Elevated Levels of Methylmalonate and Homocysteine in Parkinson's Disease, Progressive Supranuclear Palsy and Amyotrophic Lateral Sclerosis

Background/Aims: Increasing evidence suggests that elevated levels of homocysteine (Hcy) and methylmalonate (MMA) may be involved in the pathogenesis of neurodegenerative diseases. Methods: The urine levels of MMA and serum levels of Hcy as well as folic acid and vitamin B 12 were measured in patients suffering from the distinct neurodegenerative diseases progressive supranuclear palsy (PSP), amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD), and compared to age-and gender-matched control subjects. Results: We found significantly elevated concentrations of Hcy (PD 15.1, PSP 15.8, ALS 13.9, control 11.2 mu mol/l) and MMA (PD 3.7, PSP 3.1, ALS 3.7, control 1.8 mg/g) in all patient groups in comparison with controls. Levels of Hcy and MMA did not differ significantly between the neurodegenerative diseases. Conclusion: Our findings might imply that Hcy and MMA are released as a consequence of neurodegeneration regardless of the underlying cause and serve as surrogate markers of neurodegeneration. Alternatively they might be directly implicated in the pathogenesis of these diseases. Since elevated levels of both Hcy and MMA are neurotoxic, further studies might investigate the effect of vitamin therapy on disease progression. Copyright (C) 2010 S. Karger AG, Base

Alzheimer and vascular brain diseases: Focal and diffuse subforms.

Alois Alzheimer is best known for his description of the pre-senile neurodegenerative disease named after him. However, his previous interest in vascular brain diseases, underlying cognitive and behavioral changes, was very strong. Besides describing the Arteriosclerotic atrophy of the brain and the arteriosclerotic subtype of Senile dementia which he viewed as main forms of vascular brain diseases, he also identified and described a series of conditions he considered subforms. These may be divided, as suggested by the authors of the present paper, into 3 groups: gliosis and sclerosis, subcortical atrophies, and apoplectic. The subforms of the three groups present characteristic neuropathological features and clinical, cognitive and behavioral manifestations. These provide the basis, together with part of the main forms, for the contemporary condition known as Vascular Cognitive Impairment

Neurodegeneration in tauopathies and synucleinopathies

While increasing life expectancy is a major achievement, the global aging of societies raises a number of medical issues, such as the development of age-related disorders, including neurodegenerative diseases. The three main disease groups constituting the majority of neurodegenerative diseases are tauopathies, alpha-synucleinopathies and diseases due to repetitions of glutamine (including Huntington's disease). In each neurodegenerative disease, the accumulation of one or more aggregated proteins has been identified as the molecular signature of the disease (as seen, for example, in Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, amyotrophic lateral sclerosis and frontotemporal dementia). The etiology of neurodegenerative diseases is often multifactorial, and the known risk factors include, in addition to genetic polymorphisms and age, some other possible causes, such as certain immune and metabolic conditions, endocrine pathologies, gender, socioeconomic or professional status, oxidative stress or inflammation, vitamin deficiencies and environmental factors (chemical exposure, metals). However, innovative strategies to elaborate suitable diagnostic and therapeutic approaches (aiming to at least delay or possibly even reverse disease progression) require further knowledge of the genetic and adaptive immunological characteristics of neurodegenerative diseases

Neuroprotective Effect of Coenzyme Q10 in Hippocampal Injury in Balb/c Mouse

Coenzyme Q10 is a promising agent for neuroprotection in neurodegenerative diseases. Neuroprotective effects of Coenzyme Q10 demonstrated in some neurodegenerative diseases such as Parkinson, Alzheimer and etc. Hippocampus is home of these diseases. We assayed Coenzyme Q10 effects on Hippocampal injury model and our hypothesis is that Coenzyme Q10 has Neuroprotective effects in some neurodegenerative diseases via hippocampus. For this purpose 24 Balb/c mouse took in 4 groups: Control (Without any treatment), Vehicle (Treated with sesame oil as Coenzyme Q10 vehicle), Hyppocampal injury model (Treated with Trimethyltin chlorideneurotoxin, 2.5 mg per kg IP), and test (Treated with Coenzyme Q10 after Trimethyltin chloride injection, 10 mg per kg IP for 2 weeks). After two weeks brain harvested and hippocampus tissue assayed by Nissl and Tunnel staining. Hystological study showed significantly increase of normal cells and decrease of apoptotic cells in test group after Coenzyme Q10 treatment in hippocampus. This study showed Coenzyme Q10 has protective effects in hippocampus after injury and it seems that Neuroprotective effects of Coenzyme Q10 in some neurodegenerative diseases com from that

Vitamin B12 measurements across neurodegenerative disorders.

Background:Vitamin B12 deficiency causes a number of neurological features including cognitive and psychiatric disturbances, gait instability, neuropathy, and autonomic dysfunction. Clinical recognition of B12 deficiency in neurodegenerative disorders is more challenging because it causes defects that overlap with expected disease progression. We sought to determine whether B12 levels at the time of diagnosis in patients with Parkinson's disease (PD) differed from those in patients with other neurodegenerative disorders. Methods:We performed a cross-sectional analysis of B12 levels obtained around the time of diagnosis in patients with PD, Multiple System Atrophy (MSA), Dementia with Lewy Bodies (DLB), Alzheimer's disease (AD), Progressive Supranuclear Palsy (PSP), Frontotemporal Dementia (FTD), or Mild Cognitive Impairment (MCI). We also evaluated the rate of B12 decline in PD, AD, and MCI. Results:In multivariable analysis adjusted for age, sex, and B12 supplementation, we found that B12 levels were significantly lower at time of diagnosis in patients with PD than in patients with PSP, FTD, and DLB. In PD, AD, and MCI, the rate of B12 decline ranged from - 17 to - 47 pg/ml/year, much greater than that reported for the elderly population. Conclusions:Further studies are needed to determine whether comorbid B12 deficiency affects progression of these disorders

Common dysregulation network in the human prefrontal cortex underlies two neurodegenerative diseases.

Using expression profiles from postmortem prefrontal cortex samples of 624 dementia patients and non-demented controls, we investigated global disruptions in the co-regulation of genes in two neurodegenerative diseases, late-onset Alzheimer's disease (AD) and Huntington's disease (HD). We identified networks of differentially co-expressed (DC) gene pairs that either gained or lost correlation in disease cases relative to the control group, with the former dominant for both AD and HD and both patterns replicating in independent human cohorts of AD and aging. When aligning networks of DC patterns and physical interactions, we identified a 242-gene subnetwork enriched for independent AD/HD signatures. This subnetwork revealed a surprising dichotomy of gained/lost correlations among two inter-connected processes, chromatin organization and neural differentiation, and included DNA methyltransferases, DNMT1 and DNMT3A, of which we predicted the former but not latter as a key regulator. To validate the inter-connection of these two processes and our key regulator prediction, we generated two brain-specific knockout (KO) mice and show that Dnmt1 KO signature significantly overlaps with the subnetwork (P = 3.1 × 10(-12)), while Dnmt3a KO signature does not (P = 0.017)

Serum heart-type fatty acid-binding protein and cerebrospinal fluid tau: Marker candidates for dementia with Lewy bodies

Background: The measurement of biomarkers in cerebrospinal fluid (CSF) has gained increasing acceptance in establishing the diagnosis of some neurodegenerative diseases. Heart-type fatty acid-binding protein (H-FABP) was recently discovered in CSF and serum of patients with neurodegenerative diseases. Objective: We investigated H-FABP in CSF and serum alone and in combination with CSF tau protein to evaluate these as potential biomarkers for the differentiation between dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). Methods: We established H-FABP and tau protein values in a set of 144 persons with DLB (n = 33), Parkinson disease with dementia (PDD; n = 25), AD (n = 35) and nonclemented neurological controls (NNC; n = 51). Additionally, serum H-FABP levels were analyzed in idiopathic Parkinson disease patients without evidence of cognitive decline (n = 45) using commercially available enzyme-linked immunosorbent assays. We calculated absolute values of HFABP and tau protein in CSF and serum and established relative ratios between the two to obtain the best possible match for the clinical working diagnosis. Results: Serum HFABP levels were elevated in DLB and PDD patients compared with NNC and AD subjects. To better discriminate between DLB and AD, we calculated the ratio of serum H-FABP to CSF tau protein levels. At the arbitrary chosen cutoff ratio >= 8 this quotient reached a sensitivity of 91% and a specificity of 66%. Conclusion: Our results suggest that the measurement of CSF tau protein, together with H-FABP quantification in serum and CSF, and the ratio of serum H-FABP to CSF tau protein represent marker candidates for the differentiation between AD and DLB. Copyright (c) 2007 S. Karger AG, Basel

Disease modifying therapy for multiple system atrophy – Parkinsonian Type

BACKGROUND: Multiple System Atrophy –Parkinsonian Type (MSA-P) is a rare, rapidly progressive neurodegenerative disease without any current treatment. Recent research has increased the understanding of brain iron accumulation and its association with neurodegenerative synucleinopathies, like MSA-P. Because of this improved understanding of the disease process, there is potential for new therapies that could benefit patients with MSA-P. Unfortunately, many attempts at finding a new and effective treatments for MSA-P have been unsuccessful. Two drugs that have shown potential in neurodegenerative synucleinopathies associated with brain iron accumulation are iron chelators (Deferiprone) and tyrosine kinase inhibitors (Nilotinib.) METHODS: The proposed study is a multicenter, double blind, randomized control study of Nilotinib and Deferiprone for the treatment of MSA-P. There will be two treatment arms; Nilotinib and a placebo group vs. Nilotinib and Deferiprone. There will be a 24 week treatment phase, followed by a 24 week wash-out phase. All patients will have a baseline evaluation including: a full neurological exam with rating scales (UMSARS, UPDRS, SCOPA, and MOCA) to assess motor and non-motor symptoms of MSA-P. Lab and imaging data will include CBC, CMP, serum iron panel, CSF iron panel and brain SWI-MR scans. Neurological exams and rating scales will be assessed every four weeks while imaging and laboratory data will be assessed at baseline (week 0) at the end of the intervention phase (week 24) and at the end of the follow-up phase (week 48). CONCLUSIONS: Deferiprone and Nilotinib when used together will have a synergistic impact on the symptoms of MSA-P and will be more effective when used together versus when they are used individually. SIGNIFICANCE: Patients with MSA-P have shortened life expectancy as well as severely diminished quality of life due to rapidly progressive neurodegeneration. This trial aims to implementing evidence based treatment for MSA-P that could potentially improve life expectancy as well as quality of life in this patient population

Training Neurodegenerative Disease Support Group Leaders: A New Support Group Functioning Scale

Support group leaders play pivotal roles in maintaining healthy community support groups; however, these leaders also have personal support needs and typically lack formal training in managing complex behaviors of neurodegenerative disorders. A support group well-being questionnaire, assessing support group functioning, was developed and piloted among participants of an educational training program designed for support group leaders of various neurodegenerative disorder-specific support groups. An exploratory factor analysis evaluated the questionnaire’s psychometric properties and identified a reliable single factor five-item solution, which was titled the Support Group Functioning Scale (SGFS). Preliminary interpretation guidelines were proposed. Development of this scale is a first step in identifying support group leaders’ needs as they provide frontline assistance to caregivers and individuals with neurodegenerative illnesses. This tool shows promise as an efficient way to identify support groups in need of assistance and to assess the impact of trainings on support group functioning. Further validation of the scale is needed

SIRT3 Protects Rotenone-induced Injury in SH-SY5Y Cells by Promoting Autophagy through the LKB1-AMPK-mTOR Pathway.

SIRT3 is a class III histone deacetylase that modulates energy metabolism, genomic stability and stress resistance. It has been implicated as a potential therapeutic target in a variety of neurodegenerative diseases, including Parkinson's disease (PD). Our previous study demonstrates that SIRT3 had a neuroprotective effect on a rotenone-induced PD cell model, however, the exact mechanism is unknown. In this study, we investigated the underlying mechanism. We established a SIRT3 stable overexpression cell line using lentivirus infection in SH-SY5Y cells. Then, a PD cell model was established using rotenone. Our data demonstrate that overexpression of SIRT3 increased the level of the autophagy markers LC3 II and Beclin 1. After addition of the autophagy inhibitor 3-MA, the protective effect of SIRT3 diminished: the cell viability decreased, while the apoptosis rate increased; α-synuclein accumulation enhanced; ROS production increased; antioxidants levels, including SOD and GSH, decreased; and MMP collapsed. These results reveal that SIRT3 has neuroprotective effects on a PD cell model by up-regulating autophagy. Furthermore, SIRT3 overexpression also promoted LKB1 phosphorylation, followed by activation of AMPK and decreased phosphorylation of mTOR. These results suggest that the LKB1-AMPK-mTOR pathway has a role in induction of autophagy. Together, our findings indicate a novel mechanism by which SIRT3 protects a rotenone-induced PD cell model through the regulation of autophagy, which, in part, is mediated by activation of the LKB1-AMPK-mTOR pathway