Over the past few decades, abnormalities in sensory functions, such as tactile, proprioceptive and nociceptive processing, have been increasingly recognized in patients with focal dystonias. In this ...Review, we ask whether sensory system abnormalities are specific to particular types of dystonia, whether a causal link exists between sensory alterations and dystonic motor activity and how mechanisms underlying the sensory abnormalities fit in with the proposed 'network model' of dystonia. We suggest that alterations in the various sensory modalities participate at three different levels in the pathophysiological cascade that leads to dystonia: a background level that predisposes individuals to dystonia, a disease-related level that is evident only when dystonia becomes manifest and a causative level that triggers dystonia. We conclude that it is crucial to study sensory as well as motor pathophysiology to fully understand focal dystonias.
Parkinson's disease (PD) is a neurodegenerative disorder whose pathogenesis depends on a combination of genetic and environmental factors. The aim of the present review was to provide an updated ...description of the findings emerging from prospective longitudinal cohort studies on the possible risk/protective factors underlying the development, progression and clinical subtypes of PD. We reviewed all the environmental, lifestyle, dietary, comorbid and pharmacological factors that have been investigated as possible modifiable protective/risk factors for PD by longitudinal studies. Only a few factors have the epidemiological evidence and the biological plausibility to be considered risk (pesticides, dairy products, β2-adrenoreceptor antagonists) or protective (smoking, caffeine and tea intake, physical activity, gout, vitamin E intake, non-steroidal anti-inflammatory drugs and β2-adrenoreceptor agonists) factors for PD. Caffeine intake and physical activity also seem to slow down the progression of the disease, thus representing good candidates for primary prevention and disease modifying strategies in PD. Possible modifiable risk factors of PD subtypes is almost unknown and this might depend on the uncertain biological and neuropathological reliability of clinical subtypes. The results of the present review suggest that only eleven risk/protective factors may be associated with the risk of PD. It may be possible to target some of these factors for preventive interventions aimed at reducing the risk of developing and the rate of progression of PD.
•Eleven risk/protective factors may affect Parkinson's disease development.•Caffeine and physical activity may improve Parkinson's disease progression.•Risk factors for Parkinson's disease subtypes are unknown.
Abstract Parkinson's disease is a neurodegenerative disease that causes the death of dopaminergic neurons in the substantia nigra. The resulting dopamine deficiency in the basal ganglia leads to a ...movement disorder that is characterized by classical parkinsonian motor symptoms. Parkinson's disease is recognized as the most common neurodegenerative disorder after Alzheimer's disease. PD ethiopathogenesis remains to be elucidated and has been connected to genetic, environmental and immunologic conditions. The past decade has provided evidence for a significant role of the immune system in PD pathogenesis, either through inflammation or an autoimmune response. Several autoantibodies directed at antigens associated with PD pathogenesis have been identified in PD patients. This immune activation may be the cause of, rather than a response to, the observed neuronal loss. Parkinsonian motor symptoms include bradykinesia, muscular rigidity and resting tremor. The non-motor features include olfactory dysfunction, cognitive impairment, psychiatric symptoms and autonomic dysfunction. Microscopically, the specific degeneration of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies, which are brain deposits containing a substantial amount of α-synuclein, have been recognized. The progression of Parkinson's disease is characterized by a worsening of motor features; however, as the disease progresses, there is an emergence of complications related to long-term symptomatic treatment. The available therapies for Parkinson's disease only treat the symptoms of the disease. A major goal of Parkinson's disease research is the development of disease-modifying drugs that slow or stop the neurodegenerative process. Drugs that enhance the intracerebral dopamine concentrations or stimulate dopamine receptors remain the mainstay treatment for motor symptoms. Immunomodulatory therapeutic strategies aiming to attenuate PD neurodegeneration have become an attractive option and warrant further investigation.
In Parkinson's disease (PD), alpha-synuclein (a-syn) can be detected in biological fluids including saliva. Although previous studies found reduced a-syn total (a-syntotal) concentration in saliva of ...PD patients, no studies have previously examined salivary a-syn oligomers (a-synolig) concentrations or assessed the correlation between salivary a-syntotal, a-synolig and clinical features in a large cohort of PD patients. Is well known that a-synolig exerts a crucial neurotoxic effect in PD. We collected salivary samples from 60 PD patients and 40 age- and sex-comparable healthy subjects. PD was diagnosed according to the United Kingdom Brain Bank Criteria. Samples of saliva were analyzed by specific anti-a-syn and anti-oligomeric a-syn ELISA kits. A complete clinical evaluation of each patient was performed using MDS-Unified Parkinson's Disease Rating Scale, Beck Depression Inventory, Montreal Cognitive Assessment and Frontal Assessment Battery. Salivary a-syntotal was lower, whereas a-synolig was higher in PD patients than healthy subjects. The a-synolig/a-syntotal ratio was also higher in patients than in healthy subjects. Salivary a-syntotal concentration negatively correlated with that of a-synolig and correlated with several patients' clinical features. In PD, decreased salivary concentration of a-syntotal may reflect the reduction of a-syn monomers (a-synmon), as well as the formation of insoluble intracellular inclusions and soluble oligomers. The combined detection of a-syntotal and a-synolig in the saliva might help the early diagnosis of PD.
Salivary caffeine in Parkinson's disease Leodori, Giorgio; De Bartolo, Maria Ilenia; Belvisi, Daniele ...
Scientific reports,
05/2021, Letnik:
11, Številka:
1
Journal Article
Recenzirano
Odprti dostop
We aimed to investigate salivary caffeine content, caffeine absorption and metabolism in Parkinson's disease (PD) and verify whether salivary caffeine can be used as a biomarker of PD. We enrolled 98 ...PD patients and 92 healthy subjects. Caffeine and its major metabolite, paraxanthine, were measured in saliva samples collected before and 4 h after the oral intake of caffeine (100 mg). We measured caffeine absorption as the normalized increase in caffeine levels, and caffeine metabolism as the paraxanthine/caffeine ratio. The Movement Disorder Society Unified Parkinson's Disease Rating Scale part III, the Hoehn & Yahr, the presence of motor complications, and levodopa equivalent dose (LED) were assessed and correlated with caffeine levels, absorption, and metabolism. The effects of demographic and environmental features possibly influencing caffeine levels were also investigated. Caffeine levels were decreased in patients with moderate/advanced PD, while caffeine levels were normal in patients with early and de-novo PD, unrelated to caffeine intake. Caffeine absorption and metabolism were normal in PD. Decreased salivary caffeine levels in PD were associated with higher disease severity, longer duration, and the presence of motor complications, no significant association was found with LED. Salivary caffeine decrease correlates with PD progression.
Patients with Parkinson's disease (PD) show impaired short-term potentiation (STP) mechanisms in the primary motor cortex (M1). However, the role played by this neurophysiological abnormality in ...bradykinesia pathophysiology is unknown. In this study, we used a multimodal neuromodulation approach to test whether defective STP contributes to bradykinesia. We evaluated STP by measuring motor-evoked potential facilitation during 5 Hz-repetitive transcranial magnetic stimulation (rTMS) and assessed repetitive finger tapping movements through kinematic techniques. Also, we used transcranial alternating current stimulation (tACS) to drive M1 oscillations and experimentally modulate bradykinesia. STP was assessed during tACS delivered at beta (β) and gamma (γ) frequency, and during sham-tACS. Data were compared to those recorded in a group of healthy subjects. In PD, we found that STP was impaired during sham- and γ-tACS, while it was restored during β-tACS. Importantly, the degree of STP impairment was associated with the severity of movement slowness and amplitude reduction. Moreover, β-tACS-related improvements in STP were linked to changes in movement slowness and intracortical GABA-A-ergic inhibition during stimulation, as assessed by short-interval intracortical inhibition (SICI). Patients with prominent STP amelioration had greater SICI reduction (cortical disinhibition) and less slowness worsening during β-tACS. Dopaminergic medications did not modify β-tACS effects. These data demonstrate that abnormal STP processes are involved in bradykinesia pathophysiology and return to normal levels when β oscillations increase. STP changes are likely mediated by modifications in GABA-A-ergic intracortical circuits and may represent a compensatory mechanism against β-induced bradykinesia in PD.
•Parkinson's disease patients demonstrated impaired short-term potentiation (STP).•The degree of STP impairment correlated with movement velocity and amplitude.•Beta-transcranial alternating current stimulation (tACS) restored STP in patients.•Beta-tACS-related improvements in STP were linked to changes in movement slowness.•Beta-tACS-related changes in STP were also related to GABAergic inhibitory activity.
Background
Frailty is an age-related state of increased risk for health-related adverse outcomes that reflects multisystem physiological changes and likely influences the clinical expression and ...disease progression of neurodegenerative disorders. The aim of the present study was to assess the potential relationship between frailty, as assessed by a frailty index (FI), and motor symptom severity, motor subtypes, and non-motor domains in Parkinson’s disease (PD).
Methods
We consecutively enrolled 150 PD patients. We administered an FI specifically designed for PD that included 50 age-related multidimensional biological deficits. Patients underwent a clinical assessment that evaluated motor and non-motor manifestations of PD. Using the FI score, we classified PD patients as relatively fit (FI ≤ 0.10), less fit (0.10 < FI ≤ 0.21), or frail (FI > 0.21). A linear regression model was designed to explore possible associations between frailty level and PD motor and non-motor manifestations.
Results
Frail patients showed greater motor symptom severity and motor complications than fitter patients. A trend towards a higher prevalence of the postural instability/gait disorder subtype was also observed in frail versus relatively fit and less fit patients. The global burden of non-motor symptoms was higher in frail patients. Increased frailty was associated with more severe motor and non-motor symptoms, as well as with more pronounced cognitive deficits. These associations remained significant even when “traditional” predictors of PD severity (age, disease duration, and levodopa equivalent daily dose) were considered.
Conclusions
The present findings indicate that the FI is associated with both motor and non-motor features of PD.
Animal models of Parkinson's Disease (PD) demonstrated increased facilitatory cortico-striatal activity, reflecting overactive glutamatergic neurotransmission and contributing to the pathophysiology ...of l-dopa induced dyskinesias (LIDs).
To assess different facilitatory intracortical circuits in the primary motor cortex (M1) in patients with PD and LIDs by means of a combination of transcranial magnetic stimulation (TMS) protocols.
We tested the Input/Output (I/O) curve, intracortical facilitation (ICF) and short-interval intracortical facilitation (SICF) at baseline (T0), ‘OFF’ and ‘ON’ state, in 20 PD patients with LIDs. The same parameters were examined after 2 weeks of chronic intake of 50 mg (T1) and 100 mg/day (T2) of safinamide. Finally, we tested SICF in a further group of patients without LIDs.
At T0, patients with LIDs showed increased I/O curve steepness, which was partly ameliorated by l-dopa. These patients also had normal ICF, and abnormally increased SICF, which did not change with l-dopa. Safinamide improved the I/O curve both at T1 and T2, it reduced SICF at T1 and normalized this measure at T2. In patients with PD and LIDs, SICF correlated with the severity of dyskinesia. In patients without LIDs, SICF was less prominently abnormal and responsive to l-dopa.
Patients with PD and LIDs have abnormal cortical facilitation, possibly suggesting overactive glutamatergic neurotransmission in specific circuits within M1. Although not responsive to l-dopa, this dysfunction is restored by the anti-glutamatergic properties of safinamide 100 mg. The results suggest that the abnormal cortical facilitation in M1 contributes to the pathophysiology of LIDs.
•PD patients with LIDs had an increased SICF, correlating with the severity of LIDs.•SICF was more altered in patients with LIDs than in patients without LIDs.•Safinamide modulated SICF and restored this measure at the dose of 100 mg/day.•Abnormal cortical facilitation in M1 may contribute to the pathophysiology of LIDs.
Levodopa-induced dyskinesias Fabbrini, Giovanni; Brotchie, Jonathan M.; Grandas, Francisco ...
Movement disorders,
30 July 2007, Letnik:
22, Številka:
10
Journal Article
Abnormal glutamatergic neurotransmission in the primary motor cortex (M1) contributes to Parkinson's disease (PD) pathophysiology and is related to l-dopa-induced dyskinesia (LID). We previously ...showed that short-term treatment with safinamide, a monoamine oxidase type-B inhibitor with anti-glutamatergic properties, improves abnormally enhanced short-interval intracortical facilitation (SICF) in PD patients.
To examine whether a long-term SICF modulation has beneficial effects on clinical measures, including LID severity, and whether these changes parallel improvement in cortical plasticity mechanisms in PD.
We tested SICF in patients with and without LID before (S0) and after short- (14 days - S1) and long-term (12 months - S2) treatment with safinamide 100 mg/day. Possible changes in M1 plasticity were assessed using intermittent theta-burst stimulation (iTBS). Finally, we correlated safinamide-related neurophysiological changes with modifications in clinical scores.
SICF was enhanced at S0, and prominently in patients with LID. Safinamide normalized SICF at S1, and this effect persisted at S2. Impaired iTBS-induced plasticity was present at S0 and safinamide restored this alteration at S2. There was a significant correlation between the degree of SICF and the amount of iTBS-induced plasticity at S0 and S2. In patients with LID, the degree of SICF at S0 and S2 correlated with long-term changes in LID severity.
Altered SICF contributes to M1 plasticity impairment in PD. Both SICF and M1 plasticity improve after long-term treatment with safinamide. The abnormality in SICF-related glutamatergic circuits plays a role in LID pathophysiology, and its long-term modulation may prevent LID worsening over time.
•Short-interval intracortical facilitation (SICF) was enhanced at baseline (S0).•The primary motor cortex (M1) plasticity was impaired at S0.•SICF and M1 plasticity improved after long-term treatment with safinamide (S2).•The degree of SICF and M1 plasticity alteration correlated at both S0 and S2.•SICF at S0 and S2 correlated with changes in l-dopa-induced dyskinesia.
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