Effects of Amantadine Sulfate on Motor Impairment and Execution of Motor Sequences in Patients With Parkinson Disease.

BACKGROUND: Intravenous application of amantadine sulfate induces a rapid improvement of motor behavior in patients with Parkinson disease. OBJECTIVES: To determine efficacy of daily infusion of 200 mg amantadine sulfate on scored motor symptoms and performance of standardized movement sequences with components of low and high cognitive efforts. METHODS: Thirty-one participants received infusions of amantadine sulfate in addition to their previous stable drug regimens on 3 consecutive days. Motor symptoms of upper limbs were determined with selected items of the part motor examination of the Unified Parkinson's Disease Rating Scale. Instrumental tasks were executed under cued conditions before and after the infusions. RESULTS: Scored motor symptoms and components with a need for a higher cognitive load became better. Performance of motion series, characterized by an automated set with low cognitive efforts, did not improve. CONCLUSION: Our trial outcomes suggest that the amantadine has a positive impact on cognitive abilities, drive, and vigilance, all of which are necessary for carrying out of higher brain functions.

Aminoadamantanes: from treatment of Parkinson's and Alzheimer's disease to symptom amelioration of long COVID-19 syndrome?

INTRODUCTION: The aminoadamantanes amantadine and memantine are well known. They mainly act as N-methyl-D-aspartate antagonists. AREAS COVERED: The antiviral drug amantadine moderately ameliorates impaired motor behavior in patients with Parkinson's disease. Memantine provides beneficial effects on memory function in patients with advanced Alzheimer's disease already treated with acetylcholine esterase inhibitors. Both compounds counteract impaired monoamine neurotransmission with associated symptoms, such as depression. They improve vigilance, lack of attention and concentration, fatigue syndromes according to clinical findings in patients with chronic neurodegenerative processes. Their extrasynaptic N-methyl-D-Aspartate receptor blockade weakens a prolonged influx of Ca2+ ions as the main responsible components of neuronal excitotoxicity. This causes neuronal dying and associated functional deficits. EXPERT OPINION: We suggest aminoadamantanes as future therapies for amelioration of short- and long-term consequences of a COVID 19 infection. Particularly the extended-release amantadine formulations will be suitable. They showed better clinical efficacy compared with the conventional available compounds. Amantadine may particularly be suitable for amelioration of fatigue or chronic exhaustion, memantine for improvement of cognitive deficits. Clinical research in patients, who are affected by the short- and long-term consequences of a COVID 19 infection, is warranted to confirm these still hypothetical putative beneficial effects of aminoadamantanes.

The drugs amantadine and memantine are known as aminoadamantanes. Amantadine improves motor skills in patients with Parkinson's disease. It also reduces fatigue in individuals suffering from multiple sclerosis. Memantine improves memory dysfunction linked to Alzheimer's disease. Aminoadamantanes affect communication between nerve cells by supporting neurotransmission of monoamines. Clinical studies have found that these drugs benefit patients with chronic neurodegenerative diseases, who have depression, fatigue, loss of attention or concentration deficits. These brain function problems may also appear to some extent due to COVID-19 infection. We suggest that aminoadamantanes could improve these problems in COVID-19 patients in both the short and long term. Clinical research is needed to confirm this hypothesis.

No Vitamin D Deficiency in Patients with Parkinson's Disease.

Previous trials describe a decrease of vitamin D levels in patients with Parkinson's disease and relationships to clinical disease severity. This case control study found higher but not significant 25-OH-vitamin D plasma levels in patients with Parkinson's disease compared with age- and sex-matched controls and no associations to clinical parameters, such as rating scores of disease severity or assessments of cognitive function. A certain variability of vitamin D concentrations was observed in both cohorts, which were investigated during the same season. These outcomes put into perspective the emerging discussion on the importance of vitamin D in Parkinson's disease. Our results warrant further confirmatory research with a strict matching design of patients and controls, which has not been done in previous investigations. We stress that this case control study does not allow any comment on the putative beneficial effects of vitamin D supplementation, ie, on bone mass or bone mineral density, in patients with Parkinson's disease.

Complex motion series performance differs between previously untreated patients with Parkinson's disease and controls.

Motor behaviour in patients with Parkinson's disease is determined with instrumental tests and rating procedures. Results mirror impairment of an individual patient. Objectives were to determine the associations between two kinds of motion series and rating scores in previously untreated 64 patients and to compare outcomes to controls. The line tracing task asks to follow a given path. It measures the needed interval, the number and duration of contacts to the path. The aiming procedure asks to hit contact plates with a pencil and determines the needed time period and the number of accurate, respectively, missed key strokes. Both tests differed between patients and controls. The line tracing task was more sensitive. The line tracing task asks for a complex motion series performance with more cognitive load. The aiming task prompts for a conduction of preponderant simple, repetitive movement series. Only initially, a complex process of aiming is necessary. Performance of complex motion sequences better differs between patients with Parkinson's disease and controls than conduction of simple, repetitive movement series.

Kinesiology training in patients with Parkinson's disease: results of a pilot study.

Complementary therapies are an essential component of the treatment of patients with Parkinson's disease. They aim to ameliorate disease symptoms in conjunction with dopamine substitution. Kinesiology trains about the effective use of physical, mental and emotional skills. Objectives of this pilot study were to demonstrate the efficacy of a standardised kinesiology programme in 20 patients with Parkinson's disease. They were on a stable drug regimen during the whole trial. Ten patients received two kinesiology sessions per week over a 6-week lasting interval. The remaining ten patients were only followed over the same time period without any kinesiology training. We scored disease symptoms, tested cognition and assessed instrumental movement performance at baseline and study end. Kinesiology improved disease symptoms, cognitive abilities and execution of simple but not complex movement series. We show a certain value of a standardised kinesiology programme as adjunct, complementary therapeutic approach in patients with Parkinson's disease.

Evaluating ADS5102 (amantadine) for the treatment of Parkinson's disease patients with dyskinesia.

Introduction: Amantadine is an old, antiviral compound that moderately ameliorates impaired motor behaviour in Parkinson's disease. Its current resurgence results from the novel retarded release amantadine hydrochloride formulation, ADS5102, which has also received approval for the treatment of levodopa-related involuntary movements known as dyskinesia. Areas covered: This non-systematic, narrative drug evaluation discusses the value of ADS5102 for patients with Parkinson's disease. ADS5102 is orally applied once daily in the evening. This capsule provides higher and more continuous amantadine plasma concentrations than conventional amantadine immediate release formulations with their two to three times daily intake plan. Expert opinion: ADS5102 was superior to placebo in clinical trials. They aimed for the amelioration of motor complications, particularly at 'OFF' periods and with dyskinesia in fluctuating levodopa treated patients with Parkinson's disease. Side effects and tolerability were similar to the well-known effects of conventional amantadine formulations. ADS5102 simplifies treatment and improves compliance problems in the long run. The marketing of ADS5102 outside the US will be complex for return of research costs and investments required for its manufacturing. Indeed, worldwide institutional price regulation scenarios often only consider new therapeutic mode of actions as being innovative as opposed to old drugs with improved pharmacokinetic behaviour.

Basic science in Parkinson's disease: its impact on clinical practice.

Failures in clinical studies that were aimed to prove disease-modifying effects of treatments in Parkinson's disease (PD) raise the question as to whether basic sciences have had an impact in clinical practice. This question implies that despite well-publicized results obtained by intensive genetic and pathogenetic research, e.g. the identification of mutations and cellular biochemical pathways that underlie Parkinson-specific neurodegeneration, no relevant disease-modifying treatment options have been developed. This view neglects the fact that today there are plenty of dopaminergic and non-dopaminergic and surgical treatment options, and that PD was not treatable 50 years ago. This progress was made possible only by basic science. In this review, we underline the success of previous basic science for daily practice in PD and its impact for the understanding and development of an early diagnosis. Early, even pre-symptomatic diagnosis might be key to successfully establish disease-modifying treatments.

No increased chromosomal damage in L-DOPA-treated patients with Parkinson's disease: a pilot study.

Parkinson's disease (PD) is a neurodegenerative movement disorder affecting about 2% of the human population in old age. L-3,4-Dihydroxyphenylalanine (L-DOPA) in combination with a peripheral aromatic amino acid decarboxylase inhibition has been the most frequently prescribed drug for alleviating symptoms of PD, but a potential contribution of L-DOPA therapy to further neurodegeneration via oxidative stress is still debated. We report that the specific oxidative stress biomarker 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) level in peripheral blood lymphocyte DNA was elevated to 8.1 +/- 1.7 8-oxodG/10(6)dG in 17 chronically L-DOPA-treated PD patients, compared to 4.6 +/- 1.2 8-oxodG/10(6)dG in 12 controls. However, the total antioxidative capacity of plasma was increased to 1113 +/- 237 microM in the PD patients compared to 941 +/- 254 microM in controls. The frequency of micronuclei, a subgroup of chromosomal aberrations, in peripheral blood lymphocytes was not elevated compared to healthy age-matched individuals. In vitro, in a cell-free assay, dopamine and its precursor L-DOPA exhibited antioxidative capacity. On the other hand, the 8-oxodG concentration in cultured PC 12 cells was enhanced after dopamine treatment. This elevation may be below a threshold for manifestation as chromosomal damage.

Homocysteine levels after acute levodopa intake in patients with Parkinson's disease.

Levodopa (L-dopa) administered with a dopadecarboxylase inhibitor (DDI) increases homocysteine plasma levels. This may support the onset of atherosclerosis-related disorders and neuropsychiatric complications in patients with Parkinson's disease (PD). This homocysteine elevation is considered as long-term effect of chronic L-dopa/DDI treatment. Little is known about the acute effects of L-dopa/DDI intake on homocysteine generation. The objective of this trial was to investigate the relations between L-dopa and homocysteine after acute L-dopa/DDI administration in PD patients with different L-dopa metabolism. Thirty PD patients were divided into groups with superior (I) and less (II) L-dopa absorption after standardized intake of 125 mg L-dopa/benserazide with determination of L-dopa, 3-O-methyl-dopa (3-OMD) and homocysteine in plasma at baseline, 30, 60, and 90 minutes. There was a homocysteine increase in Group I (F = 5; P = 0.005) and a moderate decrease in Group II (F = 4.27; P = 0.01). A rise of 3-OMD (F = 10.51; P < 0.0001) appeared in Group I, but not in Group II (F = 0.91; P = 0.44), accordingly L-dopa accumulation was better in Group I than in Group II. Thus, in conclusion, L-dopa metabolism is an important component for homocysteine elevation after one time L-dopa/DDI administration in PD patients.

Cysteine elevation in levodopa-treated patients with Parkinson's disease.

Homocysteine, cysteine, and cysteinyl-glycine are all metabolically interrelated. Levodopa/decarboxylase inhibitor (LD/DCI) administration increases total homocysteine (tHcy) plasma levels. Objectives were to investigate associations between LD/DCI intake, concentrations of tHcy, cysteine, and cysteinyl-glycine in PD patients and healthy controls. Cysteine levels were significant lower in controls and PD patients with tHcy below the treshold of 15 [micromol/L] when compared with PD patients with tHcy above 15. Cysteinyl-glycine did not significantly differ between the three cohorts. Significant associations appeared between tHcys and cysteine in PD patients. tHcy and cysteine concentrations correlated to LD/DCI intake and severity of PD. The cysteine increase may be due to the significant higher dosing of daily LD/DCI and the significant higher morning LD/DCI dose 1 hour before blood sampling in PD patients with tHcy above 15 when compared with the remaining PD patients and the controls. The correlation outcomes support the view that LD/DCI intake may also increase cysteine.

Lewy body dementia and Parkinson's disease with dementia.

Parkinson's disease (PD) is characterized by its motor impairment. However, non-motor symptoms such as psychiatric disorders, autonomic disturbances and sleep disorders frequently complicate the course of the disease. In particular, psychiatric disturbances including cognitive impairment, depression and psychosis impact these patients considerably. Approximately 31 % of PD patients suffer from cognitive impairment and dementia. Currently, two different clinical presentations are distinguished in PD patients, who present with dementia: Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB), which are two different presentations of a single underlying disease process leading to the deposition of alpha-synuclein. Clinically, PDD is distinguished from DLB alone by the different temporal manifestations of extrapyramidal motor symptoms. Dementia is characterized by a subtle onset and progressive cognitive decline with a predominant dysexecutive syndrome, which can be accompanied by different behavioral symptoms such as hallucinations, depression, anxiety and sleep disorders. Dysregulation of different neurotransmitters has been associated with cognitive decline, but reduced cholinergic transmission is currently thought to be the pivotal mechanism in the development of cognitive dysfunction. Therefore, cholinesterase inhibitors are used in the treatment of dementia and accompanying behavioral symptoms in PDD and DLB. The occurrence of dementia impacts not only the patients themselves but also their care-givers and family.This article focuses on the clinical issues related to both disorders and is based on a meeting of experts which took place in April 2008 in Dresden.

Neurodegeneration and motor dysfunction in a conditional model of Parkinson's disease.

Alpha-synuclein (alpha-syn) has been implicated in the pathogenesis of many neurodegenerative disorders, including Parkinson's disease. These disorders are characterized by various neurological and psychiatric symptoms based on progressive neuropathological alterations. Whether the neurodegenerative process might be halted or even reversed is presently unknown. Therefore, conditional mouse models are powerful tools to analyze the relationship between transgene expression and progression of the disease. To explore whether alpha-syn solely originates and further incites these alterations, we generated conditional mouse models by using the tet-regulatable system. Mice expressing high levels of human wild-type alpha-syn in midbrain and forebrain regions developed nigral and hippocampal neuropathology, including reduced neurogenesis and neurodegeneration in absence of fibrillary inclusions, leading to cognitive impairment and progressive motor decline. Turning off transgene expression in symptomatic mice halted progression but did not reverse the symptoms. Thus, our data suggest that approaches targeting alpha-syn-induced pathological pathways might be of benefit rather in early disease stages. Furthermore, alpha-syn-associated cytotoxicity is independent of filamentous inclusion body formation in our conditional mouse model.

Randomized, double-blind, placebo-controlled trial on symptomatic effects of coenzyme Q(10) in Parkinson disease.

BACKGROUND: Major hallmarks in the pathophysiology of Parkinson disease are cellular energy depletion and oxidative stress leading to cellular dysfunction and death. Coenzyme Q(10) (CoQ(10)) is an electron acceptor bridging mitochondrial complexes I and II/III and a potent antioxidant that consistently partially recovers the function of dopaminergic neurons. OBJECTIVE: To determine whether nanoparticular CoQ(10) is safe and displays symptomatic effects in patients with midstage Parkinson disease without motor fluctuations. DESIGN: Multicenter, randomized, double-blind, placebo-controlled, stratified, parallel-group, single-dose trial. SETTING: Academic and nonacademic movement disorder clinics. PATIENTS: One hundred thirty-one patients with Parkinson disease without motor fluctuations and a stable antiparkinsonian treatment. Intervention Random assignment to placebo or nanoparticular CoQ(10) (100 mg 3 times a day) for a treatment period of 3 months. Stratification criterion was levodopa treatment. MAIN OUTCOME MEASURE: The subjects underwent evaluation with the Unified Parkinson's Disease Rating Scale (UPDRS) at each visit on a monthly basis. The primary outcome variable was the change of the sum score of the UPDRS parts II and III between the baseline and 3-month visits. RESULTS: One hundred thirty-one subjects were randomized according to the protocol. The mean changes of the sum UPDRS parts II/III score were -3.69 for the placebo group and -3.33 for the CoQ(10) group (P = .82). Statistical analysis according to the stratification did not result in significant changes of the primary outcome variable. No secondary outcome measure showed a significant change between the placebo group and the CoQ(10) group. The frequency and quality of adverse events were similar in both treatment groups. CONCLUSIONS: Nanoparticular CoQ(10) at a dosage of 300 mg/d is safe and well tolerated and leads to plasma levels similar to 1200 mg/d of standard formulations. Add-on CoQ(10) does not display symptomatic effects in midstage Parkinson disease.

Tolcapone decreases plasma levels of S-adenosyl-L-homocysteine and homocysteine in treated Parkinson's disease patients.

BACKGROUND: Elevated plasma total homocysteine (tHcy) appeared in levodopa/dopadecarcoxylase inhibitor (DDI) treated patients with Parkinson's disease (PD). One therapeutic approach for tHcy reduction is vitamine supplementation, since folic acid and cobalamine catalyse and enhance metabolism of tHcy to methionine. A further therapeutic alternative is inhibition of catechol-O-methyltransfrase (COMT) on a regular basis, when levodopa/DDI treatment is performed. METHODS: We measured the concentrations of S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), tHcy, levodopa and 3-O-methyldopa in plasma of 13 levodopa treated PD patients before first drug intake at 0600 hours. Blood samples were taken before and after 2 days of additional application of the centrally acting catechol-O-methyltransferase inhibitor tolcapone 100 mg t.i.d. RESULTS: Plasma levels of SAH [day 1: 48.32+/-22.52, 23.92-98.25 (mean+/-SD, range; micromol/l); day 3: 37.72+/-15.84, 23.4-61.89; p = 0.01] and tHcy (day 1: 13.88+/-5.62, 7.63-24.81; day 3: 11.38+/-4.44, 5.98-20.45; p = 0.04) significantly reduced. Plasma levels of levodopa did not significantly (p = 0.17) increase, whereas 3-OMD concentrations significantly (p = 0.0002) reduced after additional tolcapone intake. There was no significant change of SAM plasma levels (p = 0.22). CONCLUSION: Our prospective trial shows, that COMT inhibition with tolcapone lowers tHcy synthesis. Tolcapone may also possess beside its proven, occasional, hepatotoxic potency also beneficial effects via decrease of SAH and tHcy. This may hypothetically reduce homocysteine mediated progress of neuronal degeneration and the risk for onset of dementia, vascular disease and polyneuropathy in levodopa treated PD patients in the long term.

Levodopa intake increases plasma levels of S-adenosylmethionine in treated patients with Parkinson disease.

Metabolism of levodopa via the enzyme catechol-O-methyltransferase requires S-adenosylmethionine (SAM) as a methyl donor. SAM caused Parkinson disease (PD)-like symptoms in rodents. Therefore, SAM could contribute to a decreased efficacy of levodopa in the long term. SAM levels were significantly reduced in levodopa-treated PD patients, but they showed increased enzyme methionine adenosyl transferase (MAT) activity, which induces SAM synthesis from methionine (MET). This may result from a rebound increase of SAM production. The objective of the study was to demonstrate an effect of acute levodopa intake on SAM synthesis in the plasma of treated PD patients. The authors measured SAM, MET, and levodopa plasma concentrations in 13 levodopa-treated PD patients before and after application of 125 mg levodopa/benserazide. Plasma levels of SAM and levodopa significantly increased, but MET concentrations did not significantly decrease. The SAM increase after levodopa intake may exert both a certain antidepressant and cognitive function improving effect. This is often observed in untreated PD patients who receive levodopa for the first time, or in more advanced, fluctuating PD patients, when they turn from the OFF to the ON phase. Because SAM in higher dosages may also counteract the antiparkinsonian efficacy of levodopa according to animal trials, this SAM increase may hypothetically contribute to the onset of wearing-off phenomena and other clinical signs of limited efficacy of levodopa during long-term treatment with levodopa in PD patients.

Levodopa-associated increase of homocysteine levels and sural axonal neurodegeneration.

BACKGROUND: Levodopa metabolism via catechol O-methyltransferase increases levels of the neurotoxin homocysteine, which induces an axonal-accentuated degeneration in sensory peripheral nerves in vitro. OBJECTIVES: To demonstrate associations among daily levodopa/dopa decarboxylase inhibitor intake, total homocysteine plasma (tHcy) levels, and electrophysiologic sural nerve conduction findings. DESIGN: We performed bilateral assessment of sensory nerve conduction velocity and sensory nerve action potentials and determined tHcy levels. PATIENTS: Thirty-one levodopa-treated patients with Parkinson disease (PD) and 27 control subjects. RESULTS: Sensory nerve action potentials significantly (P<.001) differed between PD patients and controls. No differences between sensory nerve conduction velocities of PD patients and controls appeared. We found significant differences in sensory nerve action potentials be-tween PD patients with significantly elevated tHcy levels and controls (P<.001), PD patients with tHcy levels within the reference range and those with elevated levels (P =.001), and PD patients with tHcy levels levels within the reference range and and controls (P =.04). Our sensory nerve conduction velocity results showed no significant differences. There were significant associations between tHcy levels and sensory nerve action potentials (R = -0.52; P =.002) and and sensory nerve conduction velocity (R = -0.47; P =.008). Daily levodopa/dopa decarboxylase inhibitor intake was significantly related to tHcy levels (R = 0.43; P =.02). CONCLUSIONS: This electrophysiological sign of peripheral neuronal dysfunction may be circumstantial evidence suggesting that, to a certain extent, sensory nerve action potentials are a surrogate marker for the levodopa metabolism-induced elevation of homocysteine levels and the aggravation of the ongoing central neurodegenerative process.

Hyperhomocysteinaemia in treated patients with Huntington's disease homocysteine in HD.

Significantly increased plasma total homocysteine levels (t-Hcys) appeared in treated Huntington disease (HD) patients compared to controls and untreated HD subjects. Because the protein Huntingtin interacts with the homocysteine metabolism modulating enzyme cystathionine beta-synthase, we hypothesize that homocysteine promotes neurodegeneration in HD.