognitive flexibility as assessed by inhibitory aptitude in the 3-CSRT-R. By four weeks, exercise also elicited increased expression of Drd1, Drd3, Drd4, synaptophysin, and PSD-95 in the dorsomedial and dorsolateral CPu. Our results underscore the observation that exercise, in addition to improving motor function may benefit cognitive performance, specifically EF, and that early changes (by 4 weeks) in CPu dopamine modulation and synaptic connectivity may underlie these benefits.
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BACKGROUND: Cognitive impairment is common in Parkinson's disease (PD) and often leads to dementia, with no effective treatment. Aging studies suggest that physical activity (PA) intensity has a positive impact on cognition and enhanced functional connectivity may underlie these benefits. However, less is known in PD. This cross-sectional study examined the relationship between PA intensity, cognitive performance, and resting state functional connectivity in PD and whether PA intensity influences the relationship between functional connectivity and cognitive performance. METHODS: 96 individuals with mild-moderate PD completed a comprehensive neuropsychological battery. Intensity of PA was objectively captured over a seven-day period using a wearable device (ActiGraph). Time spent in light and moderate intensity PA was determined based on standardized actigraphy cut points. Resting-state fMRI was assessed in a subset of 50 individuals to examine brain-wide functional connectivity. RESULTS: Moderate intensity PA (MIPA), but not light PA, was associated with better global cognition, visuospatial function, memory, and executive function. Individuals who met the WHO recommendation of ≥150 min/week of MIPA demonstrated better global cognition, executive function, and visuospatial function. Resting-state functional connectivity associated with MIPA included a combination of brainstem, hippocampus, and regions in the frontal, cingulate, and parietal cortices, which showed higher connectivity across the brain in those achieving the WHO MIPA recommendation. Meeting this recommendation positively moderated the associations between identified functional connectivity and global cognition, visuospatial function, and language. CONCLUSION: Encouraging MIPA, particularly the WHO recommendation of ≥150 min of MIPA/week, may represent an important prescription for PD cognition.
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Disfunção Cognitiva , Doença de Parkinson , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico por imagem , Mapeamento Encefálico , Vias Neurais , Testes Neuropsicológicos , Estudos Transversais , Cognição , Imageamento por Ressonância Magnética , Exercício FísicoRESUMO
OBJECTIVE: Higher volume fraction of perivascular space (PVS) has recently been reported in Parkinson's disease (PD) and related disorders. Both elevated PVS and altered levels of neurometabolites, assayed by proton magnetic resonance spectroscopy (MRS), are suspected indicators of neuroinflammation, but no published reports have concurrently examined PVS and MRS neurometabolites. METHODS: In an exploratory pilot study, we acquired multivoxel 3-T MRS using a semi-Localization by Adiabatic SElective Refocusing (sLASER) pulse-sequence (repetition time/echo time = 2810/60 ms, voxels 10 × 10 × 10 mm3) from a 2D slab sampling bilateral frontal white matter (FWM) and anterior middle cingulate cortex (aMCC). PVS maps obtained from high-resolution (0.8 × 0.8 × 0.8 mm3) T1-weighted MRI were co-registered with MRS. In each MRS voxel, PVS volume and neurometabolite levels were measured. RESULTS: Linear regression accounting for age, sex, and BMI found greater PVS volume for higher levels of choline-containing compounds (Cho; P = 0.047) in FWM and lower PVS volume for higher levels of N-acetyl compounds (NAA; P = 0.012) in aMCC. Since (putatively) higher Cho is associated with inflammation while NAA has anti-inflammatory properties, these observations add to evidence that higher PVS load is a sign of inflammation. Additionally, lower Montreal Cognitive Assessment scores were associated with lower NAA in aMCC (P = 0.002), suggesting that local neuronal dysfunction and inflammation contribute to cognitive impairment in PD. CONCLUSION: These exploratory findings indicate that co-analysis of PVS and MRS is feasible and may help elucidate the cellular and metabolic substrates of glymphatic and inflammatory processes in PD.
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Doença de Parkinson , Ácido Aspártico/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Creatina/metabolismo , Estudos de Viabilidade , Humanos , Inflamação/metabolismo , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética/métodos , Doença de Parkinson/metabolismo , Projetos PilotoRESUMO
BACKGROUND: Physical activity (PA) is known to improve quality of life (QoL) as well as reduce mortality and disease progression in individuals with chronic neurological disorders. However, Latina women are less likely to participate in recommended levels of PA due to common socioeconomic barriers, including limited resources and access to exercise programs. Therefore, we developed a community-based intervention with activity monitoring and behavioral coaching to target these barriers and facilitate sustained participation in an exercise program promoting PA. OBJECTIVE: The aim of this study was to determine the feasibility and efficacy of a community-based intervention to promote PA through self-monitoring via a Fitbit and behavioral coaching among Latina participants with chronic neurological disorders. METHODS: We conducted a proof-of-concept study among 21 Spanish-speaking Latina participants recruited from the Los Angeles County and University of Southern California (LAC+USC) neurology clinic; participants enrolled in the 16-week intervention at The Wellness Center at The Historic General Hospital in Los Angeles. Demographic data were assessed at baseline. Feasibility was defined by participant attrition and Fitbit adherence. PA promotion was determined by examining change in time spent performing moderate-to-vigorous PA (MVPA) over the 16-week period. The effect of behavioral coaching was assessed by quantifying the difference in MVPA on days when coaching occurred versus on days without coaching. Change in psychometric measures (baseline vs postintervention) and medical center visits (16 weeks preintervention vs during the intervention) were also examined. RESULTS: Participants were of low socioeconomic status and acculturation. A total of 19 out of 21 (90%) participants completed the study (attrition 10%), with high Fitbit wear adherence (mean 90.31%, SD 10.12%). Time performing MVPA gradually increased by a mean of 0.16 (SD 0.23) minutes per day (P<.001), which was equivalent to an increase of approximately 18 minutes in MVPA over the course of the 16-week study period. Behavioral coaching enhanced intervention effectiveness as evidenced by a higher time spent on MVPA on days when coaching occurred via phone (37 min/day, P=.02) and in person (45.5 min/day, P=.01) relative to days without coaching (24 min/day). Participants improved their illness perception (effect size g=0.30) and self-rated QoL (effect size g=0.32). Additionally, a reduction in the number of medical center visits was observed (effect size r=0.44), and this reduction was associated with a positive change in step count during the study period (P.=04). CONCLUSIONS: Self-monitoring with behavioral coaching is a feasible community-based intervention for PA promotion among Latina women of low socioeconomic status with chronic neurological conditions. PA is known to be important for brain health in neurological conditions but remains relatively unexplored in minority populations. TRIAL REGISTRATION: ClinicalTrials.gov NCT04820153; https://clinicaltrials.gov/ct2/show/NCT04820153.
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Monocarboxylate transporters (MCTs) shuttle molecules, including L-lactate, involved in metabolism and cell signaling of the central nervous system. Astrocyte-specific MCT4 is a key component of the astrocyte-neuron lactate shuttle (ANLS) and is important for neuroplasticity and learning of the hippocampus. However, the importance of astrocyte-specific MCT4 in neuroplasticity of the M1 primary motor cortex remains unknown. In this study, we investigated astrocyte-specific MCT4 in motor learning and neuroplasticity of the M1 primary motor cortex using a cell-type specific shRNA knockdown of MCT4. Knockdown of astrocyte-specific MCT4 resulted in impaired motor performance and learning on the accelerating rotarod. In addition, MCT4 knockdown was associated with a reduction of neuronal dendritic spine density and spine width and decreased protein expression of PSD95, Arc, and cFos. Using near-infrared-conjugated 2-deoxyglucose uptake as a surrogate marker for neuronal activity, MCT4 knockdown was also associated with decreased neuronal activity in the M1 primary motor cortex and associated motor regions including the dorsal striatum and ventral thalamus. Our study supports a potential role for astrocyte-specific MCT4 and the ANLS in the neuroplasticity of the M1 primary motor cortex. Targeting MCT4 may serve to enhance neuroplasticity and motor repair in several neurological disorders, including Parkinson's disease and stroke.
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Astrócitos , Transportadores de Ácidos Monocarboxílicos , Córtex Motor , Animais , Astrócitos/metabolismo , Espinhas Dendríticas/metabolismo , Humanos , Ácido Láctico/metabolismo , Camundongos , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Córtex Motor/metabolismo , Neurônios/metabolismoRESUMO
BACKGROUND: Studies in aging older adults have shown the positive association between cognition and exercise related fitness, particularly cardiorespiratory fitness. These reports have also demonstrated the association of high cardiorespiratory fitness, as well as other types of fitness, on the reversal of age-related decline in neural network connectivity, highlighting the potential role of fitness on age- and disease-related brain changes. While the clinical benefits of exercise are well-documented in Parkinson's disease (PD), the extent to which cardiorespiratory fitness (assessed by estimated VO2max testing) or motor skill fitness (assessed by the Physical Performance Test (PPT)) affects neural network connectivity in PD remains to be investigated. The purpose of this study was to explore the hypothesis that higher fitness level is associated with an increase in the intrinsic network connectivity of cognitive networks commonly affected in PD. METHODS: In this cross-sectional resting state fMRI, we used a multivariate statistical approach based on high-dimensional independent component analysis (ICA) to investigate the association between two independent fitness metrics (estimated VO2max and PPT) and resting state network connectivity. RESULTS: We found that increased estimated VO2max was associated with increased within network connectivity in cognitive networks known to be impaired in PD, including those sub-serving memory and executive function. There was a similar trend for high levels of PPT to be associated with increased within network connectivity in distinct resting state networks. The between functional network connectivity analysis revealed that cardiorespiratory fitness was associated with increased functional connectivity between somatosensory motor network and several cognitive networks sub-serving memory, attention, and executive function. CONCLUSION: This study provides important empirical data supporting the potential association between two forms of fitness and multiple resting state networks impacting PD cognition. Linking fitness to circuit specific modulation of resting state network connectivity will help establish a neural basis for the positive effects of fitness and specific exercise modalities and provide a foundation to identify underlying mechanisms to promote repair.
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Impaired motor learning in individuals with Parkinson's disease is often attributed to deficits in executive function, which serves as an important cognitive process supporting motor learning. However, less is known about the role of other cognitive domains and its association with motor learning in Parkinson's disease. The objective of this study was to investigate the associations between motor learning and multiple domains of cognitive performance in individuals with Parkinson's disease. Twenty-nine participants with Parkinson's disease received comprehensive neuropsychological testing, followed by practice of a bimanual finger sequence task. A retention test of the finger sequence task was completed 24 h later. Hierarchical linear regressions were used to examine the associations between motor learning (acquisition rate and retention) and cognitive performance in five specific cognitive domains, while controlling for age, sex, and years of Parkinson's disease diagnosis. We found that a higher acquisition rate was associated with better episodic memory, specifically better recall in visual episodic memory, in individuals with Parkinson's disease. No significant associations were observed between retention and cognitive performance in any domains. The association between motor acquisition and episodic memory indicates an increased dependency on episodic memory as a potential compensatory cognitive strategy used by individuals with Parkinson's disease during motor learning.
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Cognição , Aprendizagem , Memória Episódica , Rememoração Mental , Destreza Motora , Doença de Parkinson , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: Cognitive deficits occur in Parkinson's disease (PD). Cardiorespiratory fitness (CRF) is associated with better cognitive performance in aging especially in executive function (EF) and memory. The association between CRF and cognitive performance is understudied in people with PD. Brain structures underlying associations also remains unknown. This cross-sectional study examined the associations between CRF and cognitive performance in PD. We also examined associations between CRF and brain structures impacted in PD. Mediation analysis were conducted to examine whether brain structures impacted in PD mediate putative associations between CRF and cognitive performance. METHODS: Individuals with PD (N = 33) underwent magnetic resonance imaging (MRI), CRF evaluation (estimated VO2max), and neuropsychological assessment. Composite cognitive scores of episodic memory, EF, attention, language, and visuospatial functioning were generated. Structural equation models were constructed to examine whether MRI volume estimates (thalamus and pallidum) mediated associations between CRF and cognitive performance (adjusting for age, education, PD disease duration, sex, MDS-UPDRS motor score, and total intracranial volume). RESULTS: Higher CRF was associated with better episodic memory (Standardized ß = 0.391; p = 0.008), EF (Standardized ß = 0.324; p = 0.025), and visuospatial performance (Standardized ß = 0.570; p = 0.005). Higher CRF was associated with larger thalamic (Standardized ß = 0.722; p = 0.004) and pallidum (Standardized ß = 0.635; p = 0.004) volumes. Thalamic volume mediated the association between higher CRF and better EF (Indirect effect = 0.309) and episodic memory (Indirect effect = 0.209) performance (p < 0.05). The pallidum did not significantly mediate associations between CRF and cognitive outcomes. CONCLUSION: The thalamus plays an important role in the association between CRF and both EF and episodic memory in PD.
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Aptidão Cardiorrespiratória/fisiologia , Disfunção Cognitiva/fisiopatologia , Doença de Parkinson/fisiopatologia , Tálamo/fisiopatologia , Idoso , Cognição/fisiologia , Disfunção Cognitiva/etiologia , Estudos Transversais , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/complicaçõesRESUMO
l-Lactate is an energetic and signaling molecule that may be produced through astrocyte-specific aerobic glycolysis and is elevated in striatal muscle during intensive exercise. l-Lactate has been shown to promote neurotrophic gene expression through astrocytes within the hippocampus, however, its role in neuroplasticity within the striatum remains unknown. This study sought to investigate the role of peripheral sources of l-lactate in promoting astrocyte-specific gene expression and morphology as well as its role in neuroplasticity within the striatum of healthy animals. Using in vitro primary astrocyte cell culture, administration of l-lactate increased the expression of the neurotrophic factors Bdnf, Gdnf, Cntf, and the immediate early gene cFos. l-Lactate's promotion of neurotrophic factor expression was mediated through the lactate receptor HCAR1 since application of the HCAR1 agonist 3,5-DHBA also increased expression of Bdnf in primary astrocytes. Similar to our previous report demonstrating exercise-induced changes in astrocytic structure within the striatum, l-lactate administration to healthy mice led to increased astrocyte morphological complexity as well as astrocyte-specific neurotrophic expression within the striatum. Our study failed to demonstrate an effect of peripheral l-lactate on synaptogenesis or motor behavior. Insufficient levels and/or inadequate delivery of l-lactate through regional cerebral blood flow within the striatum may account for the lack of these benefits. Taken together, these novel findings suggest a potential framework that links peripheral l-lactate production within muscle and intensive exercise with neuroplasticity of specific brain regions through astrocytic function.
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Astrócitos/fisiologia , Corpo Estriado/fisiologia , Ácido Láctico/farmacologia , Atividade Motora/fisiologia , Plasticidade Neuronal/fisiologia , Sinapses/fisiologia , Animais , Astrócitos/efeitos dos fármacos , Células Cultivadas , Corpo Estriado/efeitos dos fármacos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Neurogênese/fisiologia , Plasticidade Neuronal/efeitos dos fármacos , Sinapses/efeitos dos fármacosRESUMO
BACKGROUND: The glymphatic system, including the perivascular space (PVS), plays a critical role in brain homeostasis. Although mounting evidence from Alzheimer's disease has supported the potential role of PVS in neurodegenerative disorders, its contribution in Parkinson's disease (PD) has not been fully elucidated. Although idiopathic (IPD) and familial PD (FPD) share similar pathophysiology in terms of protein aggregation, the differential impact of PVS on PD subtypes remains unknown. Our objective was to examine the differences in PVS volume fraction in IPD and FPD compared to healthy controls (HCs) and nonmanifest carriers (NMCs). METHODS: A total of 470 individuals were analyzed from the Parkinson's Progression Markers Initiative database, including (1) IPD (n = 179), (2) FPD (LRRK2 [leucine-rich repeat kinase 2], glucocerebrosidase, or α-synuclein) (n = 67), (3) NMC (n = 101), and (4) HCs (n = 84). Total PVS volume fraction (%) was compared using parcellation and quantitation within greater white matter volume at global and regional levels in all cortical and subcortical white matter. RESULTS: There was a significant increase in global and regional PVS volume fraction in PD versus non-PD, particularly in FPD versus NMC and LRRK2 FPD versus NMC. Regionally, FPD and NMC differed in the medial orbitofrontal region, as did LRRK2 FPD versus NMC. Non-PD and PD differed in the medial orbitofrontal region and the banks of the superior temporal regions. IPD and FPD differed in the cuneus and lateral occipital regions. CONCLUSIONS: Our findings support the role of PVS in PD and highlight a potentially significant contribution of PVS to the pathophysiology of FPD, particularly LRRK2. © 2021 International Parkinson and Movement Disorder Society.
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Sistema Glinfático , Doença de Parkinson , Sistema Glinfático/metabolismo , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Mutação , Doença de Parkinson/genética , alfa-Sinucleína/metabolismoRESUMO
Lesions of the dorsomedial striatum elicit deficits in cognitive flexibility that are an early feature of Parkinson's disease (PD), and presumably reflect alterations in frontostriatal processing. The current study aimed to examine deficits in cognitive flexibility in rats with bilateral 6-hydroxydopamine lesions in the dorsomedial striatum. While deficits in cognitive flexibility have previously been examined in rodent PD models using the cross-maze, T-maze, and a food-digging task, the current study is the first to examine such deficits using a 3-choice serial reaction time task (3-CSRT) with reversal learning (3-CSRT-R). Although the rate of acquisition in 3-CSRT was slower in lesioned compared to control rats, lesioned animals were able to acquire a level of accuracy comparable to that of control animals following 4 weeks of training. In contrast, substantial and persistent deficits were apparent during the reversal learning phase. Our results demonstrate that deficits in cognitive flexibility can be robustly unmasked by reversal learning in the 3-CSRT-R paradigm, which can be a useful test for evaluating effects of dorsomedial striatal deafferentation and interventions.
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Comportamento de Escolha/fisiologia , Disfunção Cognitiva/patologia , Corpo Estriado/patologia , Oxidopamina/toxicidade , Tempo de Reação/fisiologia , Reversão de Aprendizagem/fisiologia , Animais , Comportamento de Escolha/efeitos dos fármacos , Cognição/efeitos dos fármacos , Cognição/fisiologia , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/psicologia , Corpo Estriado/efeitos dos fármacos , Discriminação Psicológica/efeitos dos fármacos , Discriminação Psicológica/fisiologia , Masculino , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacos , Reversão de Aprendizagem/efeitos dos fármacosRESUMO
OBJECTIVE: Mild cognitive impairment (MCI) and psychiatric symptoms (anxiety, depression, and apathy) are common in Parkinson's disease (PD). While studies have supported the association between psychiatric symptoms and cognitive performance in PD, it is unclear if the magnitude of link between psychiatric symptoms and cognitive health is stronger by MCI status. The purpose of this study was to examine the association between cognitive performance and psychiatric symptoms in PD and whether MCI status moderates this association. METHODS/DESIGN: Participants (N = 187) completed a comprehensive neuropsychological assessment that included measures of attention, language, executive function (EF), visuospatial ability, episodic memory, and psychiatric symptoms. Participants were classified as PD-MCI (N = 73) or PD-normal cognition (NC; N = 114). Linear regression analyses were conducted to examine the association between psychiatric symptoms and cognitive performance and the moderating effect of PD-MCI status. RESULTS: There were no differences in mean psychiatric symptoms between PD-MCI and PD-NC. Psychiatric symptoms were predominantly associated with worse EF. The magnitude of the association between anxiety and worse EF was larger in participants with PD-MCI compared with PD-NC. A multivariable regression analysis examining the independent contributions of each symptom demonstrated the most robust association between EF and anxiety. CONCLUSIONS: Symptoms of anxiety, depression, and apathy are associated with worse executive functioning in individuals with PD. PD-MCI may be important in moderating the association between cognitive performance, specifically anxiety, and EF. Factors that promote cognitive resilience may serve as key therapeutic modalities in managing neuropsychiatric symptoms in PD.
Assuntos
Ansiedade/psicologia , Apatia/fisiologia , Atenção/fisiologia , Cognição/fisiologia , Disfunção Cognitiva/psicologia , Função Executiva/fisiologia , Doença de Parkinson/complicações , Idoso , Disfunção Cognitiva/complicações , Feminino , Humanos , Idioma , Masculino , Memória Episódica , Pessoa de Meia-Idade , Testes Neuropsicológicos , Doença de Parkinson/psicologia , Análise de RegressãoRESUMO
BACKGROUND: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by polyglutamine (CAG) expansion in the Huntingtin (HTT) gene. The CAG140 knock-in (KI) mouse model recapitulates the progression of motor symptoms emerging at 12 months of age. OBJECTIVE: This study was aimed at assessing the effects of exercise, in the form of treadmill running, and examining its impact on motor behavior and markers of metabolism in the CAG140 KI mouse model of HD after motor symptoms have emerged. METHODS: CAG140 KI mice at 13-15 months of age were subjected to treadmill exercise 3 days per week for 1 h per day or remained sedentary. After 12 weeks of exercise brain tissues were analyzed for enzymatic activity including mitochondria Complexes I, II/III, and IV, transglutaminase, aconitase, pyruvate dehydrogenase, and phosphofructokinase1/2. In addition, the concentration was determined for nitrate/nitrite, pyruvate carboxylase, NAD+/NADH, and glutamate as well as the ratio of mitochondria and nuclear DNA. Motor behavior was tested using the rotarod. RESULTS: Exercise resulted in increased [nitrite + nitrate] levels (surmised as nitric oxide), reduced transglutaminase activity, increased aconitase activity with increased tricarboxylic acid-generated reducing equivalents and mitochondrial oxidative phosphorylation complexes activity. Mitochondrial function was strengthened by increases in glycolysis, pyruvate dehydrogenase activity, and anaplerosis component represented by pyruvate carboxylase. CONCLUSIONS: These changes in mitochondrial function were associated with improved motor performance on the rotarod test. These findings suggest that exercise may have beneficial effects on motor behavior by reversing deficits in mitochondrial function in a rodent model of HD.
Assuntos
Comportamento Animal/fisiologia , Doença de Huntington/fisiopatologia , Mitocôndrias/fisiologia , Atividade Motora/fisiologia , Condicionamento Físico Animal/fisiologia , Animais , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Teste de Esforço/métodos , Feminino , Doença de Huntington/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Fosforilação Oxidativa , Ácidos Tricarboxílicos/metabolismoRESUMO
Astrocytes are essential mediators of many aspects of synaptic transmission and neuroplasticity. Exercise has been demonstrated to induce neuroplasticity and synaptic remodeling, such as through mediating neurorehabilitation in animal models of neurodegeneration. However, the effects of exercise on astrocytic function, and how such changes may be relevant to neuroplasticity remain unclear. Here, we show that exercise remodels astrocytes in an exercise- and region-dependent manner as measured by GFAP and SOX9 immunohistochemistry and morphological analysis in male mice. Additionally, qRT-PCR analysis of reactive astrocyte gene expression showed an exercise-induced elevation in brain regions known to be activated by exercise. Taken together, these data demonstrate that exercise actively modifies astrocyte morphology and drives changes in astrocyte gene expression and suggest that astrocytes may be a central component to exercise-induced neuroplasticity and neurorehabilitation.
Assuntos
Astrócitos/citologia , Regulação da Expressão Gênica/fisiologia , Condicionamento Físico Animal/fisiologia , Animais , Astrócitos/metabolismo , Encéfalo/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade NeuronalRESUMO
Exercise and other forms of physical activity lead to the activation of specific motor and cognitive circuits within the mammalian brain. These activated neuronal circuits are subjected to increased metabolic demand and must respond to transient but significant reduction in available oxygen. The transcription factor hypoxia-inducible factor 1α (HIF-1α) is a regulatory mediator of a wide spectrum of genes involved in metabolism, synaptogenesis, and blood flow. The purpose of this study was to begin to explore the potential relationship between exercise in the form of running on a motorized treadmill and the activation of genes involved in exercise-dependent neuroplasticity to begin to elucidate the underlying molecular mechanisms involved. Mice were subjected to treadmill exercise and striatal tissues analyzed with a commercial microarray designed to identify transcripts whose expression is altered by exposure to hypoxia, a condition occurring in cells under a high metabolic demand. Several candidate genes were identified, and a subset involved in metabolism and angiogenesis were selected to elucidate their temporal and regional patterns of expression with exercise. Transcript analysis included Hif1a (hypoxia-inducible factor 1α), Ldha (lactate dehydrogenase A), Slc2a1 (glucose transporter 1), Slc16a1 (monocarboxylate transporter 1), Slc16a7 (monocarboxylate transporter 2), and Vegf (vascular endothelial growth factor). Overall these results indicate that several genes involved in the elevated metabolic response with exercise are consistent with increased expression of HIF-1α suggesting a regulatory role for HIF-1α in exercise-enhanced neuroplasticity. Furthermore, these increases in gene expression appear regionally specific; occurring with brain regions we have previously shown to be sites for increased cerebral blood flow with activity. Such findings are beginning to lay down a working hypothesis that specific forms of exercise lead to circuit specific neuronal activation and can identify a potentially novel therapeutic approach to target dysfunctional behaviors subserved by such circuitry.