Annonaceae Consumption Worsens Disease Severity and Cognitive Deficits in Degenerative Parkinsonism.

BACKGROUND: High consumption of Annona muricata fruit has been previously identified as a risk factor for atypical parkinsonism in the French Caribbean islands. OBJECTIVE: We tested whether consumption of Annonaceae products could worsen the clinical phenotype of patients with any form of degenerative parkinsonism. METHODS: We analyzed neurological data from 180 Caribbean parkinsonian patients and specifically looked for dose effects of lifelong, cumulative Annonaceae consumption on cognitive performance. Using unsupervised clustering, we identified one cluster with mild/moderate symptoms (N = 102) and one with severe symptoms including cognitive impairment (N = 78). RESULTS: We showed that even low cumulative consumption of fruits/juices (>0.2 fruit-years) or any consumption of herbal tea from Annonaceae worsen disease severity and cognitive deficits in degenerative parkinsonism including Parkinson's disease (OR fruits-juices: 3.76 [95% CI: 1.13-15.18]; OR herbal tea: 2.91 [95% CI: 1.34-6.56]). CONCLUSION: We suggest that more restrictive public health preventive recommendations should be made regarding the consumption of Annonaceae products. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The Beneficial Effect of Rice Bran Extract Against Rotenone-Induced Experimental Parkinson's Disease in Rats.

BACKGROUND: Neurodegenerative diseases have become an increasing cause of various disabilities worldwide, followed by aging, including Parkinson's disease (PD). Parkinson's disease is a degenerative brain disorder distinguished by growing motor & non-motor failure due to the degeneration of medium-sized spiked neurons in the striatum region. Rotenone is often employed to originate the animal model of PD. It is a powerful blocker of mitochondrial complex-I, mitochondrial electron transport chain that reliably produces Parkinsonism-like symptoms in rats. Rice bran (RB) is very rich in polyunsaturated fatty acids (PUFA) and nutritionally beneficial compounds, such as γ-oryzanol, tocopherols, and tocotrienols and sterols are believed to have favorable outcomes on oxidative stress & mitochondrial function. OBJECTIVE: The present study has been designed to explore RB extract's effect against rotenone-induced neurotoxicity in rats. METHODS: In the present study, Rotenone (2 mg/kg, s.c) was administered systemically for 28 days. The hexane extract of RB was prepared using Soxhlation. Hexane extract (250 & 500 mg/kg) was administered per oral for 28 days in rotenone-treated groups. Behavioral parameters (grip strength, motor coordination, locomotion, and catalepsy) were conducted on the 7th, 14th, 21st, and 28th day. Animals were sacrificed on the 29th day for biochemical estimation in the striatum and cortex. RESULTS: This study demonstrates significant alteration in behavioral parameters, oxidative burden (increased lipid peroxidation, nitrite concentration, and decreased glutathione, catalase, SOD) in rotenone-treated animals. Administration of hexane extract of RB prevented the behavioral, biochemical alterations induced by rotenone. The current research has been sketched to inspect RB extract's effect against rotenone-developed neurotoxicity in rats. CONCLUSION: The findings support that PD is associated with impairments in motor activity. The results also suggest that the nutraceutical rice bran that contains γ-oryzanol, Vitamin-E, ferulic acid etc., may underlie the adjuvant susceptibility towards rotenone-induced PD in experimental rats.

Food toxins and the Caribbean Parkinson plus types.

In the 90's, clinico pathological studies have considerably improved the diagnosis of specific and rare neurodegenerative diseases. After a training in Parkinsons' disease in Paris, the author moved to French West Indies (Guadeloupe) and observed a high incidence of atypical parkinsonism with dementia, unresponsive to levodopa. Similar features were observed in Martinique. An environmental origin has been suspected with the exposure to toxins of annonaceae leaves and seeds. The candidate toxins are acetogenins acting as mitochondrial poison. This was demonstrated in neuronal cell cultures, and in animals. However, the agency for food security did not conclude that Annonaceae should not be used for herbal (medicinal) tea, even if the population is now aware about the possible risk of parkinsonism after exposure to annonaceae acetogenins.

Inhibition of Parkinsonian tremor with cutaneous afferent evoked by transcutaneous electrical nerve stimulation.

BACKGROUND: Recent study suggests that tremor signals are transmitted by way of multi-synaptic corticospinal pathway. Neurophysiological studies have also demonstrated that cutaneous afferents exert potent inhibition to descending motor commands by way of spinal interneurons. We hypothesize in this study that cutaneous afferents could also affect the transmission of tremor signals, thus, inhibit tremor in patients with PD. METHODS: We tested this hypothesis by activating cutaneous afferents in the dorsal hand skin innervated by superficial radial nerve using transcutaneous electrical nerve stimulation (TENS). Eight patients with PD having tremor dominant symptom were recruited to participate in this study using a consistent experimental protocol for tremor inhibition. Resting tremor and electromyogram (EMG) of muscles in the upper extremity of these subjects with PD were recorded, while surface stimulation was applied to the dorsal skin of the hand. Fifteen seconds of data were recorded for 5 s prior to, during and post stimulation. Power spectrum densities (PSDs) of tremor and EMG signals were computed for each data segment. The peak values of PSDs in three data segments were compared to detect evidence of tremor inhibition. RESULTS: At stimulation intensity from 1.5 to 1.75 times of radiating sensation threshold, apparent suppressions of tremor at wrist, forearm and upper arm and in the EMGs were observed immediately at the onset of stimulation. After termination of stimulation, tremor and rhythmic EMG bursts reemerged gradually. Statistical analysis of peak spectral amplitudes showed a significant difference in joint tremors and EMGs during and prior to stimulation in all 8 subjects with PD. The average percentage of suppression was 61.56% in tremor across all joints of all subjects, and 47.97% in EMG of all muscles. The suppression appeared to occur mainly in distal joints and muscles. There was a slight, but inconsistent effect on tremor frequency in the 8 patients with PD tested. CONCLUSIONS: Our results provide direct evidence that tremor in the upper extremity of patients with PD can be inhibited to a large extent with evoked cutaneous reflexes via surface stimulation of the dorsal hand skin area innervated by the superficial radial nerve.

Effects of gypenosides on anxiety disorders in MPTP-lesioned mouse model of Parkinson's disease.

Ethanol extract (GP-EX) of Gynostemma pentaphyllum (GP) ameliorates chronic stress-induced anxiety in mice. The present study investigated the effects of gypenoside-enriched components (GPS), GP-EX and water extract of GP (GP-WX) on MPTP lesion-induced affective disorders in C57BL/6 mice. GPS (50mg/kg) and GP-EX (50mg/kg) for 21 day-treatment period improved the symptom of anxiety disorders in the MPTP-lesioned mouse model of PD with or without L-DOPA treatment, which was examined by the elevated plus-maze and marble burying tests. In these states, treatments with GPS (50mg/kg) and GP-EX (50mg/kg) significantly increased the brain levels of dopamine and serotonin in the MPTP-lesioned mouse model of PD with or without l-DOPA treatment. In addition, treatments with GPS (50mg/kg) and GP-EX (50mg/kg) showed protective effects on dopaminergic neurons in MPTP-lesioned mouse model of PD with or without L-DOPA treatment. In contrast, GPS (30 mg/kg) and GP-WX (50mg/kg) showed anxiolytic effects in the same animal models, but it was not significant. These results suggest that GPS (50mg/kg) and GP-EX (50mg/kg) showed anxiolytic effects on affective disorders and protective effects on dopaminergic neurons by modulating the brain levels of dopamine and serotonin in the MPTP-lesioned mouse model of PD with or without l-DOPA treatment. Clinical trials of GPS and GP-EX need to be conducted further so as to develop adjuvant therapeutic agents for PD patients.

Nobiletin treatment improves motor and cognitive deficits seen in MPTP-induced Parkinson model mice.

Nobiletin, a polymethoxylated flavonoid found in citrus fruit peel, reportedly improves memory impairment in rodent models. Here we report its effect on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced motor and cognitive deficits. Nobiletin administration (50mg/kg i.p.) for 2 consecutive weeks improved motor deficits seen in MPTP-induced Parkinson model mice by 2weeks, an effect that continued until 2weeks after drug withdrawal. Drug treatment promoted similar rescue of MPTP-induced cognitive impairment at equivalent time points. Nonetheless, nobiletin treatment did not block loss of dopaminergic neurons seen in the MPTP-treated mouse midbrain, nor did it rescue decreased tyrosine hydroxylase (TH) protein levels seen in the striatum or hippocampal CA1 region of these mice. Interestingly, nobiletin administration (50mg/kg i.p.) rescued reduced levels of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation and phosphorylation at Thr-34 of dopamine- and cAMP-regulated phosphoprotein-32 (DARPP-32) in striatum and hippocampal CA1 to levels seen in sham-operated mice. Likewise, CaMKII- and cAMP kinase-dependent TH phosphorylation was significantly restored by nobiletin treatment. MPTP-induced reduction of dopamine contents in the striatum and hippocampal CA1 region was improved by nobiletin administration (50mg/kg i.p.). Acute intraperitoneal administration of nobiletin also enhanced dopamine release in striatum and hippocampal CA1, an effect partially inhibited by treatment with nifedipine (a L-type Ca(2+) channel inhibitor) or NNC 55-0396 (a T-type Ca(2+) channel inhibitor) and completely abolished by combined treatment with both. Overall, our study describes a novel nobiletin activity in brain and suggests that nobiletin rescues motor and cognitive dysfunction in MPTP-induced Parkinson model mice, in part by enhancing dopamine release.

Skin discolouration with acute onset parkinsonism secondary to systemic zirconium intoxication.

A 72-year-old woman presented with suspected parkinsonism and discolouration of the skin especially on sun-exposed areas. Thorough investigation revealed systemic zirconium intoxication due to intake of metallic colloids as a home remedy as a cause of the skin colour change. There may be an association between skin discolouration and her parkinsonism. This is unique in that various clinical manifestations developed following systemic ingestion of zirconium and this should serve as a warning on the risk of taking illicit dietary supplements.

The habenula couples the dopaminergic and the serotonergic systems: application to depression in Parkinson's disease.

A high percentage of patients with Parkinson's disease suffer from depression in addition to their motor disabilities. However, the etiology of this depression and its relation to Parkinson's disease are unknown. Within the framework of the monoamine deficiency hypothesis of depression, we propose that the dopaminergic and serotonergic systems are coupled by the lateral habenula, and argue that altered basal ganglia activity leads to lateral habenula hyperactivity, which in turn down-regulates the serotonergic system, resulting in depressive symptoms in patients with Parkinson's disease. We tested this hypothesis using the unilateral 6-hydroxydopamine hemiparkinsonian rat model of Parkinson's disease. Behavior was assessed using the novelty suppressed feeding and forced swim tests, and the effective connectivity of the serotonergic system was estimated by manganese-enhanced magnetic resonance imaging of the raphe nuclei. The results show depression-like behaviors and reduced raphe connectivity with the lateral habenula, dentate gyrus of the hippocampus, thalamus and hypothalamus in the 6-hydroxydopamine rat groups. More importantly, partial restoration of the raphe connectivity and partial normalization of behavior were achieved by dopamine replacement therapy (apomorphine, 10 mg/kg, s.c. daily). Furthermore, nearly complete behavioral normalization was reached after a bilateral electric lesion of the lateral habenula. These findings provide a plausible link between Parkinson's disease and depression and open up avenues for new therapeutic interventions in depression and possibly in Parkinson's disease.

Imaging gait disorders in parkinsonism: a review.

Gait difficulties--including freezing of gait--are frequent and disabling symptoms of advanced Parkinson's disease and other parkinsonian syndromes. They respond poorly to current medical and surgical treatments, making patient management very difficult. The underlying pathophysiology remains largely unknown. The late onset of levodopa resistance of Parkinson's disease gait abnormalities has been suggested to result from the progressive extension of the degenerative process to non-dopaminergic structures involved in locomotion, such as cortico-frontal and brainstem networks. Deficiencies in other neurotransmission systems, involving acetylcholine, serotonin or norepinephrine, have also been evoked. Neuroimaging tools appear well suited to decipher the cerebral substrates of parkinsonian gait disorders and their modulation by dopaminergic medication or deep brain stimulation. Here the main functional and metabolic neuroimaging studies aimed at identifying these cerebral networks are reviewed, in both healthy subjects and parkinsonian patients. After a brief overview of the physiology and pathophysiology of gait control, the methodology, main results and limits of the studies published to date are examined. The most promising methods to examine gait difficulties and their response to currently available treatments are then discussed.

Hypothalamic abnormalities and Parkinsonism associated with H1N1 influenza infection.

OBJECTIVE: To describe a case of a young adult with severe H1N1 influenza illness associated with hypothalamic abnormalities and post-influenza parkinsonism. DESIGN: Case report. PATIENT: A 22-year-old woman with H1N1 influenza infection developed encephalopathy followed by diverse hypothalamic dysfunction manifestations, sleeplessness, and persistent parkinsonian features. RESULTS: CSF analysis, brain imaging and EEG ruled out hypoxic brain injury or other illnesses. CONCLUSIONS: A number of viruses have been associated with both acute and chronic parkinsonism. A link between parkinsonism and influenza viruses is somewhat controversial. This is the first reported case of parkinsonism following an H1N1 influenza infection.

Perry syndrome due to the DCTN1 G71R mutation: a distinctive levodopa responsive disorder with behavioral syndrome, vertical gaze palsy, and respiratory failure.

Perry syndrome is a rare form of autosomal dominant Parkinsonism with respiratory failure recently defined as being due to mutations in the DCTN1 gene. We describe a new family carrying a G71R mutation in the DCTN1 gene. The proband displayed a series of distinctive features not previously described in Perry syndrome: a disorder of vertical downward saccades accompanied by progressive midbrain atrophy, predominant nonmotor symptoms responsive to levodopa, distinctive craniocervical levodopa induced dyskinesias, and a good response to high-dose levodopa therapy and respiratory support. The family was initially thought to have autosomal dominant behavioral variant frontotemporal dementia with Parkinsonism. This report expands the clinical definition of this distinctive syndrome.

Frequency-velocity mismatch: a fundamental abnormality in parkinsonian gait.

Gait dysfunction and falling are major sources of disability for patients with advanced Parkinson's disease (PD). It is presently thought that the fundamental defect is an inability to generate normal stride length. Our data suggest, however, that the basic problem in PD gait is an impaired ability to match step frequency to walking velocity. In this study, foot movements of PD and normal subjects were monitored with an OPTOTRAK motion-detection system while they walked on a treadmill at different velocities. PD subjects were also paced with auditory stimuli at different frequencies. PD gait was characterized by step frequencies that were faster and stride lengths that were shorter than those of normal controls. At low walking velocities, PD stepping had a reduced or absent terminal toe lift, which truncated swing phases, producing shortened steps. Auditory pacing was not able to normalize step frequency at these lower velocities. Peak forward toe velocities increased with walking velocity and PD subjects could initiate appropriate foot dynamics during initial phases of the swing. They could not control the foot appropriately in terminal phases, however. Increased treadmill velocity, which matched the natural PD step frequency, generated a second toe lift, normalizing step size. Levodopa increased the bandwidth of step frequencies, but was not as effective as increases in walking velocity in normalizing gait. We postulate that the inability to control step frequency and adjust swing phase dynamics to slower walking velocities are major causes for the gait impairment in PD.

Successful treatment with Yokukansan for behavioral and psychological symptoms of Parkinsonian dementia.

OBJECTIVE: To evaluate the efficacy and safety of Yokukansan, a traditional Chinese herbal medicine, for treating behavioral and psychological symptoms of dementia (BPSD) in patients with Parkinson disease (PD; n=7) and those with PD with dementia (PDD; n=7). BACKGROUND: BPSD are often seen in patients with senile dementia and have serious deleterious effects on the lives of patients and caregivers. Recent studies indicate that the traditional Chinese herbal medicine Yokukansan may be safe and beneficial for the treatment of BPSD patients. METHODS: We treated 7 PD and 7 PDD patients for 4 weeks with Yokukansan and observed them without Yokukansan for 4 weeks. Changes in behavioral and psychological symptoms were evaluated every 4 weeks according to the Neuropsychiatric Inventory (NPI) scale. RESULTS: Significant improvements in behavioral and psychological symptoms, particularly in the incidence and duration of hallucinations, were observed in most PD and PDD patients after 4 weeks of Yokukansan treatment. No significant changes were observed in the laboratory tests, cognitive function, activities of daily living, or parkinsonism. CONCLUSION: Our results suggest that Yokukansan improves BPSD in both PD and PDD patients without worsening their cognitive function, ability to perform activities of daily living, or parkinsonism.

Oral creatine supplementation attenuates L-DOPA-induced dyskinesia in 6-hydroxydopamine-lesioned rats.

L-DOPA-induced dyskinesia (LID) is among the motor complications that arise in Parkinson patients after a prolonged treatment with levodopa (L-DOPA). Since previous transcriptome and proteomic studies performed in the rat model of LID suggested important changes in striatal energy-related components, we hypothesize that oral creatine supplementation could prevent or attenuate the occurrence of LID. In this study, 6-hydroxydopamine-lesioned rats received a 2% creatine-supplemented diet for 1 month prior to L-DOPA therapy. During the 21 days of L-DOPA treatment, significant reductions in abnormal involuntary movements (AIMs) have been observed in the creatine-supplemented group, without any worsening of parkinsonism. In situ hybridization histochemistry and immunohistochemistry analysis of the striatum also showed a reduction in the levels of prodynorphin mRNA and FosB/DeltaFosB-immunopositive cells in creatine-supplemented diet group, an effect that was dependant on the development of AIMs. Further investigation of the bioenergetics' status of the denervated striatum revealed significant changes in the levels of creatine both after L-DOPA alone and with the supplemented diet. In conclusion, we demonstrated that combining L-DOPA therapy with a diet enriched in creatine could attenuate LID, which may represent a new way to control the motor complications associated with L-DOPA therapy.

Levodopa affects functional brain networks in Parkinsonian resting tremor.

Resting tremor in idiopathic Parkinson's disease (PD) is associated with an oscillatory network comprising cortical as well as subcortical brain areas. To shed light on the effect of levodopa on these network interactions, we investigated 10 patients with tremor-dominant PD and reanalyzed data in 11 healthy volunteers mimicking PD resting tremor. To this end, we recorded surface electromyograms of forearm muscles and neuromagnetic activity using a 122-channel whole-head magnetometer (MEG). Measurements were performed after overnight withdrawal of levodopa (OFF) and 30 min after oral application of fast-acting levodopa (ON). During OFF, patients showed the typical antagonistic resting tremor. Using the analysis tool Dynamic Imaging of Coherent Sources, we identified the oscillatory network associated with tremor comprising contralateral primary sensorimotor cortex (S1/M1), supplementary motor area (SMA), contralateral premotor cortex (PMC), thalamus, secondary somatosensory cortex (S2), posterior parietal cortex (PPC), and ipsilateral cerebellum oscillating at 8 to 10 Hz. After intake of levodopa, we found a significant decrease of cerebro-cerebral coupling between thalamus and motor cortical areas. Similarly, in healthy controls mimicking resting tremor, we found a significant decrease of functional interaction within a thalamus-premotor-motor network during rest. However, in patients with PD, decrease of functional interaction between thalamus and PMC was significantly stronger when compared with healthy controls. These data support the hypothesis that (1) in patients with PD the basal ganglia and motor cortical structures become more closely entrained and (2) levodopa is associated with normalization of the functional interaction between thalamus and motor cortical areas.

Mitochondrial function and morphology are impaired in parkin-mutant fibroblasts.

OBJECTIVE: There are marked mitochondrial abnormalities in parkin-knock-out Drosophila and other model systems. The aim of our study was to determine mitochondrial function and morphology in parkin-mutant patients. We also investigated whether pharmacological rescue of impaired mitochondrial function may be possible in parkin-mutant human tissue. METHODS: We used three sets of techniques, namely, biochemical measurements of mitochondrial function, quantitative morphology, and live cell imaging of functional connectivity to assess the mitochondrial respiratory chain, the outer shape and connectivity of the mitochondria, and their functional inner connectivity in fibroblasts from patients with homozygous or compound heterozygous parkin mutations. RESULTS: Parkin-mutant cells had lower mitochondrial complex I activity and complex I-linked adenosine triphosphate production, which correlated with a greater degree of mitochondrial branching, suggesting that the functional and morphological effects of parkin are related. Knockdown of parkin in control fibroblasts confirmed that parkin deficiency is sufficient to explain these mitochondrial effects. In contrast, 50% knockdown of parkin, mimicking haploinsufficiency in human patient tissue, did not result in impaired mitochondrial function or morphology. Fluorescence recovery after photobleaching assays demonstrated a lower level of functional connectivity of the mitochondrial matrix, which further worsened after rotenone exposure. Treatment with experimental neuroprotective compounds resulted in a rescue of the mitochondrial membrane potential. INTERPRETATION: Our study demonstrates marked abnormalities of mitochondrial function and morphology in parkin-mutant patients and provides proof-of-principle data for the potential usefulness of this new model system as a tool to screen for disease-modifying compounds in genetically homogenous parkinsonian disorders.

Sporadic rapid-onset dystonia-parkinsonism syndrome: failure of bilateral pallidal stimulation.

We report on a woman who had a severe sporadic nonprogressive dystonia-parkinsonism syndrome with rapid onset of symptoms at age 21. Secondary causes for dystonia were ruled out. No response to levodopa/carbidopa was seen. The patient fulfilled all diagnostic criteria of rapid-onset dystonia-parkinsonism, except for autosomal-dominant inheritance. Bilateral deep brain stimulation of the globus pallidus failed to alleviate her symptoms.