RESUMO
Sirtuin 1 (SIRT1) is a histone deacetylase and plays diverse functions in various physiological events, from development to lifespan regulation. Here, in Parkinson's disease (PD) model mice, we demonstrated that SIRT1 ameliorates parkinsonism, while SIRT1 knockdown further aggravates PD phenotypes. Mechanistically, SIRT1 interacts with and deacetylates pyruvate kinase M2 (PKM2) at K135 and K206, thus leading to reduced PKM2 enzyme activity and lactate production, which eventually results in decreased glial activation in the brain. Administration of lactate in the brain recapitulates PD-like phenotypes. Furthermore, increased expression of PKM2 worsens PD symptoms, and, on the contrary, inhibition of PKM2 by shikonin or PKM2-IN-1 alleviates parkinsonism in mice. Collectively, our data indicate that excessive lactate in the brain might be involved in the progression of PD. By improving lactate homeostasis, SIRT1, together with PKM2, are likely drug targets for developing agents for the treatment of neurodegeneration in PD.
Assuntos
Encéfalo , Homeostase , Ácido Láctico , Piruvato Quinase , Sirtuína 1 , Sirtuína 1/metabolismo , Sirtuína 1/genética , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Piruvato Quinase/metabolismo , Piruvato Quinase/genética , Camundongos , Ácido Láctico/metabolismo , Humanos , Acetilação/efeitos dos fármacos , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/patologia , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/genética , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos C57BL , Proteínas de Ligação a Hormônio da Tireoide , Hormônios Tireóideos/metabolismo , Naftoquinonas/farmacologiaRESUMO
Parkinson's disease (PD) involves the degeneration of dopaminergic neurons in the substantia nigra (SNpc) and manifests with both classic and non-classic motor symptoms, including respiratory failure. Our study aims to investigate the involvement of the commissural and intermediate nucleus of the solitary tract (cNTS and iNTS) in the attenuated respiratory response to hypoxia in PD. Using a PD rat model induced by bilateral injection of 6-hydroxydopamine (6-OHDA) into the striatum of male Wistar rats, we explored potential alterations in the population of Phox2b neurons or hypoxia-activated neurons in the NTS projecting to the retrotrapezoid nucleus (RTN). Additionally, we explored neuronal connectivity between SNpc and cNTS. Projections pathways were assessed using unilateral injection of the retrograde tracer Fluorogold (FG) in the cNTS and RTN. Neuronal activation was evaluated by analyzing fos expression in rats exposed to hypoxia. In the PD model, the ventilatory response, measured through whole-body plethysmography, was impaired at both baseline and in response to hypoxia. A reduction in Phox2b-expressing neurons or hypoxia-activated neurons projecting to the RTN was observed. Additionally, we identified an indirect pathway linking the SNpc and cNTS, which passes through the periaqueductal gray (PAG). In conclusion, our findings suggest impairment in the SNpc-PAG-cNTS pathway in the PD model, explaining the loss of Phox2b-expressing neurons or hypoxia-activated neurons in the cNTS and subsequent respiratory impairment during hypoxic stimulation. We propose that the reduced population of Phox2b-expressing neurons in the NTS may include the same neurons activated by hypoxia and projecting to the RTN.
Assuntos
Hipóxia , Oxidopamina , Ratos Wistar , Núcleo Solitário , Animais , Masculino , Ratos , Núcleo Solitário/patologia , Hipóxia/patologia , Oxidopamina/toxicidade , Proteínas de Homeodomínio/metabolismo , Modelos Animais de Doenças , Degeneração Neural/patologia , Neurônios/patologia , Transtornos Parkinsonianos/patologia , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/fisiopatologia , Fatores de Transcrição/metabolismoRESUMO
Background: The interrelationship of parkinsonism, Parkinson's disease (PD) and other Alzheimer's disease (AD) and Alzheimer's disease and related dementias (ADRD) pathologies is unclear. Objective: We examined the progression of parkinsonian signs in adults with and without parkinsonism, and their underlying brain pathologies. Methods: Annual parkinsonian signs were based on a modified Unified Parkinson's Disease Rating Scale. We used linear mixed effects models to compare the progression of parkinsonian signs in 3 groups categorized based on all available clinical evaluations: Group1 (never parkinsonism or clinical PD), Group2 (ever parkinsonism, but never clinical PD), Group3 (ever clinical PD). In decedents, we examined the progression of parkinsonian signs with PD and eight other AD/ADRD pathologies. Results: During average follow-up of 8 years, parkinsonian signs on average increased by 7.3% SD/year (Nâ=â3,807). The progression of parkinsonian signs was slowest in Group1 (never parkinsonism or clinical PD), intermediate in Group2, and fastest in Group3. In decedents (nâ=â1,717) pathologic PD and cerebrovascular (CVD) pathologies were associated with a faster rate of progressive parkinsonian signs (all p values <0.05). However, pathologic PD was rare in adults without clinical PD (Group1, 5%; Group2, 7% versus Group3, 55%). Yet, 70% of adults in Group2 without pathologic PD showed one or more CVD pathologies. In Group2, adults with pathologic PD showed faster progression of parkinsonian signs compared with those without evidence of pathologic PD and their rate of progression was indistinguishable from adults with clinical PD. Conclusions: Parkinsonism in old age is more commonly related to cerebrovascular pathologies relative to pathologic PD and only a minority manifest prodromal PD.
Assuntos
Doença de Alzheimer , Demência , Progressão da Doença , Doença de Parkinson , Humanos , Feminino , Masculino , Idoso , Doença de Parkinson/patologia , Doença de Alzheimer/patologia , Demência/patologia , Idoso de 80 Anos ou mais , Transtornos Parkinsonianos/patologia , Seguimentos , Encéfalo/patologia , Encéfalo/diagnóstico por imagem , Pessoa de Meia-IdadeRESUMO
Anderson-Fabry disease (AFD) is a genetic sphingolipidosis involving virtually the entire body. Among its manifestation, the involvement of the central and peripheral nervous system is frequent. In recent decades, it has become evident that, besides cerebrovascular damage, a pure neuronal phenotype of AFD exists in the central nervous system, which is supported by clinical, pathological, and neuroimaging data. This neurodegenerative phenotype is often clinically characterized by an extrapyramidal component similar to the one seen in prodromal Parkinson's disease (PD). We analyzed the biological, clinical pathological, and neuroimaging data supporting this phenotype recently proposed in the literature. Moreover, we compared the neurodegenerative PD phenotype of AFD with a classical monogenic vascular disease responsible for vascular parkinsonism and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). A substantial difference in the clinical and neuroimaging features of neurodegenerative and vascular parkinsonism phenotypes emerged, with AFD being potentially responsible for both forms of the extrapyramidal involvement, and CADASIL mainly associated with the vascular subtype. The available studies share some limitations regarding both patients' information and neurological and genetic investigations. Further studies are needed to clarify the potential association between AFD and extrapyramidal manifestations.
Assuntos
Doença de Fabry , Fenótipo , Humanos , Doença de Fabry/genética , Doença de Fabry/patologia , Doença de Fabry/complicações , Transtornos Parkinsonianos/genética , Transtornos Parkinsonianos/diagnóstico por imagem , Transtornos Parkinsonianos/patologia , CADASIL/genética , CADASIL/patologiaRESUMO
AIMS: Astrocytic tau pathology is a major feature of tauopathies and ageing-related tau astrogliopathy (ARTAG). The substantia nigra (SN) is one of the important degenerative areas in tauopathies with parkinsonism. Nigral tau pathology is usually reported as neuronal predominant with less prominent astrocytic involvement. We aimed to identify cases with prominent astrocytic tau pathology in the SN. METHODS: We use the term nigral tau-astrogliopathy (NITAG) to describe cases showing an unusually high density of ARTAG with less neuronal tau pathology in the SN. We collected clinical information and studied the distribution of tau pathology, morphological features and immunostaining profiles in three cases. RESULTS: Three cases, all males with parkinsonism, were identified with the following clinicopathological diagnoses: (i) atypical parkinsonism with tau pathology reminiscent to that in postencephalitic parkinsonism (69-year-old); (ii) multiple system atrophy (73-year-old); (iii) traumatic encephalopathy syndrome/chronic traumatic encephalopathy (84-year-old). Double-labelling immunofluorescence confirmed co-localization of GFAP and phosphorylated tau in affected astrocytes. Staining profiles of NITAG revealed immunopositivity for various phosphorylated tau antibodies. Some astrocytic tau lesions were also seen in other brainstem regions and cerebral grey matter. CONCLUSIONS: We propose NITAG is a rare neuropathological feature, and not a distinct disease entity, in the frame of multiple system ARTAG, represented by abundant tau-positive astrocytes in various brain regions but having the highest density in the SN. The concept of NITAG allows the stratification of cases with various background pathologies to understand its relevance and contribution to neuronal dysfunction.
Assuntos
Envelhecimento , Astrócitos , Substância Negra , Tauopatias , Proteínas tau , Humanos , Masculino , Substância Negra/patologia , Substância Negra/metabolismo , Idoso , Astrócitos/patologia , Astrócitos/metabolismo , Tauopatias/patologia , Tauopatias/metabolismo , Idoso de 80 Anos ou mais , Envelhecimento/patologia , Proteínas tau/metabolismo , Transtornos Parkinsonianos/patologia , Transtornos Parkinsonianos/metabolismoRESUMO
Parkinson's disease (PD) is the most common neurodegenerative movement disorder worldwide. Current treatments for PD largely center around dopamine replacement therapies and fail to prevent the progression of pathology, underscoring the need for neuroprotective interventions. Approaches that target neuroinflammation, which occurs prior to dopaminergic neuron (DAn) loss in the substantia nigra (SN), represent a promising therapeutic strategy. The glucocorticoid receptor (GR) has been implicated in the neuropathology of PD and modulates numerous neuroinflammatory signaling pathways in the brain. Therefore, we investigated the neuroprotective effects of the novel GR modulator, PT150, in the rotenone mouse model of PD, postulating that inhibition of glial inflammation would protect DAn and reduce accumulation of neurotoxic misfolded âº-synuclein protein. C57Bl/6 mice were exposed to 2.5â¯mg/kg/day rotenone by intraperitoneal injection for 14 days. Upon completion of rotenone dosing, mice were orally treated at day 15 with 30â¯mg/kg/day or 100â¯mg/kg/day PT150 in the 14-day post-lesioning incubation period, during which the majority of DAn loss and α-synuclein (α-syn) accumulation occurs. Our results indicate that treatment with PT150 reduced both loss of DAn and microgliosis in the nigrostriatal pathway. Although morphologic features of astrogliosis were not attenuated, PT150 treatment promoted potentially neuroprotective activity in these cells, including increased phagocytosis of hyperphosphorylated α-syn. Ultimately, PT150 treatment reduced the loss of DAn cell bodies in the SN, but not the striatum, and prohibited intra-neuronal accumulation of α-syn. Together, these data indicate that PT150 effectively reduced SN pathology in the rotenone mouse model of PD.
Assuntos
Neurônios Dopaminérgicos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores , Receptores de Glucocorticoides , Rotenona , alfa-Sinucleína , Animais , Rotenona/toxicidade , Fármacos Neuroprotetores/farmacologia , Camundongos , Masculino , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Neurônios Dopaminérgicos/metabolismo , Receptores de Glucocorticoides/metabolismo , alfa-Sinucleína/metabolismo , Substância Negra/efeitos dos fármacos , Substância Negra/patologia , Substância Negra/metabolismo , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/patologia , Modelos Animais de Doenças , FenantrenosRESUMO
Parkinson's disease (PD) is characterized by motor impairments caused by degeneration of dopamine neurons in the substantia nigra pars compacta. In addition to these symptoms, PD patients often suffer from non-motor comorbidities including sleep and psychiatric disturbances, which are thought to depend on concomitant alterations of serotonergic and noradrenergic transmission. A primary locus of serotonergic neurons is the dorsal raphe nucleus (DRN), providing brain-wide serotonergic input. Here, we identified electrophysiological and morphological parameters to classify serotonergic and dopaminergic neurons in the murine DRN under control conditions and in a PD model, following striatal injection of the catecholamine toxin, 6-hydroxydopamine (6-OHDA). Electrical and morphological properties of both neuronal populations were altered by 6-OHDA. In serotonergic neurons, most changes were reversed when 6-OHDA was injected in combination with desipramine, a noradrenaline (NA) reuptake inhibitor, protecting the noradrenergic terminals. Our results show that the depletion of both NA and dopamine in the 6-OHDA mouse model causes changes in the DRN neural circuitry.
Assuntos
Modelos Animais de Doenças , Neurônios Dopaminérgicos , Núcleo Dorsal da Rafe , Oxidopamina , Transtornos Parkinsonianos , Neurônios Serotoninérgicos , Animais , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Neurônios Serotoninérgicos/metabolismo , Núcleo Dorsal da Rafe/metabolismo , Núcleo Dorsal da Rafe/efeitos dos fármacos , Camundongos , Transtornos Parkinsonianos/fisiopatologia , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/patologia , Masculino , Camundongos Endogâmicos C57BL , Desipramina/farmacologia , Norepinefrina/metabolismoRESUMO
The abnormal accumulation of fibrillar α-synuclein in the substantia nigra contributes to Parkinson's disease (PD). Chemical chaperones like 4-phenyl butyric acid (4PBA) show neuroprotective potential, but high doses are required. A derivative, 5-phenyl valeric acid (5PVA), has reported therapeutic potential for PD by reducing Pael-R expression. This study assessed 5PVA's efficacy in PD animals and its molecular mechanism. In vitro studies revealed 5PVA's anti-aggregation ability against alpha-synuclein and neuroprotective effects on SHSY5Y neuroblastoma cells exposed to rotenone. PD-like symptoms were induced in SD rats with rotenone, followed by 5PVA treatment at 100 mg/kg and 130 mg/kg. Behavioral analysis showed significant improvement in memory and motor activity with 5PVA administration. Histopathological studies demonstrated normal neuronal histoarchitecture in mid-brain tissue sections of 5PVA-treated animals compared to the PD group. mRNA studies revealed significant suppression in the expression of various protein folding and heat-shock protein markers in the 5PVA-treated group. In conclusion, 5PVA, with its anti-aggregation ability against alpha-synuclein, acts as a chemical chaperone, showing potential as a therapeutic candidate for PD treatment.
Assuntos
Estresse do Retículo Endoplasmático , Ratos Sprague-Dawley , Rotenona , alfa-Sinucleína , Animais , alfa-Sinucleína/metabolismo , Rotenona/toxicidade , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ratos , Masculino , Linhagem Celular Tumoral , Humanos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Ácidos Pentanoicos/farmacologia , Ácidos Pentanoicos/uso terapêutico , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/patologia , Agregados Proteicos/efeitos dos fármacosRESUMO
Parkinson's is the most common neurodegenerative disease after Alzheimer's. Motor findings in Parkinson's occur as a result of the degeneration of dopaminergic neurons starting in the substantia nigra pars compacta and ending in the putamen and caudate nucleus. Loss of neurons and the formation of inclusions called Lewy bodies in existing neurons are characteristic histopathological findings of Parkinson's. The disease primarily impairs the functional capacity of the person with cardinal findings such as tremor, bradykinesia, etc., as a result of the loss of dopaminergic neurons in the substantia nigra. Experimental animal models of Parkinson's have been used extensively in recent years to investigate the pathology of this disease. These models are generally based on systemic or local(intracerebral) administration of neurotoxins, which can replicate many features of Parkinson's mammals. The development of transgenic models in recent years has allowed us to learn more about the modeling of Parkinson's. Applying animal modeling, which shows the most human-like effects in studies, is extremely important. It has been demonstrated that oxidative stress increases in many neurodegenerative diseases such as Parkinson's and various age-related degenerative diseases in humans and that neurons are sensitive to it. In cases where oxidative stress increases and antioxidant systems are inadequate, natural molecules such as flavonoids and polyphenols can be used as a new antioxidant treatment to reduce neuronal reactive oxygen species and improve the neurodegenerative process. Therefore, in this article, we examined experimental animal modeling in Parkinson's disease and the effect of green chemistry approaches on Parkinson's disease.
Assuntos
Modelos Animais de Doenças , Animais , Humanos , Química Verde , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Estresse Oxidativo/fisiologia , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Transtornos Parkinsonianos/patologia , Transtornos Parkinsonianos/metabolismo , Antioxidantes/farmacologiaRESUMO
INTRODUCTION: The substantia nigra pars compacta (SNc) is the key pathologic locus in neurodegenerative parkinsonian disorders. Recently, in vivo susceptibility MRI metrics were associated with postmortem glial cell density and tau burden in the SNc of parkinsonism subjects. This study investigated the red nucleus (RN), another iron-rich region adjacent to the SNc and a potential site of higher functionality in parkinsonisms. METHODS: In vivo MRI and postmortem data were obtained from 34 parkinsonism subjects and 3 controls. Neuron density, glial cell density, and percentages of area occupied by α-synuclein and tau were quantified using digitized midbrain slides. R2* and quantitative susceptibility mapping (QSM) metrics in the RN and SNc were derived from multi-gradient echo images. Histopathology data were compared between the RN and SNc using paired t-tests. MRI-histology associations were analyzed using partial Pearson correlations. RESULTS: The RN had greater neuron (t23 = 3.169, P = 0.004) and glial cell densities (t23 = 2.407, P = 0.025) than the SNc, whereas the SNc had greater α-synuclein (t28 = 4.614, P < 0.0001) and tau burden (t24 = 4.513, P = 0.0001). In both the RN (R2*: r = 0.47, P = 0.043; QSM: r = 0.52, P = 0.024) and SNc (R2*: r = 0.57, P = 0.01; QSM: r = 0.58, P = 0.009), MRI values were associated with glial cell density but not neuron density or α-synuclein (Ps > 0.092). QSM associated with tau burden (r = 0.49, P = 0.038) in the SNc, but not the RN. CONCLUSIONS: The RN is resilient to parkinsonian-related pathological processes compared to the SNc, and susceptibility MRI captured glial cell density in both regions. These findings help to further our understanding of the underlying pathophysiological processes in parkinsonisms.
Assuntos
Imageamento por Ressonância Magnética , Transtornos Parkinsonianos , Parte Compacta da Substância Negra , Núcleo Rubro , Substância Negra , Humanos , Núcleo Rubro/diagnóstico por imagem , Núcleo Rubro/patologia , Núcleo Rubro/metabolismo , Masculino , Idoso , Feminino , Parte Compacta da Substância Negra/diagnóstico por imagem , Parte Compacta da Substância Negra/patologia , Parte Compacta da Substância Negra/metabolismo , Idoso de 80 Anos ou mais , Pessoa de Meia-Idade , Transtornos Parkinsonianos/diagnóstico por imagem , Transtornos Parkinsonianos/patologia , Transtornos Parkinsonianos/metabolismo , Substância Negra/diagnóstico por imagem , Substância Negra/patologia , Substância Negra/metabolismo , Proteínas tau/metabolismo , Neuroglia/patologia , Neuroglia/metabolismo , alfa-Sinucleína/metabolismo , Neurônios/patologia , Neurônios/metabolismoRESUMO
INTRODUCTION: Magnetic resonance imaging (MRI) based brain morphometric changes in unilateral 6-hydroxydopamine (6-OHDA) induced Parkinson's disease (PD) model can be elucidated using voxel-based morphometry (VBM), study of alterations in gray matter volume and Machine Learning (ML) based analyses. METHODS: We investigated gray matter atrophy in 6-OHDA induced PD model as compared to sham control using statistical and ML based analysis. VBM and atlas-based volumetric analysis was carried out at regional level. Support vector machine (SVM)-based algorithms wherein features (volume) extracted from (a) each of the 150 brain regions (b) statistically significant features (only) and (c) volumes of each cluster identified after application of VBM (VBM_Vol) were used for training the decision model. The lesion of the 6-OHDA model was validated by estimating the net contralateral rotational behaviour by the injection of apomorphine drug and motor impairment was assessed by rotarod and open field test. RESULTS AND DISCUSSION: In PD, gray matter volume (GMV) atrophy was noted in bilateral cortical and subcortical brain regions, especially in the internal capsule, substantia nigra, midbrain, primary motor cortex and basal ganglia-thalamocortical circuits in comparison with sham control. Behavioural results revealed an impairment in motor performance. SVM analysis showed 100% classification accuracy, sensitivity and specificity at both 3 and 7 weeks using VBM_Vol. CONCLUSION: Unilateral 6-OHDA induced GMV changes in both hemispheres at 7th week may be associated with progression of the disease in the PD model. SVM based approaches provide an increased classification accuracy to elucidate GMV atrophy.
Assuntos
Atrofia , Substância Cinzenta , Imageamento por Ressonância Magnética , Oxidopamina , Substância Cinzenta/patologia , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/efeitos dos fármacos , Atrofia/patologia , Animais , Masculino , Modelos Animais de Doenças , Apomorfina/farmacologia , Encéfalo/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Máquina de Vetores de Suporte , Doença de Parkinson/patologia , Doença de Parkinson/diagnóstico por imagem , Transtornos Parkinsonianos/patologia , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/diagnóstico por imagemRESUMO
INTRODUCTION: Patients with classic-onset corticobasal syndrome (CBS) present with asymmetric limb apraxia and parkinsonism. We have, however, observed patients who initially present with speech and/or language (SL) problems and several years later develop CBS (i.e., SL-onset CBS). We aimed to compare clinical, neuroimaging and pathological characteristics of classic-onset CBS with SL-onset CBS. METHODS: We conducted a retrospective cohort study of 62 patients who met criteria for CBS (17 presented with classic-onset CBS and 45 had SL-onset CBS). We compared demographics, clinical characteristics, and grey and white matter volume loss with SPM12 between groups and assessed pathology and corticobasal degeneration (CBD) pathological lesion counts in patients who had died and undergone autopsy. RESULTS: Median age at CBS diagnosis was 66.4 years in classic-onset CBS and 73.6 years in SL-onset CBS. Classic-onset CBS had higher frequencies of dystonia, myoclonus, and alien limb phenomenon, while SL-onset CBS had a higher frequency of vertical supranuclear gaze palsy. Both groups showed smaller frontoparietal volumes than controls, with SL-onset CBS having greater volume loss in the left supplementary motor area than classic-onset CBS. All three classic-onset CBS cases with autopsy (100 %) had CBD pathology while 8/21 of SL-onset CBS cases (38 %) had CBD. Pathological lesion burden (including astrocytic plaques) did not differ between classic-onset and SL-onset CBS. CONCLUSION: Classic-onset and SL-onset CBS appear to be different syndromes, with the former being a more profuse motor syndrome. The more widespread volume loss in SL-onset CBS likely reflects longer disease course.
Assuntos
Degeneração Corticobasal , Humanos , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Estudos Retrospectivos , Degeneração Corticobasal/patologia , Idoso de 80 Anos ou mais , Distúrbios da Fala/etiologia , Distúrbios da Fala/patologia , Transtornos da Linguagem/etiologia , Transtornos da Linguagem/patologia , Transtornos Parkinsonianos/patologia , Transtornos Parkinsonianos/diagnóstico por imagem , Transtornos Parkinsonianos/complicaçõesRESUMO
Parkinson's Disease (PD) is a neurodegenerative movement disorder characterized by dopamine (DA) cell loss in the substantia nigra pars compacta (SNc). As PD progresses, patients display disruptions in gait such as changes in posture, bradykinesia, and shortened stride. DA replacement via L-DOPA alleviates many PD symptoms, though its effects on gait are not well demonstrated. This study aimed to assess the relationship between DA lesion, gait, and deficit-induced reversal with L-DOPA. To do so, Sprague-Dawley rats (N = 25, 14 males, 11 females) received unilateral medial forebrain bundle (MFB) DA lesions with 6-hydroxydopamine (6-OHDA). An automated gait analysis system assessed spatiotemporal gait parameters pre- and post-lesion, and after various doses of L-DOPA (0, 3, or 6 mg/kg; s.c.). The forepaw adjusting steps (FAS) test was implemented to evaluate lesion efficacy while the abnormal involuntary movements (AIMs) scale monitored the emergence of L-DOPA-induced dyskinesia (LID). High performance liquid chromatography (HPLC) assessed changes in brain monoamines on account of lesion and treatment. Results revealed lesion-induced impairments in gait, inclusive of max-contact area and step-sequence alterations that were not reversible with L-DOPA. However, the emergence of AIMs were observed at higher doses. Post-mortem, 6-OHDA lesions induced a loss of striatal DA and norepinephrine (NE), while prefrontal cortex (PFC) displayed noticeable reduction in NE but not DA. Our findings indicate that hemiparkinsonian rats display measurable gait disturbances similar to PD patients that are not rescued by DA replacement. Furthermore, non-DA mechanisms such as attention-related NE in PFC may contribute to altered gait and may constitute a novel target for its treatment.
Assuntos
Transtornos Neurológicos da Marcha , Levodopa , Oxidopamina , Ratos Sprague-Dawley , Animais , Levodopa/farmacologia , Levodopa/efeitos adversos , Masculino , Feminino , Ratos , Transtornos Neurológicos da Marcha/induzido quimicamente , Transtornos Neurológicos da Marcha/tratamento farmacológico , Transtornos Neurológicos da Marcha/etiologia , Antiparkinsonianos/farmacologia , Modelos Animais de Doenças , Feixe Prosencefálico Mediano/efeitos dos fármacos , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/fisiopatologia , Transtornos Parkinsonianos/patologia , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Lateralidade Funcional/efeitos dos fármacos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/patologia , Doença de Parkinson/fisiopatologia , Marcha/efeitos dos fármacos , Discinesia Induzida por MedicamentosRESUMO
BACKGROUND AND OBJECTIVES: Degeneration of the presynaptic nigrostriatal dopaminergic system is one of the main biological features of Parkinson disease (PD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD), which can be measured using single-photon emission CT imaging for diagnostic purposes. Despite its widespread use in clinical practice and research, the diagnostic properties of presynaptic nigrostriatal dopaminergic (DAT) imaging in parkinsonism have never been evaluated against the diagnostic gold standard of neuropathology. The aim of this study was to evaluate the diagnostic parameters of DAT imaging compared with pathologic diagnosis in patients with parkinsonism. METHODS: Retrospective cohort study of patients with DAT imaging for the investigation of a clinically uncertain parkinsonism with brain donation between 2010 and 2021 to the Queen Square Brain Bank (London). Patients with DAT imaging for investigation of pure ataxia or dementia syndromes without parkinsonism were excluded. Those with a pathologic diagnosis of PD, MSA, PSP, or CBD were considered presynaptic dopaminergic parkinsonism, and other pathologies were considered postsynaptic for the analysis. DAT imaging was performed in routine clinical practice and visually classified by hospital nuclear medicine specialists as normal or abnormal. The results were correlated with neuropathologic diagnosis to calculate diagnostic accuracy parameters for the diagnosis of presynaptic dopaminergic parkinsonism. RESULTS: All of 47 patients with PD, 41 of 42 with MSA, 68 of 73 with PSP, and 6 of 10 with CBD (sensitivity 100%, 97.6%, 93.2%, and 60%, respectively) had abnormal presynaptic dopaminergic imaging. Eight of 17 patients with presumed postsynaptic parkinsonism had abnormal scans (specificity 52.9%). DISCUSSION: DAT imaging has very high sensitivity and negative predictive value for the diagnosis of presynaptic dopaminergic parkinsonism, particularly for PD. However, patients with CBD, and to a lesser extent PSP (of various phenotypes) and MSA (with predominant ataxia), can show normal DAT imaging. A range of other neurodegenerative disorders may have abnormal DAT scans with low specificity in the differential diagnosis of parkinsonism. DAT imaging is a useful diagnostic tool in the differential diagnosis of parkinsonism, although clinicians should be aware of its diagnostic properties and limitations. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that DAT imaging does not accurately distinguish between presynaptic dopaminergic parkinsonism and non-presynaptic dopaminergic parkinsonism.
Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina , Atrofia de Múltiplos Sistemas , Transtornos Parkinsonianos , Tomografia Computadorizada de Emissão de Fóton Único , Humanos , Feminino , Idoso , Masculino , Estudos Retrospectivos , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Transtornos Parkinsonianos/diagnóstico por imagem , Transtornos Parkinsonianos/patologia , Transtornos Parkinsonianos/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/diagnóstico por imagem , Atrofia de Múltiplos Sistemas/patologia , Atrofia de Múltiplos Sistemas/metabolismo , Paralisia Supranuclear Progressiva/diagnóstico por imagem , Paralisia Supranuclear Progressiva/patologia , Paralisia Supranuclear Progressiva/metabolismo , Idoso de 80 Anos ou mais , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Estudos de Coortes , Degeneração Corticobasal/diagnóstico por imagem , Degeneração Corticobasal/metabolismo , Dopamina/metabolismo , Terminações Pré-Sinápticas/metabolismo , Terminações Pré-Sinápticas/patologia , Sensibilidade e Especificidade , Imageamento DopaminérgicoRESUMO
Neurodegenerative diseases have common underlying pathological mechanisms including progressive neuronal dysfunction, axonal and dendritic retraction, and mitochondrial dysfunction resulting in neuronal death. The retina is often affected in common neurodegenerative diseases such as Parkinson's and Alzheimer's disease. Studies have demonstrated that the retina in patients with Parkinson's disease undergoes changes that parallel the dysfunction in the brain. These changes classically include decreased levels of dopamine, accumulation of alpha-synuclein in the brain and retina, and death of dopaminergic nigral neurons and retinal amacrine cells leading to gross neuronal loss. Exploring this disease's retinal phenotype and vision-related symptoms is an important window for elucidating its pathophysiology and progression, and identifying novel ways to diagnose and treat Parkinson's disease. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is commonly used to model Parkinson's disease in animal models. MPTP is a neurotoxin converted to its toxic form by astrocytes, transported to neurons through the dopamine transporter, where it causes mitochondrial Complex I inhibition and neuron degeneration. Systemic administration of MPTP induces retinal changes in different animal models. In this study, we assessed the effects of MPTP on the retina directly via intravitreal injection in mice (5 mg/mL and 50 mg/mL to 7, 14 and 21 days post-injection). MPTP treatment induced the reduction of retinal ganglion cells-a sensitive neuron in the retina-at all time points investigated. This occurred without a concomitant loss of dopaminergic amacrine cells or neuroinflammation at any of the time points or concentrations tested. The observed neurodegeneration which initially affected retinal ganglion cells indicated that this method of MPTP administration could yield a fast and straightforward model of retinal ganglion cell neurodegeneration. To assess whether this model could be amenable to neuroprotection, mice were treated orally with nicotinamide (a nicotinamide adenine dinucleotide precursor) which has been demonstrated to be neuroprotective in several retinal ganglion cell injury models. Nicotinamide was strongly protective following intravitreal MPTP administration, further supporting intravitreal MPTP use as a model of retinal ganglion cell injury. As such, this model could be utilized for testing neuroprotective treatments in the context of Parkinson's disease and retinal ganglion cell injury.
Assuntos
Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores , Niacinamida , Células Ganglionares da Retina , Animais , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/patologia , Células Ganglionares da Retina/metabolismo , Niacinamida/farmacologia , Niacinamida/administração & dosagem , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/administração & dosagem , Masculino , Camundongos , Administração Oral , Injeções Intravítreas , Modelos Animais de Doenças , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/patologia , Transtornos Parkinsonianos/tratamento farmacológico , Intoxicação por MPTP/patologia , Intoxicação por MPTP/metabolismo , Intoxicação por MPTP/tratamento farmacológicoRESUMO
Although manifesting contrasting phenotypes, Parkinson's disease and dystonia, the two most common movement disorders, can originate from similar pathophysiology. Previously, we demonstrated that lesioning (silencing) of a discrete dorsal region in the globus pallidus (rodent equivalent to globus pallidus externa) in rats and produced parkinsonism, while lesioning a nearby ventral hotspot-induced dystonia. Presently, we injected fluorescent-tagged multi-synaptic tracers into these pallidal hotspots (n = 36 Long Evans rats) and permitted 4 days for the viruses to travel along restricted connecting pathways and reach the motor cortex before sacrificing the animals. Viral injections in the Parkinson's hotspot fluorescent labeled a circumscribed region in the secondary motor cortex, while injections in the dystonia hotspot labeled within the primary motor cortex. Custom probability mapping and N200 staining affirmed the segregation of the cortical territories for Parkinsonism and dystonia to the secondary and primary motor cortices. Intracortical microstimulation localized territories specifically to their respective rostral and caudal microexcitable zones. Parkinsonian features are thus explained by pathological signaling within a secondary motor subcircuit normally responsible for initiation and scaling of movement, while dystonia is explained by abnormal (and excessive) basal ganglia signaling directed at primary motor corticospinal transmission.
Assuntos
Gânglios da Base , Distonia , Córtex Motor , Vias Neurais , Transtornos Parkinsonianos , Ratos Long-Evans , Animais , Córtex Motor/fisiopatologia , Córtex Motor/patologia , Transtornos Parkinsonianos/fisiopatologia , Transtornos Parkinsonianos/patologia , Ratos , Vias Neurais/fisiopatologia , Distonia/fisiopatologia , Distonia/patologia , Distonia/etiologia , Gânglios da Base/patologia , Masculino , Globo Pálido/patologia , Modelos Animais de DoençasRESUMO
BACKGROUND: MAPT is a causative gene in frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), a hereditary degenerative disease with various clinical manifestations, including progressive supranuclear palsy, corticobasal syndrome, Parkinson's disease, and frontotemporal dementia. OBJECTIVES: To analyze genetically, biochemically, and pathologically multiple members of two families who exhibited various phenotypes of the disease. METHODS: Genetic analysis included linkage analysis, homozygosity haplotyping, and exome sequencing. We conducted tau protein microtubule polymerization assay, heparin-induced tau aggregation, and western blotting with brain lysate from an autopsy case. We also evaluated abnormal tau aggregation by using anti-tau antibody and PM-PBB3. RESULTS: We identified a variant, c.896_897insACA, p.K298_H299insQ, in the MAPT gene of affected patients. Similar to previous reports, most patients presented with atypical parkinsonism. Biochemical analysis revealed that the mutant tau protein had a reduced ability to polymerize microtubules and formed abnormal fibrous aggregates. Pathological study revealed frontotemporal lobe atrophy, midbrain atrophy, depigmentation of the substantia nigra, and four-repeat tau-positive inclusions in the hippocampus, brainstem, and spinal cord neurons. The inclusion bodies also stained positively with PM-PBB3. CONCLUSIONS: This study confirmed that the insACA mutation caused FTDP-17. The affected patients showed symptoms resembling Parkinson's disease initially and symptoms of progressive supranuclear palsy later. Despite the initial clinical diagnosis of frontotemporal dementia in the autopsy case, the spread of lesions could explain the process of progressive supranuclear palsy. The study of more cases in the future will help clarify the common pathogenesis of MAPT mutations or specific pathogeneses of each mutation.
Assuntos
Demência Frontotemporal , Mutação , Proteínas tau , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Encéfalo/patologia , Encéfalo/metabolismo , Cromossomos Humanos Par 17/genética , Demência Frontotemporal/genética , Demência Frontotemporal/patologia , Demência Frontotemporal/metabolismo , Demência Frontotemporal/diagnóstico , Transtornos Parkinsonianos/genética , Transtornos Parkinsonianos/patologia , Transtornos Parkinsonianos/metabolismo , Linhagem , Paralisia Supranuclear Progressiva/genética , Paralisia Supranuclear Progressiva/patologia , Proteínas tau/genética , Proteínas tau/metabolismoRESUMO
Parkinson's disease (PD) is a neurodegenerative disease characterized by dopaminergic neuron death and neuroinflammation. Emerging evidence points to the involvement of the transient receptor potential melastatin 2 (TRPM2) channel in neuron death and glial activation in several neurodegenerative diseases. However, the involvement of TRPM2 in PD and specifically its relation to the neuroinflammation aspect of the disease remains poorly understood. Here, we hypothesized that AG490, a TRPM2 inhibitor, can be used as a treatment in a mouse model of PD. Mice underwent stereotaxic surgery for 6-hydroxydopamine (6-OHDA) administration in the right striatum. Motor behavioral tests (apomorphine, cylinder, and rotarod) were performed on day 3 post-injection to confirm the PD model induction. AG490 was then daily injected i.p. between days 3 to 6 after surgery. On day 6, motor behavior was assessed again. Substantia nigra (SNc) and striatum (CPu) were collected for immunohistochemistry, immunoblotting, and RT-qPCR analysis on day 7. Our results revealed that AG490 post-treatment reduced motor behavior impairment and nigrostriatal neurodegeneration. In addition, the compound prevented TRPM2 upregulation and changes of the Akt/GSK-3ß/caspase-3 signaling pathway. The TRPM2 inhibition also avoids the glial morphology changes observed in the PD group. Remarkably, the morphometrical analysis revealed that the ameboid-shaped microglia, found in 6-OHDA-injected animals, were no longer present in the AG490-treated group. These results indicate that AG490 treatment can reduce dopaminergic neuronal death and suppress neuroinflammation in a PD mouse model. Inhibition of TRPM2 by AG490 could then represent a potential therapeutical strategy to be evaluated for PD treatment.
Assuntos
Camundongos Endogâmicos C57BL , Neuroglia , Canais de Cátion TRPM , Tirfostinas , Animais , Canais de Cátion TRPM/antagonistas & inibidores , Canais de Cátion TRPM/metabolismo , Camundongos , Masculino , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Neuroglia/patologia , Tirfostinas/farmacologia , Tirfostinas/uso terapêutico , Progressão da Doença , Oxidopamina/toxicidade , Modelos Animais de Doenças , Degeneração Neural/patologia , Degeneração Neural/tratamento farmacológico , Transtornos Parkinsonianos/patologia , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/prevenção & controle , Substância Negra/efeitos dos fármacos , Substância Negra/patologia , Substância Negra/metabolismo , Doença de Parkinson/patologia , Doença de Parkinson/metabolismo , Doença de Parkinson/tratamento farmacológicoRESUMO
The lateral habenula (LHb) projects to the ventral tegmental area (VTA) and dorsal raphe nuclei (DRN) that deliver dopamine (DA) and serotonin (5-HT) to cortical and limbic regions such as the medial prefrontal cortex (mPFC), hippocampus and basolateral amygdala (BLA). Dysfunctions of VTA-related mesocorticolimbic dopaminergic and DRN-related serotonergic systems contribute to non-motor symptoms in Parkinson's disease (PD). However, how the LHb affects the VTA and DRN in PD remains unclear. Here, we used electrophysiological and neurochemical approaches to explore the effects of LHb lesions on the firing activity of VTA and DRN neurons, as well as the levels of DA and 5-HT in related brain regions in unilateral 6-hydroxydopamie (6-OHDA)-induced PD rats. We found that compared to sham lesions, lesions of the LHb increased the firing rate of DA neurons in the VTA and 5-HT neurons in the DRN, but decreased the firing rate of GABAergic neurons in the same nucleus. In addition, lesions of the LHb increased the levels of DA and 5-HT in the mPFC, ventral hippocampus and BLA compared to sham lesions. These findings suggest that lesions of the LHb enhance the activity of mesocorticolimbic dopaminergic and serotonergic systems in PD.
Assuntos
Dopamina , Neurônios Dopaminérgicos , Núcleo Dorsal da Rafe , Habenula , Ratos Sprague-Dawley , Neurônios Serotoninérgicos , Serotonina , Área Tegmentar Ventral , Animais , Área Tegmentar Ventral/metabolismo , Habenula/metabolismo , Masculino , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Núcleo Dorsal da Rafe/metabolismo , Neurônios Serotoninérgicos/metabolismo , Neurônios Serotoninérgicos/fisiologia , Ratos , Serotonina/metabolismo , Dopamina/metabolismo , Oxidopamina/toxicidade , Transtornos Parkinsonianos/fisiopatologia , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/patologia , Córtex Pré-Frontal/metabolismo , Vias Neurais/metabolismo , Vias Neurais/fisiopatologiaRESUMO
Progressive Supranuclear Palsy (PSP) is an atypical parkinsonism. Major subtypes of the disease: PSP-Richardson's Syndrome (PSP-RS) and PSP Parkinsonism Predominant (PSP-P) vary in clinical features, the pathomechanism remains unexplored. The aim of this work is to analyze the relevance of glial cell line-derived neurotrophic factor (GDNF) evaluation in the serum and cerebrospinal fluid (CSF) in PSP subtypes and to verify its significance as a possible factor in the in vivo examination. Authors assessed the concentration of GDNF in the serum and CSF of 12 patients with PSP-RS, 12 with PSP-P and 12 controls. Additionally authors evaluated patients using Unified Parkinson's Disease Rating Scale-III part (UPDRS-III), Frontal Assessment Battery (FAB) and Magnetic Resonance Imaging (MRI). The evaluation revealed significantly increased concentrations of GDNF in the CSF among PSP-RS patients and substantially increased concentrations of GDNF in the serum in PSP-P. Though the GDNF concentrations differentiated PSP subtypes, no correlations between with clinical factors were observed however certain correlations with atrophic changes in MRI were detected. GDNF is a factor which may impact the pathogenesis of PSP. Possible implementation of GDNF as a therapeutic factor could be a perspective in the search for therapy in this currently incurable disease.