Parkinsons Abstracts 4


Neuroprotective effects of creatine.
            (Beal, 2011) Download
There is a substantial body of literature, which has demonstrated that creatine has neuroprotective effects both in vitro and in vivo. Creatine can protect against excitotoxicity as well as against β-amyloid toxicity in vitro. We carried out studies examining the efficacy of creatine as a neuroprotective agent in vivo. We demonstrated that creatine can protect against excitotoxic lesions produced by N-methyl-D: -aspartate. We also showed that creatine is neuroprotective against lesions produced by the toxins malonate and 3-nitropropionic acid (3-NP) which are reversible and irreversible inhibitors of succinate dehydrogenase, respectively. Creatine produced dose-dependent neuroprotective effects against MPTP toxicity reducing the loss of dopamine within the striatum and the loss of dopaminergic neurons in the substantia nigra. We carried out a number of studies of the neuroprotective effects of creatine in transgenic mouse models of neurodegenerative diseases. We demonstrated that creatine produced an extension of survival, improved motor performance, and a reduction in loss of motor neurons in a transgenic mouse model of amyotrophic lateral sclerosis (ALS). Creatine produced an extension of survival, as well as improved motor function, and a reduction in striatal atrophy in the R6/2 and the N-171-82Q transgenic mouse models of Huntington's disease (HD), even when its administration was delayed until the onset of disease symptoms. We recently examined the neuroprotective effects of a combination of coenzyme Q10 (CoQ10) with creatine against both MPTP and 3-NP toxicity. We found that the combination of CoQ and creatine together produced additive neuroprotective effects in a chronic MPTP model, and it blocked the development of alpha-synuclein aggregates. In the 3-NP model of HD, CoQ and creatine produced additive neuroprotective effects against the size of the striatal lesions. In the R6/2 transgenic mouse model of HD, the combination of CoQ and creatine produced additive effects on improving survival. Creatine may stabilize mitochondrial creatine kinase, and prevent activation of the mitochondrial permeability transition. Creatine, however, was still neuroprotective in mice, which were deficient in mitochondrial creatine kinase. Administration of creatine increases the brain levels of creatine and phosphocreatine. Due to its neuroprotective effects, creatine is now in clinical trials for the treatment of Parkinson's disease (PD) and HD. A phase 2 futility trial in PD showed approximately a 50% improvement in Unified Parkinson's Disease Rating Scale at one year, and the compound was judged to be non futile. Creatine is now in a phase III clinical trial being carried out by the NET PD consortium. Creatine reduced plasma levels of 8-hydroxy-2-deoxyguanosine in HD patients phase II trial and was well-tolerated. Creatine is now being studied in a phase III clinical trial in HD, the CREST trial. Creatine, therefore, shows great promise in the treatment of a variety of neurodegenerative diseases.

Living on the edge with too many mouths to feed: why dopamine neurons die.
            (Bolam and Pissadaki, 2012) Download
Although genes, protein aggregates, environmental toxins, and other factors associated with Parkinson's disease (PD) are widely distributed in the nervous system and affect many classes of neurons, a consistent feature of PD is the exceptional and selective vulnerability of dopamine (DA) neurons of the SNc. What is it about these neurons, among all other neurons in the brain, that makes them so susceptible in PD? We hypothesize that a major contributory factor is the unique cellular architecture of SNc DA neuron axons. Their large, complex axonal arbour puts them under such a tight energy budget that it makes them particularly susceptible to factors that contribute to cell death, including unique molecular characteristics associated with SNc DA neurons and nonspecific, nervous-system-wide factors.

Neurotransmitter testing of the urine: a comprehensive analysis.
            (Hinz et al., 2010) Download
UNLABELLED:  This paper analyzes the statistical correlation of urinary serotonin and dopamine data in subjects not suffering from monoamine-secreting tumors such as pheochromocytoma or carcinoid syndrome. Peer-reviewed literature and statistical analyses were searched and monoamine (serotonin and dopamine) assays defined in order to facilitate their proper interpretation. Many research findings in the literature are novel. Baseline assays completed with no monoamine precursors differ from baseline assays performed on a different day in the same subject. There is currently no scientific basis, value, or predictability in obtaining baseline monoamine assays. Urinary assays performed while taking precursors can demonstrate a lack of correlation or unexpected correlations such as inverse relationships. The only valid model for interpretation of urinary monoamine assays is the "three-phase model" which leads to predictability between monoamine assays and precursor administration in varied amounts. PURPOSE:  This paper reviews the basic science of urinary monoamine assays. Results of statistical analysis correlating baseline and nonbaseline assays are reported and provide valid methods for interpretation of urinary serotonin and dopamine results. PATIENTS AND METHODS:  Key scientific claims promoting the validity of the urinary neurotransmitter testing (UNT) model applications are discussed. Many of these claims were not supported by the scientific literature. Matched-pairs t-tests were performed on several groupings. Results of all statistical tests were compared with peer-reviewed literature. RESULTS:  The statistical analysis failed to support the UNT model. Peer-reviewed literature search failed to verify scientific clams made in support of applications of the UNT model in many cases.

Amino acid management of Parkinson's disease: a case study.
            (Hinz et al., 2011) Download
An extensive list of side effects and problems are associated with the administration of l-dopa (l-3, 4-dihydroxyphenylalanine) during treatment of Parkinson's disease. These problems can preclude achieving an optimal response with l-dopa treatment. PURPOSE: To present a case study outlining a novel approach for the treatment of Parkinson's disease that allows for management of problems associated with l-dopa administration and discusses the scientific basis for this treatment. PATIENTS AND METHODS: The case study was selected from a database containing 254 Parkinson's patients treated in developing and refining this novel approach to its current state. The spectrum of patients comprising this database range from newly diagnosed, with no previous treatment, to those who were diagnosed more than 20 years before and had virtually exhausted all medical treatment options. Parkinson's disease is associated with depletion of tyrosine hydroxylase, dopamine, serotonin, and norepinephrine. Exacerbating this is the fact that administration of l-dopa may deplete l-tyrosine, l-tryptophan, 5-hydroxytryptophan (5-HTP), serotonin, and sulfur amino acids. The properly balanced administration of l-dopa in conjunction with 5-HTP, l-tyrosine, l-cysteine, and cofactors under the guidance of organic cation transporter functional status determination (herein referred to as "OCT assay interpretation") of urinary serotonin and dopamine, is at the heart of this novel treatment protocol. RESULTS: When 5-HTP and l-dopa are administered in proper balance along with l-tyrosine, l-cysteine, and cofactors under the guidance of OCT assay interpretation, the long list of problems that can interfere with optimum administration of l-dopa becomes controllable and manageable or does not occur at all. Patient treatment then becomes more effective by allowing the implementation of the optimal dosing levels of l-dopa needed for the relief of symptoms without the dosing value barriers imposed by side effects and adverse reactions seen in the past.

Parkinson's disease-associated melanin steal.
            (Hinz et al., 2014) Download
Urinary dopamine fluctuations in the competitive inhibition state were first documented in 2009. At that time, it was noted that progressively higher daily dosing values of L-tyrosine decreased the magnitude of these fluctuations. While extensive statistical analysis has been performed by the authors since 2004, it was not until 2012 that a plausible explanation was formulated. In the process, correlations with L-tyrosine administration and the on/off effect of Parkinson's disease were defined. This paper documents the current knowledge with regard to the management of retrograde phase 1 dopamine fluctuations and investigates the hypothesis that they are caused by a melanin steal phenomenon.

The genetics and neuropathology of Parkinson's disease.
            (Houlden and Singleton, 2012) Download
There has been tremendous progress toward understanding the genetic basis of Parkinson's disease and related movement disorders. We summarize the genetic, clinical and pathological findings of autosomal dominant disease linked to mutations in SNCA, LRRK2, ATXN2, ATXN3, MAPT, GCH1, DCTN1 and VPS35. We then discuss the identification of mutations in PARK2, PARK7, PINK1, ATP13A2, FBXO7, PANK2 and PLA2G6 genes. In particular we discuss the clinical and pathological characterization of these forms of disease, where neuropathology has been important in the likely coalescence of pathways highly relevant to typical PD. In addition to the identification of the causes of monogenic forms of PD, significant progress has been made in defining genetic risk loci for PD; we discuss these here, including both risk variants at LRRK2 and GBA, in addition to discussing the results of recent genome-wide association studies and their implications for PD. Finally, we discuss the likely path of genetic discovery in PD over the coming period and the implications of these findings from a clinical and etiological perspective.

Sodium benzoate, a metabolite of cinnamon and a food additive, upregulates neuroprotective Parkinson disease protein DJ-1 in astrocytes and neurons.
            (Khasnavis and Pahan, 2012) Download
DJ-1 (PARK7) is a neuroprotective protein that protects cells from oxidative stress. Accordingly, loss-of-function DJ-1 mutations have been linked with a familial form of early onset Parkinson disease. Mechanisms by which DJ-1 level could be enriched in the CNS are poorly understood. Recently we have discovered anti-inflammatory activity of sodium benzoate (NaB), a metabolite of cinnamon and a widely-used food additive. Here we delineate that NaB is also capable of increasing the level of DJ-1 in primary mouse and human astrocytes and human neurons highlighting another novel neuroprotective effect of this compound. Reversal of DJ-1-inducing effect of NaB by mevalonate, farnesyl phosphate, but not cholesterol and ubiquinone, suggests that depletion of intermediates, but not end products, of the mevalonate pathway is involved in the induction of DJ-1 by NaB. Accordingly, either an inhibitor of p21(ras) farnesyl protein transferase (FPTI) or a dominant-negative mutant of p21(ras) alone was also able to increase the expression of DJ-1 in astrocytes suggesting an involvement of p21(ras) in DJ-1 expression. However, an inhibitor of geranyl geranyl transferase (GGTI) and a dominant-negative mutant of p21(rac) had no effect on the expression of DJ-1, indicating the specificity of the effect. Similarly lipopolysaccharide (LPS), an activator of small G proteins, also inhibited the expression of DJ-1, and NaB and FPTI, but not GGTI, abrogated LPS-mediated inhibition. Together, these results suggest that NaB upregulates DJ-1 via modulation of mevalonate metabolites and that p21(ras), but not p21(rac), is involved in the regulation of DJ-1.

Effect of ferulic acid and Angelica archangelica extract on behavioral and psychological symptoms of dementia in frontotemporal lobar degeneration and dementia with Lewy bodies.
            (Kimura et al., 2011) Download
AIM:  The behavioral and psychological symptoms of dementia place a heavy burden on caregivers. Antipsychotic drugs, though used to reduce the symptoms, frequently decrease patients' activities of daily living and reduce their quality of life. Recently, it was suggested that ferulic acid is an effective treatment for behavioral and psychological symptoms. We have also reported several patients with dementia with Lewy bodies showing good responses to ferulic acid and Angelica archangelica extract (Feru-guard). The present study investigated the efficacy of Feru-guard in the treatment of behavioral and psychological symptoms in frontotemporal lobar degeneration and dementia with Lewy bodies. METHODS:  We designed a prospective, open-label trial of daily Feru-guard (3.0 g/day) lasting 4 weeks in 20 patients with frontotemporal lobar degeneration or dementia with Lewy bodies. Behavioral and psychological symptoms of dementia were assessed at baseline and 4 weeks after the start of treatment, using the Neuropsychiatric Inventory. The Neuropsychiatric Inventory scores were analyzed using the Wilcoxon rank sum test. RESULTS:  Treatment with Feru-guard led to decreased scores on the Neuropsychiatric Inventory in 19 of 20 patients and significantly decreased the score overall. The treatment also led to significantly reduced subscale scores on the Neuropsychiatric Inventory ("delusions", "hallucinations", "agitation/aggression", "anxiety", "apathy/indifference", "irritability/lability" and "aberrant behavior"). There were no adverse effects or significant changes in physical findings or laboratory data. CONCLUSION:  Feru-guard may be effective and valuable for treating the behavioral and psychological symptoms of dementia in frontotemporal lobar degeneration and dementia with Lewy bodies.

LRRK2: cause, risk, and mechanism.
            (Paisan-Ruiz et al., 2013) Download
In 2004 it was first shown that mutations in LRRK2 can cause Parkinson's disease. This initial discovery was quickly followed by the observation that a single particular mutation is a relatively common cause of Parkinson's disease across varied populations. Further genetic investigation has revealed a variety of genetic ties to Parkinson's disease across this gene. These include common alleles with quite broad effects on risk, likely through both alterations at the protein sequence level, and in the context of expression. A great deal of functional characterization of LRRK2 and disease-causing mutations in this protein has occurred over the last 9 years, and considerable progress has been made. Particular attention has been paid to the kinase activity of LRRK2 as a therapeutic target, and while it is no means certain that this is viable target it is likely that this hypothesis will be tested in clinical trials sooner rather than later. We believe that the future goals for LRRK2 research are, while challenging, relatively clear and that the next 10 years of research promises to be perhaps more exciting than the last.

Subclinical Elevation of Plasma C-Reactive Protein and Illusions/Hallucinations in Subjects with Parkinson's Disease: Case-control Study
            (Sawada et al., 2014) Download
BACKGROUND: Though infections are associated with psychotic symptoms, whether or not subclinical inflammation is associated with hallucinations is not known in Parkinson's disease (PD). PURPOSE: To investigate the association of illusions/hallucinations and plasma CRP levels in PD patients without symptomatic infections. METHODS: PD patients not diagnosed as having infections were assessed for illusions and hallucinations using the Parkinson Psychosis Questionnaire (PPQ). It comprises four-domain questions: PPQ-A for sleep problems, PPQ-B for hallucinations/illusions, PPQ-C for delusions, and PPQ-D for disorientation. Assigning patients with >/=1 points in the PPQ-B score to be cases and others as controls, the association of hallucinations/illusions and clinical features (age, sex, duration of PD, Unified Parkinson's Disease Rating Scale part 3 (UPDRS-3), Mini-Mental State Examination (MMSE) score, sleep disturbance (PPQ-A score) as well as daily doses of L-Dopa, dopamine agonists, amantadine, and selegiline) were analyzed using a case-control design. RESULTS: A total of 111 patients were examined and plasma CRP levels were <0.1-6.0 mg/L. Hallucinations or illusions were detected in 28 (25.2%). There were significant differences in age, UPDRS-3 score, MMSE score, PPQ-A, daily doses of L-Dopa and dopamine agonists and plasma CRP levels between cases and controls. A multivariate logistic regression model revealed that UPDRS-3 scores and plasma CRP levels were significantly associated with hallucinations/illusions with an adjusted odds ratio of 1.96 (95% confidence interval (CI) 1.20-3.20) per 10 points and 1.57 (95% confidence interval 1.13-2.16) per two-fold, respectively. Dividing patients into thirds by CRP levels (</=0.2, 0.3-0.6, >/=0.7 mg/L), the prevalence of hallucinations/illusions was 13.2%, 21.6%, and 41.7%, in the bottom-, middle-, and top-thirds, respectively (for trend p = 0.012). CONCLUSIONS: Subclinical elevation of plasma CRP levels was associated with hallucinations or illusions after adjustment for motor disability, suggesting that subclinical elevations of CRP levels might be an independent risk for hallucinations/illusions.


Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline
            (Shults et al., 2002) Download
BACKGROUND: Parkinson disease (PD) is a degenerative neurological disorder for which no treatment has been shown to slow the progression. OBJECTIVE: To determine whether a range of dosages of coenzyme Q10 is safe and well tolerated and could slow the functional decline in PD. DESIGN: Multicenter, randomized, parallel-group, placebo-controlled, double-blind, dosage-ranging trial. SETTING: Academic movement disorders clinics. PATIENTS: Eighty subjects with early PD who did not require treatment for their disability. INTERVENTIONS: Random assignment to placebo or coenzyme Q10 at dosages of 300, 600, or 1200 mg/d. MAIN OUTCOME MEASURE: The subjects underwent evaluation with the Unified Parkinson Disease Rating Scale (UPDRS) at the screening, baseline, and 1-, 4-, 8-, 12-, and 16-month visits. They were followed up for 16 months or until disability requiring treatment with levodopa had developed. The primary response variable was the change in the total score on the UPDRS from baseline to the last visit. RESULTS: The adjusted mean total UPDRS changes were +11.99 for the placebo group, +8.81 for the 300-mg/d group, +10.82 for the 600-mg/d group, and +6.69 for the 1200-mg/d group. The P value for the primary analysis, a test for a linear trend between the dosage and the mean change in the total UPDRS score, was.09, which met our prespecified criteria for a positive trend for the trial. A prespecified, secondary analysis was the comparison of each treatment group with the placebo group, and the difference between the 1200-mg/d and placebo groups was significant (P =.04). CONCLUSIONS: Coenzyme Q10 was safe and well tolerated at dosages of up to 1200 mg/d. Less disability developed in subjects assigned to coenzyme Q10 than in those assigned to placebo, and the benefit was greatest in subjects receiving the highest dosage. Coenzyme Q10 appears to slow the progressive deterioration of function in PD, but these results need to be confirmed in a larger study.

The genetics of Parkinson's disease: progress and therapeutic implications.
            (Singleton et al., 2013) Download
The past 15 years has witnessed tremendous progress in our understanding of the genetic basis for Parkinson's disease (PD). Notably, whereas most mutations, such as those in SNCA, PINK1, PARK2, PARK7, PLA2G6, FBXO7, and ATP13A2, are a rare cause of disease, one particular mutation in LRRK2 has been found to be common in certain populations. There has been considerable progress in finding risk loci. To date, approximately 16 such loci exist; notably, some of these overlap with the genes known to contain disease-causing mutations. The identification of risk alleles has relied mostly on the application of revolutionary technologies; likewise, second-generation sequencing methods have facilitated the identification of new mutations in PD. These methods will continue to provide novel insights into PD. The utility of genetics in therapeutics relies primarily on leveraging findings to understand the pathogenesis of PD. Much of the investigation into the biology underlying PD has used these findings to define a pathway, or pathways, to pathogenesis by trying to fit disparate genetic defects onto the same network. This work has had some success, particularly in the context of monogenic disease, and is beginning to provide clues about potential therapeutic targets. Approaches toward therapies are also being provided more directly by genetics, notably by the reduction and clearance of alpha-synuclein and inhibition of Lrrk2 kinase activity. We believe this has been an exciting, productive time for PD genetics and, furthermore, that genetics will continue to drive the etiologic understanding and etiology-based therapeutic approaches in this disease.

Functional COMT variant predicts response to high dose pyridoxine in Parkinson's disease.
            (Tan et al., 2005) Download
Pyridoxal-5-phosphate, the biological active form of pyridoxine, is a cofactor for dopa-decarboxylase (DDC) enzyme. Pyridoxine may augment the conversion of levodopa to dopamine in the periphery and therefore decrease availability of levodopa to the brain. However, this effect can be negated in the presence of a DDC inhibitor, which potentiates plasma levodopa level. A single nucleotide polymorphism at the nucleotide 1947 in the catechol-O-methyltransferase (COMT) gene encodes the high (COMT(H)) and low activity (COMT(L)) forms of the enzyme. In this study, we examined the effect of the COMT(L) allele on the clinical response to pyridoxine in Parkinson's disease (PD) patients. PD patients who were on stable and optimized dose of levodopa were included in this study. Their mean motor and activities of living score improved after high dose pyridoxine (P = 0.09, P = 0.04), and worsened after a washout period (P = 0.005, P = 0.001). Using a multivariate model, the presence of the COMT(L) allele predicted response to pyridoxine, with the best outcome observed in COMT(L/L) homozygotes. Our observational study suggests that the status the functional COMT(L) variant may be potentially useful to select PD patients for high dose pyridoxine therapy.

Genetics of Parkinson disease and essential tremor.
            (Wider et al., 2010) Download
PURPOSE OF REVIEW:  Elucidating the genetic background of Parkinson disease and essential tremor is crucial to understand the pathogenesis and improve diagnostic and therapeutic strategies. RECENT FINDINGS:  A number of approaches have been applied including familial and association studies, and studies of gene expression profiles to identify genes involved in susceptibility to Parkinson disease. These studies have nominated a number of candidate Parkinson disease genes and novel loci including Omi/HtrA2, GIGYF2, FGF20, PDXK, EIF4G1 and PARK16. A recent notable finding has been the confirmation for the role of heterozygous mutations in glucocerebrosidase (GBA) as risk factors for Parkinson disease. Finally, association studies have nominated genetic variation in the leucine-rich repeat and Ig containing 1 gene (LINGO1) as a risk for both Parkinson disease and essential tremor, providing the first genetic evidence of a link between the two conditions. SUMMARY:  Although undoubtedly genes remain to be identified, considerable progress has been achieved in the understanding of the genetic basis of Parkinson disease. This same effort is now required for essential tremor. The use of next-generation high-throughput sequencing and genotyping technologies will help pave the way for future insight leading to advances in diagnosis, prevention and cure.



Khasnavis, S and K Pahan (2012), ‘Sodium benzoate, a metabolite of cinnamon and a food additive, upregulates neuroprotective Parkinson disease protein DJ-1 in astrocytes and neurons.’, J Neuroimmune Pharmacol, 7 (2), 424-35. PubMed: 21701815
Beal, MF (2011), ‘Neuroprotective effects of creatine.’, Amino Acids, 40 (5), 1305-13. PubMed: 21448659
Bolam, JP and EK Pissadaki (2012), ‘Living on the edge with too many mouths to feed: why dopamine neurons die.’, Mov Disord, 27 (12), 1478-83. PubMed: 23008164
Hinz, M, et al. (2010), ‘Neurotransmitter testing of the urine: a comprehensive analysis.’, Open Access J Urol, 2 177-83. PubMed: 24198626
Hinz, M, A Stein, and T Uncini (2011), ‘Amino acid management of Parkinson’s disease: a case study.’, Int J Gen Med, 4 165-74. PubMed: 21475622
Hinz, M, A Stein, and T Cole (2014), ‘Parkinson’s disease-associated melanin steal.’, Neuropsychiatr Dis Treat, 10 2331-37. PubMed: 25525362
Houlden, H and AB Singleton (2012), ‘The genetics and neuropathology of Parkinson’s disease.’, Acta Neuropathol, 124 (3), 325-38. PubMed: 22806825
Kimura, T, et al. (2011), ‘Effect of ferulic acid and Angelica archangelica extract on behavioral and psychological symptoms of dementia in frontotemporal lobar degeneration and dementia with Lewy bodies.’, Geriatr Gerontol Int, 11 (3), 309-14. PubMed: 21272180
Paisan-Ruiz, C, PA Lewis, and AB Singleton (2013), ‘LRRK2: cause, risk, and mechanism.’, J Parkinsons Dis, 3 (2), 85-103. PubMed: 23938341
Sawada, H., et al. (2014), ‘Subclinical Elevation of Plasma C-Reactive Protein and Illusions/Hallucinations in Subjects with Parkinson’s Disease: Case-control Study’, PLoS One, 9 (1), e85886. PubMed: 24497930
Shults, C. W., et al. (2002), ‘Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline’, Arch Neurol, 59 (10), 1541-50. PubMed: 12374491
Singleton, AB, MJ Farrer, and V Bonifati (2013), ‘The genetics of Parkinson’s disease: progress and therapeutic implications.’, Mov Disord, 28 (1), 14-23. PubMed: 23389780
Tan, EK, et al. (2005), ‘Functional COMT variant predicts response to high dose pyridoxine in Parkinson’s disease.’, Am J Med Genet B Neuropsychiatr Genet, 137B (1), 1-4. PubMed: 15965967
Wider, C, OA Ross, and ZK Wszolek (2010), ‘Genetics of Parkinson disease and essential tremor.’, Curr Opin Neurol, 23 (4), 388-93. PubMed: 20489616