Levodopa, vitamins, ageing and the neuropathy of Parkinson’s disease

Higher prevalence of neuropathy has been described in patients with Parkinson’s disease (PD) in comparison with age and gender-matched controls. The cause of neuropathy may be levodopa-induced impairment of vitamin B₁₂ metabolism, suggesting levodopa-naïve subjects should be unaffected. There may, however, be other yet unidentified determinants of neuropathy in PD. We screened 33 consecutive levodopa-naïve PD patients for neuropathy. Demographics, vitamin B₁₂ and folate levels were studied. Findings were analyzed in the light of our previous available data on levodopa-treated PD patients. Four of 33 (12.1 %) levodopa-naïve PD patients were diagnosed with neuropathy. This compared to 13/36 (36.1 %) previously evaluated levodopa-treated patients (p = 0.027) and 3/37 controls (p = 0.7). Analysis of our whole PD cohort consisting of a total of 70 subjects, including levodopa-naïve and levodopa-treated patients, revealed that neuropathy correlated with use of levodopa (p = 0.041), cumulative levodopa exposure (p = 0.046), age at time of study (p = 0.005) and serum folate levels <10 μg/L (p = 0.003). There was no association of neuropathy with PD duration. Multivariate regression analysis showed that neuropathy was only independently associated with age (p = 0.016) and serum folate levels <10 μg/L (p = 0.012). We conclude that this study confirms the roles of levodopa usage and cumulative levodopa exposure in the neuropathy of PD. However, the effects of levodopa only appear contributory and are surpassed by age and lower folate levels. In view of the independent implication of lower folate levels, the need for preventative/protective supplementation including folate in addition to vitamin B₁₂, probably irrespective of levodopa use, may deserve consideration in patients with PD.     

Dietary intakes of vitamin E, vitamin C, and β-carotene and risk of Alzheimer's disease: a meta-analysis

In view of the vital role of oxidative stress in the pathogenesis of Alzheimer's disease (AD), the potential of antioxidant supplements to prevent AD have gained much interest, while there are conflicting results on this topic in recent years. The purpose of the present study is to comprehensively evaluate the association between dietary intakes, instead of supplements, of the most common three antioxidants (vitamin E, vitamin C, and β-carotene) and the risk of AD on the basis of the meta-analysis studies published up to October 2011 in Medline and Scopus databases. In total, seven articles were included in the meta-analysis. According to the pooled relative risk [(95% CI) 0.76 (0.67-0.84) for vitamin E, 0.83 (0.72-0.94) for vitamin C, and 0.88 (0.73-1.03) for β-carotene], dietary intakes of the three antioxidants can lower the risk of AD, with vitamin E exhibiting the most pronounced protective effects. The findings will be of significance to the prevention and interventional treatment of AD.     

DNA fragmentation, gliosis and histological hallmarks of Alzheimer’s disease

The extent of DNA fragmentation analysed using the TUNEL technique was evaluated in post-mortem human brain tissue. Twenty-four patients with clinical and histopathological diagnosis of Alzheimer’s disease (AD) and a short post-mortem delay were analysed. We report an increase in the count of TUNEL-labelled cells as the pathology of AD intensifies. Our results point out a significant correlation between neurofibrillary tangle and senile/neuritic plaque score and TUNEL-labelled cells. Patients with two copies of apolipoprotein (Apo) E ɛ4 allele had highest number of histopathological hallmarks lesions of AD, whereas the ApoE genotype did not significantly influence the density of TUNEL-positive cells. No significant correlation was found between β-amyloid protein load and TUNEL-labelled cells. There was no relationship between the age at death, age at onset, extent of astrogliosis or microgliosis and TUNEL-labelled cells in our material. Received: 23 November 1999 / Revised: 18 January 2000, 22 February2000 / Accepted: 22 February 2000     

The incidence,baseline predictors,and outcomes of dementia in an incident cohort of Parkinson’s disease and controls

Journal of Neurology - There are few long-term data on the incidence, baseline predictors, and outcomes of dementia in Parkinson’s disease (PD) from prospective community-based incident...     

Pathophysiology of Parkinson's disease: Mitochondria,alpha-synuclein and much more…

Parkinson's disease (PD) is a complex, age-related, neurodegenerative disease whose pathogenesis remains incompletely understood. Here, we give an overview of the progress that has been made over the past four decades in our understanding of this disorder. We review the role of mitochondria, environmental toxicants, alpha-synuclein and neuroinflammation in the development of PD. We also discuss more recent data from genetics, which strongly support the endosomal-lysosomal pathways and mitophagy as being central to PD. Finally, we discuss the emerging role of the gut-brain axis as a modulator of PD progression. This article is intended to provide a comprehensive, general and practical review of PD pathogenesis for the general neurologist.     

Evaluation of CSF-Chlamydia pneumoniae,CSF-tau,and CSF-Abeta42 in Alzheimer’s disease and vascular dementia

The potential role of microbiological factors such as Chlamydia pneumoniae (ChP) in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease (AD) and vascular dementia (VD), has been suggested, but the correctness of this hypothesis still needs to be tested. In this study the appearance of ChP in the cerebrospinal fluid (CSF) of 57 AD and 21 VD patients and in 47 controls (CG) as well as the influence of ChP on the levels of tau protein and Abeta42 were investigated. The frequency of ChP occurrence in the AD patient group (43.9%) was significantly higher (p < 0.001) than in the control group (10.6%). In the case of VD patients, 9.5% of this group was positive for ChP. The presence of ChP DNA in the CSF of patients with AD significantly increases the occurrence of this disease (odds ratio = 7.21). Cerebrospinal fluid Abeta42 levels were significantly lower in patients with AD than in the CG (p < 0.001). Cerebrospinal tau protein was significantly higher in AD vs. CG (p = 0.007). However, no relationships between the presence of the bacterium in CSF and the level of either tau or Abeta42 protein were observed. In conclusion, we may suspect that testing for the presence of ChP in CSF, along with the tau and Abeta42 markers, may be used in the clinic diagnosis of AD.     

Differential distribution of presenilin-1, Bax, and Bcl-XL in Alzheimer’s disease and frontotemporal dementia

We have previously reported that presenilin-1 (PS-1)-immunoreactive neurons survive in late-onset sporadic Alzheimer’s disease (AD). To examine if this is also the case in other dementing conditions, and if it is associated with changes in the expression of the main apoptosis-related proteins, a quantitative immunocytochemical study of presenilin-1, Bax, and Bcl-X_L in the cerebral cortex of non-demented and AD patients, and patients with frontotemporal dementia (FTD) was performed. In non-demented cases, the frequency of neurons showing PS-1 immunoreactivity was 25–60%, Bax immunoreactivity 36–54%, and Bcl-X_L immunoreactivity 26–63% depending on the cortical area. The frequency of NFT-free neurons which contained PS-1 or Bax was consistently increased in all of the areas in AD. In FTD cases, the percentage of PS-1-, but not Bax-immunoreactive neurons was increased only in areas displaying a substantial neuronal loss. Conversely, there was no difference in the densities of Bcl-X_L-containing neurons among the three diagnosis groups. These data suggest that surviving neurons in affected cortical areas in AD show a high expression of PS-1 and Bax, indicating that these proteins play a key role in the mechanisms of cell death in this disorder. In FTD, neurons containing PS-1 are preserved, further supporting a neuroprotective role for this protein in other neurodegenerative disorders. Received: 27 October 1998 / Revised: 4 January 1999 / Accepted: 5 January 1999     

Cholesterol,Aβ and Alzheimer's disease

Statins have been used for many years for the treatment of hypercholesterolemia. They lower low-density lipoprotein (LDL) cholesterol, increase high-density lipoprotein (HDL) levels and are considered to be very safe. Recently, a set of potential new applications was identified for statins. In the future, these drugs could be used to treat Alzheimer's disease (AD). Past studies have suggested a link between AD and lipids and a series of reports has recently been published that significantly tightens this link and also provides some explanations at the cellular level. This review focuses on these recent developments and perspectives that appear to link cholesterol, β-amyloid and AD.     

Presenilins, β-amyloid precursor protein and the molecular basis of Alzheimer's disease

Progressive cerebral deposition of the 40- and 42-residue amyloid β-proteins is an early and invariant event in all forms of Alzheimer's disease (AD). Aβ proteins are generated from the β-amyloid precursor protein (APP) via two sequential cleavages by proteases designated β-secretase and γ-secretase and are constitutively secreted by essentially all cells throughout life. APP can undergo these cleavages during its secretory trafficking to the cell surface, yet much of Aβ appears to be generated after APP reaches the surface, i.e. in the endosomal pathway. Presenilin (PS) 1 and 2, homologous proteins with eight transmembrane (TM) domains, play a critical role in the γ-secretase cleavage of APP. Deletion of presenilin 1 (PS1) in mice markedly decreases Aβ production, whereas AD-causing PS1 mutations selectively increase Aβ₄₂ production, thereby markedly accelerating amyloid plaque formation, both in humans and transgenic mice. Small amounts of APP and PS can be co-immunoprecipitated from cells, suggesting a direct role of PS1 in the cleavage of APP by γ-secretase. We recently observed and mutated two unusual intramembranous aspartate residues in TM6 and TM7 of each presenilin, resulting in complete blockage of the γ-secretase cleavage of APP, with no detectable Aβ production by cells. Because our protease inhibitor studies suggest that γ-secretase is an aspartyl protease, we hypothesize that these two key aspartates serve as the active site of an unprecedented intramembranous aspartyl protease (i.e. γ-secretase). The recent discovery that Notch, a protein critical for cell fate determination during development, also undergoes an intramembranous cleavage mediated by PS suggests that presenilin may be a key regulatory enzyme for several vital proteolytic events. Thought of in this context, AD may arise late in the post-reproductive life of humans as an ancillary metabolic consequence of a proteolytic mechanism which confers strong evolutionary advantage. Specific and potent inhibitors of γ-secretase/presenilin or of the recently cloned β-secretase may well prove useful for the treatment and the prevention of AD.     

Parkinson’s disease in patients and obligate carriers of Gaucher disease

BackgroundGaucher disease is an autosomal recessive disorder caused by glucocerebrosidase gene mutations. Accumulating evidence from several Parkinson’s disease cohorts of varying ethnicities suggests that glucocerebrosidase mutations even in the heterozygous state (carriers) may be a susceptibility factor for Parkinson’s. Very few studies have analyzed the frequency of Parkinson’s in carriers and individuals with Gaucher disease.ObjectiveTo determine frequency of Parkinson’s in patients with Gaucher disease and obligate carriers of glucocerebrosidase mutations and compare it with a control group.MethodsA questionnaire was completed by 100 Ashkenazi Jewish Gaucher patients followed at our center and 109 ethnicity-matched controls with no personal or family history of Gaucher disease.ResultsFrequency of Parkinson’s was higher in Gaucher patients (8/100) than in controls (0/109; P = 0.0024). Frequency of Parkinson’s in obligate carriers (11/200) was higher than controls (6/218), but the difference was not statistically significant (P = 0.215). Average age of onset of Parkinson’s was earlier in Gaucher patients (57.2) than the general population and in obligate carriers (60) when compared with controls (76.8; P = 0.01). The L444P genotype was more frequent in Gaucher patients who reported a parent with Parkinson’s (36.40%) than those who did not (4.50%).ConclusionOur study suggests that the risk for developing Parkinson’s may be higher in affected versus carriers of glucocerebrosidase mutations and suggests that L444P may pose a higher risk of developing Parkinson’s than other mutations. It also confirms previous findings that the age of onset of Parkinson’s associated with glucocerebrosidase mutations is earlier than in the general population.     

Diagnosis and treatment of Wilson’s disease

Wilson’s disease (WD) is an autosomal recessive disease that causes increased copper deposition in the liver and basal ganglia with resultant hepatic and neurologic sequelae. In the past few years, dramatic new discoveries have changed our understanding of the pathophysiology of WD. Although there are potentially life-saving therapies for WD, there is much controversy surrounding the optimal treatments of patients in the various stages of the disease. Specifically, the relative roles of penicillamine, trientene, and tetrathiomolybdate in the initial treatment of the symptomatic patient with WD remain to be defined. Zinc monotherapy for maintenance treatment and in the treatment of asymptomatic patients with WD is still controversial. It is also unclear whether neurologic status alone is an indication for liver transplantation in WD. This paper reviews the pathogenesis, genetics, clinical presentation, and diagnosis, with a special emphasis on the treatment controversies that arise in the care of the WD patient.     

Quantitative assessment of finger tapping characteristics in mild cognitive impairment,Alzheimer’s disease,and Parkinson’s disease

Background

Fine motor impairments are common in neurodegenerative disorders, yet standardized, quantitative measurements of motor abilities are uncommonly used in neurological practice. Thus, understanding and comparing fine motor abilities across disorders have been limited.

Objectives

The current study compared differences in finger tapping, inter-tap interval, and variability in Alzheimer’s disease (AD), Parkinson’s disease (PD), mild cognitive impairment (MCI), and healthy older adults (HOA).

Methods

Finger tapping was measured using a highly sensitive light-diode finger tapper. Total number of finger taps, inter-tap interval, and intra-individual variability (IIV) of finger tapping was measured and compared in AD (n?=?131), PD (n?=?63), MCI (n?=?46), and HOA (n?=?62), controlling for age and sex.

Results

All patient groups had fine motor impairments relative to HOA. AD and MCI groups produced fewer taps with longer inter-tap interval and higher IIV compared to HOA. The PD group, however, produced more taps with shorter inter-tap interval and higher IIV compared to HOA.

Conclusions

Disease-specific changes in fine motor function occur in the most common neurodegenerative diseases. The findings suggest that alterations in finger tapping patterns are common in AD, MCI, and PD. In addition, the present results underscore the importance of motor dysfunction even in neurodegenerative disorders without primary motor symptoms.

     

Genetics and genetic counseling: Recommendations for Alzheimer’s disease,frontotemporal dementia,and Creutzfeldt-Jakob disease

In this paper we discuss the clinical genetics of three neurodegenerative diseases (Alzheimer’s disease, frontotemporal dementia, and Creutzfeldt-Jakob disease), the current application of genetic testing for these diseases, and the role of genetic counseling in familial dementia. We review the literature addressing the clinical application of these genetic findings, including susceptibility testing and predictive testing. In addition, we share our own experience working with families with familial neurodegenerative disease, the genetic counseling process, and the major issues that need attention in the genetic counseling setting.     

Levels of HVA, 5-HIAA, and MHPG in the CSF of vascular parkinsonism compared to Parkinson’s disease and controls

The neurochemical abnormalities underlying vascular parkinsonism (VP) have not been well characterised. A better understanding may help to optimize pharmacological interventions. Since VP patients generally have a poorer response to l-Dopa than Parkinson’s disease (PD) patients, we investigated whether levels of relevant CSF neurotransmitter metabolites may be differentially altered in VP and PD and assessed the potential of neurotransmitter metabolites as biomarkers. We compared CSF levels of homovanillic acid (HVA), 5-hydroxyindolacetic acid, and 3-methoxy-4-hydroxyphenylethyleneglycol, in 16 VP patients, 57 PD patients and 60 non-neurological controls. We found that levels of HVA were reduced in PD compared with both VP and controls but did not differ significantly between VP and controls indicating that dopamine deficiency was less pronounced in VP.     

Pathologic correlates of nondemented aging,mild cognitive impairment,and early-stage alzheimer’s disease

The results of studies from the Washington University Alzheimer Disease (AD) Research Center and those from other centers and investigators regarding the neuropathologic correlates of normal aging and early-stage AD are reviewed. We conclude that widespread amyloid plaques in the neocortex best distinguishes very early stage AD, including "MCI" stage, and preclinical stages, from healthy brain aging. Other AD lesions, including increased formation of neurofibrillary tangles and neuronal degeneration appear to result from the amyloid-initiated pathologic process, although they may have a more immediate effect on expression and severity of dementia. These data provide strong support for anti-amyloid intervention as a preventive therapy for AD. It is now critical to develop methods to detect preclinical AD during life.     

α-Synuclein, leucine-rich repeat kinase-2, and manganese in the pathogenesis of Parkinson disease

Parkinson disease (PD) is the most common movement disorder. It is characterized by bradykinesia, postural instability, resting tremor, and rigidity associated with the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Another pathological hallmark of PD is the presence of α-synuclein proteiniacous inclusions, known as Lewy bodies and Lewy neurites, in some of the remaining dopaminergic neurons. Mounting evidence indicates that both genetic and environmental factors contribute to the etiology of PD. For example, genetic mutations (duplications, triplications or missense mutations) in the α-synuclein gene can lead to PD, but even in these patients, age-dependent physiological changes or environmental exposures appear to be involved in disease presentation. Several additional alterations in many other genes have been established to either cause or increase the risk of parkinson disease. More specifically, autosomal dominant missense mutations in the gene for leucine-rich repeat kinase 2 (LRRK2/PARK8) are the most common known cause of PD. Recently it was shown that G2019S, the most common diseasing-causing mutant of LRRK2, has dramatic effects on the kinase activity of LRRK2: while activity of wild-type LRRK2 is inhibited by manganese, the G2019S mutation abrogates this inhibition. Based on the in vitro kinetic properties of LRRK2 in the presence of manganese, we proposed that LRRK2 may be a sensor of cytoplasmic manganese levels and that the G2019S mutant has lost this function. This finding, alongside a growing number of studies demonstrating an interaction between PD-associated proteins and manganese, suggest that dysregulation of neuronal manganese homeostasis over a lifetime can play an important role in the etiology of PD.     

UK research expenditure on dementia,heart disease,stroke and cancer: are levels of spending related to disease burden?

Background and purpose: A UK government review recommended that the impact of disease on the population and economy should be assessed to inform health research priorities. This study aims to quantify UK governmental and charity research funding for dementia, cancer, coronary heart disease (CHD) and stroke in 2007/08 and assess whether the levels of research expenditure are aligned with disease and economic burden. Methods: We identified UK governmental agencies and charities providing health research funding and determined their levels of funding for dementia, cancer, CHD and stroke. Research funding levels were compared to the number of cases, disability‐adjusted life years (DALYs) and economic burden. Economic costs were estimated using data on morbidity, mortality, health and social care use, private costs and other related indicators. Results: Research funding to the four diseases was £833 million, of which £590 million (71%) was devoted to cancer, £169 million (20%) to CHD, £50 million (6%) to dementia and £23 million (4%) to stroke. Cancer received £482 in research funding per 1000 DALYs lost, CHD received £266, dementia received £166, with stroke receiving £71. In terms of economic burden, for every £1 million of health and social care costs attributable to each disease, cancer received £129 269 in research funding, CHD received £73 153, stroke received £8745 and dementia received £4882. Conclusions: Most health research funding in the UK is currently directed towards cancer. When compared to their burden, our analysis suggests that research spending on dementia and stroke is severely underfunded in comparison with cancer and CHD.     

Prevalence of Parkinson’s disease and other types of Parkinsonism

OBJECTIVES: To assess the prevalence of Parkinson's disease and parkinsonism in two Spanish populations (Irun and Hondarribia, Bidasoa Region) and to compare the results with those of similar surveys. METHODS: The survey included 2000 participants aged 65 years or older in a door-to-door, three-phase design. In the screening phase we used the SNES (Sicilian Neuro-Epidemiologic Study) screening questionnaire, which has 100% sensitivity. In phases 2 and 3 we carried out a 3-year follow-up of all cases diagnosed with parkinsonism in phase 2. Progressively stricter diagnostic criteria were chosen in order to minimize the impact of false positives on the final results. RESULTS: The prevalence of Parkinson's disease (PD) was 1.5 % (95% confidence interval, 0.9 to 2.3) and the prevalence of other types of parkinsonism (OP) was 1.1 % (95% confidence interval 0.6 to 1.9). The overall prevalence by age group was 0.4 % (65-74 years), 4.7% (75-84 years), and 2.9% (> or =85 years) for Parkinson's disease and 0.7%, 2%, and 3.9 % for parkinsonism, respectively. The other parkinsonism prevalence was 1.3 % in men and 1.6 % in women. CONCLUSIONS: These prevalence rates are similar than those found in studies made in other European countries. The prevalence of both Parkinson's disease and other types of parkinsonism increased with age, with no significant differences between men and women.