Loss Of Neurons In Substantia Nigra Research Articles

Role of GBA variants in Lewy body disease neuropathology.

Rare and common GBA variants are risk factors for both Parkinson's disease (PD) and dementia with Lewy bodies (DLB). However, the degree to which GBA variants are associated with neuropathological features in Lewy body disease (LBD) is unknown. Herein, we assessed 943 LBD cases and examined associations of 15 different neuropathological outcomes with common and rare GBA variants. Neuropathological outcomes included LBD subtype, presence of a high likelihood of clinical DLB (per consensus guidelines), LB counts in five cortical regions, tyrosine hydroxylase immunoreactivity in the dorsolateral and ventromedial putamen, ventrolateral substantia nigra neuronal loss, Braak neurofibrillary tangle (NFT) stage, Thal amyloid phase, phospho-ubiquitin (pS65-Ub) level, TDP-43 pathology, and vascular disease. Sequencing of GBA exons revealed a total of 42 different variants (4 common [MAF > 0.5%], 38 rare [MAF < 0.5%]) in our series, and 165 cases (17.5%) had a copy of the minor allele for ≥ 1 variant. In analysis of common variants, p.L483P was associated with a lower Braak NFT stage (OR = 0.10, P < 0.001). In gene-burden analysis, presence of the minor allele for any GBA variant was associated with increased odds of a high likelihood of DLB (OR = 2.00, P < 0.001), a lower Braak NFT stage (OR = 0.48, P < 0.001), a lower Thal amyloid phase (OR = 0.55, P < 0.001), and a lower pS65-Ub level (β: -0.37, P < 0.001). Subgroup analysis revealed that GBA variants were most common in LBD cases with a combination of transitional/diffuse LBD and Braak NFT stage 0-II or Thal amyloid phase 0-1, and correspondingly that the aforementioned associations of GBA gene-burden with a decreased Braak NFT stage and Thal amyloid phase were observed only in transitional or diffuse LBD cases. Our results indicate that in LBD, GBA variants occur most frequently in cases with greater LB pathology and low AD pathology, further informing disease-risk associations of GBA in PD, PD dementia, and DLB.

Sex differences for clinical correlates of substantia nigra neuron loss in people with Lewy body pathology

BackgroundLewy body dementia (LBD) phenotype is associated with the presence and degree of Lewy body, Alzheimer’s pathologies, and substantia nigra neuron loss. Nigral neuron loss is associated with parkinsonism in LBD, and females with LBD are less likely than males to have parkinsonism. As sex differences were reported for clinical correlates of Lewy body and Alzheimer’s pathologies, we aimed to investigate whether there are also sex differences for correlates of nigral neuron loss.MethodsData were obtained from the National Alzheimer’s Coordinating Center for females (n = 159) and males (n = 263) with brainstem, limbic, and neocortical Lewy body pathology. Sex differences for the nigral neuron loss’ association with Lewy body pathology staging and core clinical LBD features (cognitive fluctuations, visual hallucinations, rapid eye movement sleep behavior disorder, parkinsonism) during follow-up were analyzed with generalized linear models adjusting for age and Alzheimer’s pathology staging. Whether any of the core clinical features at the time of dementia onset can predict underlying nigral neuron loss for females and males were also analyzed with generalized linear models.ResultsCompared to males, females died older and had higher levels of Braak tau staging, but had similar levels of Lewy body pathology staging and nigral neuron loss. Females were less likely than males to have a clinical Lewy body disease diagnosis during follow-up. More advanced Lewy body pathology staging was associated with more nigral neuron loss, more so for males than females. More nigral neuron loss was associated with parkinsonism and clinical LBD diagnosis during follow-up, more so for males than females. Across the subgroup with dementia (40 females, 58 males), core LBD features at first visit with dementia were not associated with nigral neuron loss.ConclusionsNigral neuron loss’ association with Lewy body pathology staging and core LBD features can differ by sex. Compared to males, females with Lewy body pathology have a higher risk of underdiagnosis. There is a need to elucidate the mechanisms underlying sex differences for pathology and clinicopathological correlations to advance diagnostic and therapeutic efforts in LBD.

Sex differences for clinical correlates of substantia nigra neuron loss and Lewy body pathology

AbstractBackgroundLewy body pathology staging and substantia nigra neuron loss levels are associated with clinical features in Lewy body dementia (LBD). Compared to women, neocortical Lewy body pathology is more common and co‐pathologies are less common in men. Clinical features of people with limbic and neocortical Lewy body also differ based on sex, although sex differences for additional Lewy body pathology stages or nigral neuron loss are unclear.MethodData was obtained from the National Alzheimer’s Coordinating Center Uniform Data Set (UDS) and Neuropathology Data Set for UDS visits conducted between September 2005 and August 2019. Analysis included 31 women and 62 men from 25 AD Research Centers with Lewy body pathology and substantia nigra neuron loss data, excluding those with other neuropathologic diagnoses including moderate/severe Alzheimer’s disease. Linear models assessed the sex differences for clinical associations of nigral neuron loss level and Lewy body pathology staging controlling for age at last visit.ResultWomen were older at last visit and at death, had less years of education than men (Table 1). Men were more likely to have a clinical LBD diagnosis, had cognitive decline at a younger age, worse dementia at last visit, and higher levels of Lewy body pathology staging and nigral neuron loss. Higher Lewy body pathology stage was associated with more nigral neuron loss more for men compared to women (Table 2). Higher Lewy body pathology stage and greater degrees of nigral neuron loss were associated with more severe dementia and behavioral symptoms and a higher likelihood for a clinical Lewy body diagnosis in men compared to women.ConclusionLewy body pathology staging and the level of substantia nigra neuron loss may be worse for men compared to women. These data also suggest that Lewy body pathology and nigral neuron loss affect men more severely than women in terms of dementia severity and behavioral profiles associated with LBD. The blunted clinical manifestations of these pathological features in women add to the difficulty in accurate diagnosis and future work on the reasons for women’s resilience to these pathological features is needed.

In vivo18F-DOPA PET imaging identifies a dopaminergic deficit in a rat model with a G51D α-synuclein mutation.

Parkinson's disease (PD) is a neurodegenerative condition with several major hallmarks, including loss of substantia nigra neurons, reduction in striatal dopaminergic function, and formation of α-synuclein-rich Lewy bodies. Mutations in SNCA, encoding for α-synuclein, are a known cause of familial PD, and the G51D mutation causes a particularly aggressive form of the condition. CRISPR/Cas9 technology was used to introduce the G51D mutation into the endogenous rat SNCA gene. SNCAG51D/+ and SNCAG51D/G51D rats were born in Mendelian ratios and did not exhibit any severe behavourial defects. L-3,4-dihydroxy-6-18F-fluorophenylalanine (18F-DOPA) positron emission tomography (PET) imaging was used to investigate this novel rat model. Wild-type (WT), SNCAG51D/+ and SNCAG51D/G51D rats were characterized over the course of ageing (5, 11, and 16 months old) using 18F-DOPA PET imaging and kinetic modelling. We measured the influx rate constant (Ki) and effective distribution volume ratio (EDVR) of 18F-DOPA in the striatum relative to the cerebellum in WT, SNCAG51D/+ and SNCAG51D/G51D rats. A significant reduction in EDVR was observed in SNCAG51D/G51D rats at 16 months of age indicative of increased dopamine turnover. Furthermore, we observed a significant asymmetry in EDVR between the left and right striatum in aged SNCAG51D/G51D rats. The increased and asymmetric dopamine turnover observed in the striatum of aged SNCAG51D/G51D rats reflects one aspect of prodromal PD, and suggests the presence of compensatory mechanisms. SNCAG51D rats represent a novel genetic model of PD, and kinetic modelling of 18F-DOPA PET data has identified a highly relevant early disease phenotype.

ИСТОРИЯ ИЗУЧЕНИЯ БОЛЕЗНИ ПАРКИНСОНА

This article discusses the history of studying Parkinson’s disease (PD), one of the most common neurodegenerative diseases in the world and Russia. Many famous personalities suffer from this disease, including a Hollywood actor Michael J. Fox. However, the history of studying PD consists of several stages. The phenomenological stage is associated with the work «An Essay on Shaking Palsy» by James Parkinson, where the author described six patients. Fifty years after the essay was published, Jean Martin Charcot drew attention to patients with shaking palsy, and based on the Parkinson’s essay, put forward the theory that the main symptom of the disease is slowness. At the pathomorphological stage, the role of the loss of substantia nigra neurons in the development of PD was determined. The key work was the nigral theory of Konstantin Tretyakov. At the beginning of the 21st century, German scientists led by Heiko Braak put forward the stages of the neurodegenerative process theory, which explained the preclinical non-motor symptoms of PD, as well as a wide range of severe non-motor and axial disorders in the late stages of the disease. The neurobiological stage is associated with the establishment of the role of dopamine in the development of PD and the start of levodopa therapy. Since 1911, levodopa had been studied in the laboratory, but it was not until the 1950s that the Swedish pharmacologist Arvid Karlsson put forward the theory about the role of dopamine deficiency in the development of PD and suggested the therapeutic effect of levodopa. For his outstanding discovery, Arvid Karlsson was awarded the Nobel Prize in Physiology or Medicine in 2000. The clinical use of levodopa is associated with the names of Oleg Hornykiewicz and George Cotzias. In parallel, neurosurgical treatment of PD is being developed, deep brain stimulation and thalamotomy under the influence of focused ultrasound are being introduced. At the moment, there is a further improvement in the diagnosis of the disease, the genetics of PD is being studied, along with it, the range of treatment options is expanding.

Differential effects of comorbid Lewy body and Alzheimer’s disease pathology on regional FDG‐PET patterns

AbstractBackgroundIn differential dementia diagnosis, an FDG‐PET pattern of pronounced posterior‐occipital hypometabolism with relative sparing of the posterior cingulate cortex (PCC) and medial temporal lobe (MTL) is indicative of an underlying Lewy body (LB) vs Alzheimer’s disease (AD) pathology. However, LB and AD pathology are often comorbid, and in patients with LB dementia the presence of AD co‐pathology correlates with a more AD‐like neurodegeneration pattern. Here we studied how concomitant LB and AD pathology affects regional FDG‐PET patterns in patients with AD dementia.MethodThe study included 52 patients from the Alzheimer’s Disease Neuroimaging Initiative autopsy cohort who had a final diagnosis of AD dementia (N=46) or amnestic mild cognitive impairment (N=6) and had an ante‐mortem FDG‐PET scan available (FDG‐PET to death interval: 3.4±2.4 years). Twenty‐one patients had autopsy‐confirmed AD without comorbid LB (‘pure‐AD’), 24 had AD with LB co‐pathology (‘AD‐LB’), and 7 had LB with no or low evidence of AD pathology (‘pure‐LB’). Pathologic groups were compared on regional FDG‐PET SUVRs, the “cingulate island sign” ratio (CISr; PCC/(precuneus+cuneus) SUVR), as well as neuropathologic ratings of substantia nigra neuron loss (SNnl). A complementary analysis assessed continuous associations of AD co‐pathology (Braak tau stage) with regional FDG‐PET SUVR and the CISr across cases with LB pathology (pure‐LB+AD‐LB).ResultCompared to healthy controls (N=179), both pure‐AD and AD‐LB showed highly similar patterns of AD‐typical temporo‐parietal hypometabolism (Fig. 1), and neither regional FDG‐PET SUVRs, CISr, nor SNnl differed between the groups. By contrast, pure‐LB showed the expected pattern of pronounced occipital hypometabolism with relative sparing of the MTL, and CISr and SNnl were significantly higher compared to both pure‐AD and AD‐LB (p&lt;0.05). Across cases with LB pathology, higher Braak tau stage was significantly correlated with a lower CISr (Spearman’s ρ=‐0.53, p=0.002), less occipital (ρ=‐0.37, p=0.043), and more MTL (ρ=0.36, p=0.047) hypometabolism.ConclusionIn autopsy‐confirmed AD dementia patients, comorbid LB pathology did not have a notable effect on the regional FDG‐PET pattern, which may complicate in‐vivo detection of this comorbid condition. By contrast, we confirm and extend previous findings that AD co‐pathology associates with a more AD‐like neurodegeneration pattern in cases with LB pathology.

Differential effects of comorbid Lewy body and Alzheimer’s disease pathology on regional FDG‐PET patterns

AbstractBackgroundIn differential dementia diagnosis, an FDG‐PET pattern of pronounced posterior‐occipital hypometabolism with relative sparing of the posterior cingulate cortex (PCC) and medial temporal lobe (MTL) is indicative of an underlying Lewy body (LB) vs Alzheimer’s disease (AD) pathology. However, LB and AD pathology are often comorbid, and in patients with LB dementia the presence of AD co‐pathology correlates with a more AD‐like neurodegeneration pattern. Here we studied how concomitant LB and AD pathology affects regional FDG‐PET patterns in patients with AD dementia.MethodThe study included 52 patients from the Alzheimer’s Disease Neuroimaging Initiative autopsy cohort who had a final diagnosis of AD dementia (N=46) or amnestic mild cognitive impairment (N=6) and had an ante‐mortem FDG‐PET scan available (FDG‐PET to death interval: 3.4±2.4 years). Twenty‐one patients had autopsy‐confirmed AD without comorbid LB (‘pure‐AD’), 24 had AD with LB co‐pathology (‘AD‐LB’), and 7 had LB with no or low evidence of AD pathology (‘pure‐LB’). Pathologic groups were compared on regional FDG‐PET SUVRs, the “cingulate island sign” ratio (CISr; PCC/(precuneus+cuneus) SUVR), as well as neuropathologic ratings of substantia nigra neuron loss (SNnl). A complementary analysis assessed continuous associations of AD co‐pathology (Braak tau stage) with regional FDG‐PET SUVR and the CISr in cases with LB pathology (pure‐LB+AD‐LB).ResultCompared to healthy controls (N=179), both pure‐AD and AD‐LB showed highly similar patterns of AD‐typical temporo‐parietal hypometabolism (Fig. 1), and neither regional FDG‐PET SUVRs, CISr, nor SNnl differed between the groups. By contrast, pure‐LB showed the expected pattern of pronounced occipital hypometabolism with relative sparing of the MTL, and CISr and SNnl were significantly higher compared to both pure‐AD and AD‐LB (p&lt;0.05). Across cases with LB pathology, higher Braak tau stage was significantly correlated with a lower CISr (Spearman’s ρ=‐0.53, p=0.002), less occipital (ρ=‐0.37, p=0.043), and more MTL (ρ=0.36, p=0.047) hypometabolism.ConclusionIn autopsy‐confirmed AD dementia patients, comorbid LB pathology did not have a notable effect on the regional FDG‐PET pattern, which may complicate in‐vivo detection of this comorbid condition. By contrast, we confirm and extend previous findings that AD co‐pathology associates with a more AD‐like neurodegeneration pattern in cases with LB pathology.

Inhibition of Calpain Attenuates Degeneration of Substantia Nigra Neurons in the Rotenone Rat Model of Parkinson's Disease.

In the central nervous system (CNS), calcium homeostasis is a critical determinant of neuronal survival. Calpain, a calcium-dependent neutral protease, is widely expressed in the brain, including substantia nigra (SN) dopaminergic (DA) neurons. Though calpain is implicated in human Parkinson's disease (PD) and corresponding animal models, the roles of specific ubiquitous calpain isoforms in PD, calpain-1 and calpain-2, remain poorly understood. In this study, we found that both isoforms are activated in a nigrostriatal pathway with increased phosphorylated synuclein following the administration of rotenone in Lewis rats, but calpain isoforms played different roles in neuronal survival. Although increased expression of calpain-1 and calpain-2 were detected in the SN of rotenone-administered rats, calpain-1 expression was not altered significantly after treatment with calpain inhibitor (calpeptin); this correlated with neuronal survival. By contrast, increased calpain-2 expression in the SN of rotenone rats correlated with neuronal death, and calpeptin treatment significantly attenuated calpain-2 and neuronal death. Calpain inhibition by calpeptin prevented glial (astroglia/microglia) activation in rotenone-treated rats in vivo, promoted M2-type microglia, and protected neurons. These data suggest that enhanced expression of calpain-1 and calpain-2 in PD models differentially affects glial activation and neuronal survival; thus, the attenuation of calpain-2 may be important in reducing SN neuronal loss in PD.

Effect of virtual reality rehabilitation on functional outcomes for return-to-work patients with Parkinson's disease: An umbrella review of systematic reviews.

Parkinson's disease (PD) is a neurodegenerative disease characterized by loss of substantia nigra neurons with deficiency of dopamine. The main symptoms are tremor, rigidity and bradykinesia. Rehabilitation has an important role in the treatment of this condition and virtual reality (VR) is one of the most recent tools. The purpose of this umbrella review is to evaluate the effectiveness of VR systems on gait control for return to work in patients with PD. The electronic search, for reviews and meta-analysis studies that investigated the effectiveness of VR on gait control in PD patients, was performed through December 2021 using the following databases: PubMed, Scopus, PEDro, and Google Scholar. Mesh terms used were: Job integration/reintegration OR return-to-work AND Parkinson's disease AND virtual reality OR exergame. No limit on the year of publication of the article was used. A total of 14 articles were included in our analysis. The included evidence shows a stride length improvement in patients treated with VR compared to conventional active treatments. No difference was found in walking speed. Also, the included articles show an improvement on various measures of balance, motor function and severity of PD motor symptoms. In addition, the literature shows an improvement in the quality of life and neuropsychiatric symptoms in patients undergoing VR rehabilitation training. he results of our study suggest that VR rehabilitation improves gait performance, particularly stride length, thus being able to provide an improvement in the quality of life and a more effective return to work training in patients with PD.

Differential Effects of Tau Stage, Lewy Body Pathology, and Substantia Nigra Degeneration on 18F-FDG PET Patterns in Clinical Alzheimer Disease.

Comorbid Lewy body (LB) pathology is common in Alzheimer disease (AD). The effect of LB copathology on 18F-FDG PET patterns in AD is yet to be studied. We analyzed associations of neuropathologically assessed tau pathology, LB pathology, and substantia nigra neuronal loss (SNnl) with antemortem 18F-FDG PET hypometabolism in patients with a clinical AD presentation. Methods: Twenty-one patients with autopsy-confirmed AD without LB neuropathologic changes (LBNC) (pure-AD), 24 with AD and LBNC copathology (AD-LB), and 7 with LBNC without fulfilling neuropathologic criteria for AD (pure-LB) were studied. Pathologic groups were compared regarding regional and voxelwise 18F-FDG PET patterns, the cingulate island sign ratio (CISr), and neuropathologic ratings of SNnl. Additional analyses assessed continuous associations of Braak tangle stage and SNnl with 18F-FDG PET patterns. Results: Pure-AD and AD-LB showed highly similar patterns of AD-typical temporoparietal hypometabolism and did not differ in CISr, regional 18F-FDG SUVR, or SNnl. By contrast, pure-LB showed the expected pattern of pronounced posterior-occipital hypometabolism typical for dementia with LB (DLB), and both CISr and SNnl were significantly higher compared with the AD groups. In continuous analyses, Braak tangle stage correlated significantly with more AD-like, and SNnl with more DLB-like, 18F-FDG PET patterns. Conclusion: In autopsy-confirmed AD dementia patients, comorbid LB pathology did not have a notable effect on the regional 18F-FDG PET pattern. A more DLB-like 18F-FDG PET pattern was observed in relation to SNnl, but advanced SNnl was mostly limited to relatively pure LB cases. AD pathology may have a dominant effect over LB pathology in determining the regional neurodegeneration phenotype.

Mitochondrial genomic variation in dementia with Lewy bodies: association with disease risk and neuropathological measures

Dementia with Lewy bodies (DLB) is clinically diagnosed when patients develop dementia less than a year after parkinsonism onset. Age is the primary risk factor for DLB and mitochondrial health influences ageing through effective oxidative phosphorylation (OXPHOS). Patterns of stable polymorphisms in the mitochondrial genome (mtDNA) alter OXPHOS efficiency and define individuals to specific mtDNA haplogroups. This study investigates if mtDNA haplogroup background affects clinical DLB risk and neuropathological disease severity. 360 clinical DLB cases, 446 neuropathologically confirmed Lewy body disease (LBD) cases with a high likelihood of having DLB (LBD-hDLB), and 910 neurologically normal controls had European mtDNA haplogroups defined using Agena Biosciences MassARRAY iPlex technology. 39 unique mtDNA variants were genotyped and mtDNA haplogroups were assigned to mitochondrial phylogeny. Striatal dopaminergic degeneration, neuronal loss, and Lewy body counts were also assessed in different brain regions in LBD-hDLB cases. Logistic regression models adjusted for age and sex were used to assess associations between mtDNA haplogroups and risk of DLB or LBD-hDLB versus controls in a case-control analysis. Additional appropriate regression models, adjusted for age at death and sex, assessed associations of haplogroups with each different neuropathological outcome measure. No mtDNA haplogroups were significantly associated with DLB or LBD-hDLB risk after Bonferroni correction.Haplogroup H suggests a nominally significant reduced risk of DLB (OR=0.61, P=0.006) but no association of LBD-hDLB (OR=0.87, P=0.34). The haplogroup H observation in DLB was consistent after additionally adjusting for the number of APOE ε4 alleles (OR=0.59, P=0.004). Haplogroup H also showed a suggestive association with reduced ventrolateral substantia nigra neuronal loss (OR=0.44, P=0.033). Mitochondrial haplogroup H may be protective against DLB risk and neuronal loss in substantia nigra regions in LBD-hDLB cases but further validation is warranted.

Effects of intraperitoneal injection of lipopolysaccharide-induced peripheral inflammation on dopamine neuron damage in rat midbrain.

IntroductionCurrent studies have documented neuroinflammation is implicated in Parkinson's disease. Recently, growing evidence indicated peripheral inflammation plays an important role in regulation of neuroinflammation and thus conferring protection against dopamine (DA) neuronal damage. However, the underlying mechanisms are not clearly illuminated.MethodsThe effects of intraperitoneal injection of LPS (LPS[i.p.])‐induced peripheral inflammation on substantia nigra (SN) injection of LPS (LPS[SN])‐elicited DA neuronal damage in rat midbrain were investigated. Rats were intraperitoneally injected with LPS (0.5 mg/kg) daily for 4 consecutive days and then given single injection of LPS (8 μg) into SN with an interval of 0 (LPS(i.p.) 0 day ± LPS(SN)), 30 (LPS(i.p.) 30 days ± LPS(SN)), and 90 (LPS(i.p.) 90 days ± LPS(SN)) days after LPS(i.p.) administration.ResultsLPS(i.p.) increased the levels of inflammatory factors in peripheral blood in (LPS(i.p.) 0 day ± LPS(SN)). Importantly, in (LPS(i.p.) 0 day ± LPS(SN)) and (LPS(i.p.) 30 days ± LPS(SN)), LPS(i.p.) attenuated LPS(SN)‐induced DA neuronal loss in SN. Besides, LPS(i.p.) reduced LPS(SN)‐induced microglia and astrocytes activation in SN. Furtherly, LPS(i.p.) reduced pro‐inflammatory M1 microglia markers mRNA levels and increased anti‐inflammatory M2 microglia markers mRNA levels. In addition, the increased T‐cell marker expression and the decreased M1 microglia marker expression and more DA neuronal survival were discerned at the same area of rat midbrain in LPS(SN)‐induced DA neuronal damage 30 days after LPS(i.p.) application.ConclusionThis study suggested LPS(i.p.)‐induced peripheral inflammation might cause T cells to infiltrate the brain to regulate microglia‐mediated neuroinflammation, thereby protecting DA neurons.

Intraperitoneal Administration of Forskolin Reverses Motor Symptoms and Loss of Midbrain Dopamine Neurons in PINK1 Knockout Rats.

Background:Parkinson’s disease (PD) is a relentless, chronic neurodegenerative disease characterized by the progressive loss of substantia nigra (SN) neurons that leads to the onset of motor and non-motor symptoms. Standard of care for PD consists of replenishing the loss of dopamine through oral administration of Levodopa; however, this treatment is not disease-modifying and often induces intolerable side effects. While the etiology that contributes to PD is largely unknown, emerging evidence in animal models suggests that a significant reduction in neuroprotective Protein Kinase A (PKA) signaling in the SN contributes to PD pathogenesis, suggesting that restoring PKA signaling in the midbrain may be a new anti-PD therapeutic alternative.Objective:We surmised that pharmacological activation of PKA via intraperitoneal administration of Forskolin exerts anti-PD effects in symptomatic PTEN-induced kinase 1 knockout (PINK1-KO), a bona fide in vivo model of PD.Methods:By using a beam balance and a grip strength analyzer, we show that Forskolin reverses motor symptoms and loss of hindlimb strength with long-lasting therapeutic effects (> 5 weeks) following the last dose.Results:In comparison, intraperitoneal treatment with Levodopa temporarily (24 h) reduces motor symptoms but unable to restore hindlimb strength in PINK1-KO rats. By using immunohistochemistry and an XF24e BioAnalyzer, Forskolin treatment reverses SN neurons loss, elevates brain energy production and restores PKA activity in SN in symptomatic PINK1-KO rats.Conclusion:Overall, our collective in vivo data suggest that Forskolin is a promising disease-modifying therapeutic alternative for PD and is superior to Levodopa because it confers long-lasting therapeutic effects.

Interactions of a boron-containing levodopa derivative on D2 dopamine receptor and its effects in a Parkinson disease model.

Levodopa is a cornerstone in Parkinson's disease treatment. Beneficial effectsare mainly bybinding on D2 receptors. Docking simulations of a set of compounds including well-known D2-ligands and a pool of Boron-Containing Compounds (BCC), particularly boroxazolidones with a tri/tetra-coordinated boron atom, were performed on the D2 Dopamine receptor (D2DR). Theoretical results yielded higher affinity of the compound DPBX, a Dopaboroxazolidone, than levodopa on D2DR. Essential interactions with residues in the third and sixth transmembrane domains of the D2DR appear to be crucial to induce and stabilize interactions in the active receptor state. Results from a motor performance evaluation of a murine model of Parkinson's disease agree with theoretical results, as DPBX showed similar efficacy to that of levodopa for diminishing MPTP-induced parkinsonism. This beneficial effect was disrupted with prior Risperidone (D2DR antagonist) administration, supporting the role of D2DR in the biological effect of DPBX. In addition, DPBX limited neuronal loss in substantia nigra in a similar manner to that of levodopa administration.

Brain β-Amyloid Links the Association of Change in Body Mass Index With Cognitive Decline in Community-Dwelling Older Adults.

We tested the hypothesis that indices of Alzheimer's disease and related dementia (ADRD) pathologies may explain associations between change in body mass index (BMI) and cognitive decline in old age. We used data from 436 older decedents participating in a prospective longitudinal cohort study who had undergone annual cognitive and BMI assessments and postmortem collection of indices of 12 brain pathologies. We identified ADRD brain pathologies associated with BMI range, a previously published metric of change in BMI. We employed sigmoidal mixed-effect models of cognitive decline to examine the associations of change in BMI and cognitive decline with and without terms for ADRD brain pathologies. Average age at baseline was 78.6 years, SD = 6.5 years with 64% female. On average, 9 cognitive assessments were obtained with average age at death 88.4 years (SD = 6.2 years). Change in BMI as measured by BMI range was associated with cognitive decline (θ 2 = 0.260). β-Amyloid, hippocampal sclerosis, and substantia nigra neuronal loss were associated with BMI range. β-Amyloid strongly attenuated the association of BMI range with cognitive decline. Hippocampal sclerosis showed only partial attenuation of the association of BMI range and cognitive decline and nigral neuronal loss did not attenuate this association. Changes in BMI and cognitive decline in older adults may be affected by similar mechanisms underlying the accumulation of brain pathologies like β-amyloid in aging brains. Elucidating the molecular mechanisms underlying these associations may provide novel targets for developing interventions that maintain brain health and metabolic homeostasis in old age.

Design of poly(DOPA)-based nanoparticle for Parkinson’s disease treatment with suppressing dyskinesia

The major cause of Parkinson's disease (PD) is thought to be the loss of dopaminergic substantia nigra neurons and the formation of alpha-synuclein-containing Lewy bodies. Although dopamine supplementation is a vital therapy, it is not facile to cross the BBB. 3,4-Dihydroxyphenylalanine (L-DOPA), a dopamine precursor, is one of the main drugs to treat PD since L-DOPA can cross the BBB better than dopamine; however, there are strong demands to develop further effective drugs due to the short half-life and several adverse effects such as dyskinesia.

Early low-dose ghrelin intervention via miniosmotic pumps could protect against the progressive dopaminergic neuron loss in Parkinson's disease mice

Ghrelin has been identified as a multifunctional peptide that has a potential application for treating Parkinson's disease (PD). The objective of this study was to assess the effects of subcutaneous administration of low-dose ghrelin via miniosmotic pumps on PD progression. The decreased levels of total and active ghrelin in plasma were rescued by ghrelin administration in PD mice. Interestingly, ghrelin did not affect weight gain in wild-type mice but improved weight loss in PD mice. We observed the attenuation of dopaminergic neuron loss in substantia nigra and a low level of dopamine content in the striatum in PD mice with ghrelin treatment. Ghrelin administration could improve the microenvironment of dopaminergic neurons by inhibiting microglial proliferation and proinflammatory cytokine expression and could enhance cell survival by upregulating Bcl-2/Bax ratio and superoxide dismutase1 protein level in the substantia nigra of PD mice. Subcutaneous administration of low-dose ghrelin could prevent the onset of the progression of PD and also provide a possible method for ghrelin application to cure PD.

Zaburzenia zachowania fazy snu REM jako wczesny marker choroby Parkinsona

Choroba Parkinsona (PD) jest jedną z najczęściej występujących chorób neurodegeneracyjnych we współczesnym świecie, związaną ze starzejącymi się społeczeństwami. PD jest chorobą postępującą, w której dochodzi do utraty neuronów dopaminowych istoty czarnej (SN) a cechą patologiczną jest obecność ciał Lewy'ego, złożonych m.in. z białka ?-synukleiny. Gdy utrata neuronów w SN przekroczy ok. 60% wówczas pojawiają się główne objawy kliniczne (ruchowe), czyli bradykinezja, sztywność mięśniowa, drżenie spoczynkowe i zaburzenia postawy, chodu. PD jest chorobą o złożonej etiopatogenezie, w której bardzo ważny jest okres przedkliniczny/prodromalny, bowiem pojawiają się wówczas objawy pozaruchowe, np. osłabienie węchu, depresja czy zaburzenia snu, wyprzedzające nawet o kilkanaście lat fazę kliniczną. Niniejsza praca, poza opisem podstawowych informacji na temat PD, skupia się na zaburzeniach snu, wśród których najważniejszym jest zaburzenie zachowania w czasie snu REM, które może stanowić wczesny marker diagnostyczny rozwijającej się choroby, a tym samym pomóc w poszukiwaniu nowych terapii neuroprotekcyjnych już na wczesnym, prodromalnym etapie.

Metformin protects rotenone-induced dopaminergic neurodegeneration by reducing lipid peroxidation.

Metformin, a widely prescribed antidiabetic drug, has been suggested to have a neuroprotective effect on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in mice. In this study, we investigated the neuroprotective potential of metformin against rotenone-induced dopaminergic neuron damage and its underlying mechanisms. C57BL/6 mice were given saline or rotenone (2.5mg/kg/day, ip) injection for 10days. Metformin treatment (300mg/kg/day, ip) was started concurrently with rotenone administration and continued for 10days. The neuroprotective effect of metformin on rotenone-induced dopaminergic toxicity was assessed by tyrosine hydroxylase (TH), cleaved caspase-3 and α-synuclein immunohistochemistry in substantia nigra (SN). SN tissues were extracted for biochemical analysis. Malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) protein levels were measured by spectrophotometric assay. We found that metformin treatment attenuated the rotenone-induced loss of TH+ neurons in the SN. Additionally, metformin significantly decreased the rotenone-induced increase of cleaved caspase-3 and α-synuclein accumulation in the SN; however, there was no difference in motor behaviours between the experimental groups. Meanwhile, the levels of MDA and 4-HNE in SN were significantly reduced in the rotenone-metformin group compared to the rotenone group. Results showed that metformin treatment attenuated dopaminergic neuron loss in SN induced by rotenone by decreasing lipid peroxidation.

Intranasal Delivery of Bone Marrow Stromal Cells Preconditioned with Fasudil to Treat a Mouse Model of Parkinson's Disease.

ObjectiveStem cell transplantation is a promising strategy with great potential to treat Parkinson’s disease (PD). Nevertheless, improving the cell delivery route and optimising implanted cells are necessary to increase the therapeutic effect. Herein, we investigated whether intranasal delivery of bone marrow stromal cells (BMSCs) has beneficial effects in a PD mouse model and whether the therapeutic potential of BMSCs could be enhanced by preconditioning with fasudil.MethodsA PD mouse model was developed by intraperitoneally administering 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Mice were treated intranasally with phosphate buffered saline (PBS), BMSCs, or BMSCs preconditioned with fasudil. One month later, the effects of BMSC treatment were analysed.ResultsOur study showed that fasudil could accelerate the proliferation of BMSCs and promote brain-derived neurotrophic factor (BDNF) secretion in vitro. Intranasally administered BMSCs were capable of surviving and migrating in the brain. Intranasal delivery of BMSCs preconditioned with fasudil significantly improved motor function and reduced dopaminergic neuron loss in substantia nigra; treatment with BMSCs and PBS resulted in similar outcomes. Preconditioning with fasudil inhibited the activation and aggregation of microglia, suppressed immune response, and reinforced BDNF secretion in MPTP-PD mice significantly more than treatment with BMSCs alone.ConclusionThe present study demonstrates that intranasally administering BMSCs preconditioned with fasudil is a promising cell-based therapy for PD.