Blood-based biological ageing and red cell distribution width are associated with prevalent Parkinson's disease: findings from a large Italian population cohort.

Background: Aging clocks tag the actual underlying age of an organism and its discrepancy with chronological age and have been reported to predict incident disease risk in the general population. However, the relationship with neurodegenerative risk and in particular with Parkinson's Disease (PD) remains unclear, with few discordant findings reporting associations with both incident and prevalent PD risk. Objective: To clarify this relationship, we computed a common aging clock based on blood markers and tested the resulting discrepancy with chronological age (ΔPhenoAge) for association with both incident and prevalent PD risk. Methods: In a large Italian population cohort - the Moli-sani study (N=23,437; age ≥ 35 years; 52% women) - we carried out both Cox Proportional Hazards regressions modelling ΔPhenoAge as exposure and incident PD as outcome, and linear models testing prevalent PD as exposure and ΔPhenoAge as outcome. All models were incrementally adjusted for age, sex, education level completed and other risk/protective factors previously associated with PD risk in the same cohort (prevalent dysthyroidism, hypertension, diabetes, use of oral contraceptives, exposure to paints, daily coffee intake and cigarette smoking). Results: No significant association between incident PD risk (209 cases, median (IQR) follow-up time 11.19 (2.03) years) and PhenoAging was observed (Hazard Ratio [95% Confidence Interval] = 0.98 [0.71; 1.37]). However, a small but significant increase of ΔPhenoAge was observed in prevalent PD cases vs healthy subjects (ß (Standard Error) = 1.39 (0.70)). An analysis of each component biomarker of PhenoAge revealed a significant positive association of prevalent PD status with red cell distribution width (RDW; ß (SE) = 0.46 (0.18)). All the remaining markers did not show any significant evidence of association. Conclusion: The reported evidence highlights systemic effects of prevalent PD status on biological aging and red cell distribution width. Further cohort and functional studies may help shedding a light on the related pathways altered at the organism level in prevalent PD, like red cells variability, inflammatory and oxidative stress mechanisms.

A systematic review of salivary biomarkers in Parkinson's disease.

The search for reliable and easily accessible biomarkers in Parkinson's disease is receiving a growing emphasis, to detect neurodegeneration from the prodromal phase and to enforce disease-modifying therapies. Despite the need for non-invasively accessible biomarkers, the majority of the studies have pointed to cerebrospinal fluid or peripheral biopsies biomarkers, which require invasive collection procedures. Saliva represents an easily accessible biofluid and an incredibly wide source of molecular biomarkers. In the present study, after presenting the morphological and biological bases for looking at saliva in the search of biomarkers for Parkinson's disease, we systematically reviewed the results achieved so far in the saliva of different cohorts of Parkinson's disease patients. A comprehensive literature search on PubMed and SCOPUS led to the discovery of 289 articles. After screening and exclusion, 34 relevant articles were derived for systematic review. Alpha-synuclein, the histopathological hallmark of Parkinson's disease, has been the most investigated Parkinson's disease biomarker in saliva, with oligomeric alpha-synuclein consistently found increased in Parkinson's disease patients in comparison to healthy controls, while conflicting results have been reported regarding the levels of total alpha-synuclein and phosphorylated alpha-synuclein, and few studies described an increased oligomeric alpha-synuclein/total alpha-synuclein ratio in Parkinson's disease. Beyond alpha-synuclein, other biomarkers targeting different molecular pathways have been explored in the saliva of Parkinson's disease patients: total tau, phosphorylated tau, amyloid-ß1-42 (pathological protein aggregation biomarkers); DJ-1, heme-oxygenase-1, metabolites (altered energy homeostasis biomarkers); MAPLC-3beta (aberrant proteostasis biomarker); cortisol, tumor necrosis factor-alpha (inflammation biomarkers); DNA methylation, miRNA (DNA/RNA defects biomarkers); acetylcholinesterase activity (synaptic and neuronal network dysfunction biomarkers); Raman spectra, proteome, and caffeine. Despite a few studies investigating biomarkers targeting molecular pathways different from alpha-synuclein in Parkinson's disease, these results should be replicated and observed in studies on larger cohorts, considering the potential role of these biomarkers in determining the molecular variance among Parkinson's disease subtypes. Although the need for standardization in sample collection and processing, salivary-based biomarkers studies have reported encouraging results, calling for large-scale longitudinal studies and multicentric assessments, given the great molecular potentials and the non-invasive accessibility of saliva.

May Bradykinesia Features Aid in Distinguishing Parkinson's Disease, Essential Tremor, And Healthy Elderly Individuals?

BACKGROUND: Bradykinesia is the hallmark feature of Parkinson's disease (PD); however, it can manifest in other conditions, including essential tremor (ET), and in healthy elderly individuals. OBJECTIVE: Here we assessed whether bradykinesia features aid in distinguishing PD, ET, and healthy elderly individuals. METHODS: We conducted simultaneous video and kinematic recordings of finger tapping in 44 PD patients, 69 ET patients, and 77 healthy elderly individuals. Videos were evaluated blindly by expert neurologists. Kinematic recordings were blindly analyzed. We calculated the inter-raters agreement and compared data among groups. Density plots assessed the overlapping in the distribution of kinematic data. Regression analyses and receiver operating characteristic curves determined how the kinematics influenced the likelihood of belonging to a clinical score category and diagnostic group. RESULTS: The inter-rater agreement was fair (Fleiss K = 0.32). Rater found the highest clinical scores in PD, and higher scores in ET than healthy elderly individuals (p < 0.001). In regard to kinematic analysis, the groups showed variations in movement velocity, with PD presenting the slowest values and ET displaying less velocity than healthy elderly individuals (all ps < 0.001). Additionally, PD patients showed irregular rhythm and sequence effect. However, kinematic data significantly overlapped. Regression analyses showed that kinematic analysis had high specificity in differentiating between PD and healthy elderly individuals. Nonetheless, accuracy decreased when evaluating subjects with intermediate kinematic values, i.e., ET patients. CONCLUSION: Despite a considerable degree of overlap, bradykinesia features vary to some extent in PD, ET, and healthy elderly individuals. Our findings have implications for defining bradykinesia and categorizing patients.

Genetics of mirror movements identifies a multifunctional complex required for Netrin-1 guidance and lateralization of motor control.

Mirror movements (MM) disorder is characterized by involuntary movements on one side of the body that mirror intentional movements on the opposite side. We performed genetic characterization of a family with autosomal dominant MM and identified ARHGEF7, a RhoGEF, as a candidate MM gene. We found that Arhgef7 and its partner Git1 bind directly to Dcc. Dcc is the receptor for Netrin-1, an axon guidance cue that attracts commissural axons to the midline, promoting the midline crossing of axon tracts. We show that Arhgef7 and Git1 are required for Netrin-1-mediated axon guidance and act as a multifunctional effector complex. Arhgef7/Git1 activates Rac1 and Cdc42 and inhibits Arf1 downstream of Netrin-1. Furthermore, Arhgef7/Git1, via Arf1, mediates the Netrin-1-induced increase in cell surface Dcc. Mice heterozygous for Arhgef7 have defects in commissural axon trajectories and increased symmetrical paw placements during skilled walking, a MM-like phenotype. Thus, we have delineated how ARHGEF7 mutation causes MM.

Clinical diagnostic utility of transcranial magnetic stimulation in neurological disorders. Updated report of an IFCN committee.

The review provides a comprehensive update (previous report: Chen R, Cros D, Curra A, Di Lazzaro V, Lefaucheur JP, Magistris MR, et al. The clinical diagnostic utility of transcranial magnetic stimulation: report of an IFCN committee. Clin Neurophysiol 2008;119(3):504-32) on clinical diagnostic utility of transcranial magnetic stimulation (TMS) in neurological diseases. Most TMS measures rely on stimulation of motor cortex and recording of motor evoked potentials. Paired-pulse TMS techniques, incorporating conventional amplitude-based and threshold tracking, have established clinical utility in neurodegenerative, movement, episodic (epilepsy, migraines), chronic pain and functional diseases. Cortical hyperexcitability has emerged as a diagnostic aid in amyotrophic lateral sclerosis. Single-pulse TMS measures are of utility in stroke, and myelopathy even in the absence of radiological changes. Short-latency afferent inhibition, related to central cholinergic transmission, is reduced in Alzheimer's disease. The triple stimulation technique (TST) may enhance diagnostic utility of conventional TMS measures to detect upper motor neuron involvement. The recording of motor evoked potentials can be used to perform functional mapping of the motor cortex or in preoperative assessment of eloquent brain regions before surgical resection of brain tumors. TMS exhibits utility in assessing lumbosacral/cervical nerve root function, especially in demyelinating neuropathies, and may be of utility in localizing the site of facial nerve palsies. TMS measures also have high sensitivity in detecting subclinical corticospinal lesions in multiple sclerosis. Abnormalities in central motor conduction time or TST correlate with motor impairment and disability in MS. Cerebellar stimulation may detect lesions in the cerebellum or cerebello-dentato-thalamo-motor cortical pathways. Combining TMS with electroencephalography, provides a novel method to measure parameters altered in neurological disorders, including cortical excitability, effective connectivity, and response complexity.

A Combined Panel of Salivary Biomarkers in de novo Parkinson's Disease.

OBJECTIVE: To investigate molecular biomarkers of a-synuclein and tau aggregation, autophagy, and inflammation in the saliva of de novo Parkinson's disease (PD) patients in comparison to healthy subjects (HS), and to correlate molecular data with clinical features of PD patients, in order to establish whether abnormalities of these parameters are associated with specific clusters of de novo PD patients, and their potential diagnostic power in differentiating PD patients from HS. METHODS: We measured total and oligomeric a-synuclein, total-tau and phosphorylated-tau, microtubule-associated protein light chain 3 beta (MAP-LC3beta), and tumor necrosis factor alpha (TNFalpha) in the saliva of 80 de novo PD patients and 62 HS, using quantitative enzyme-linked immunosorbent Assay analysis. RESULTS: Oligomeric a-synuclein, total-tau, MAP-LC3beta, and TNFalpha levels resulted significantly higher in patients with respect to HS, while no significant differences were detected for total a-synuclein or phosphorylated-tau. Phosphorylated-tau directly correlated with MAP-LC3beta, whereas it inversely correlated with TNFalpha in PD patients. An inverse correlation was detected between MAP-LC3beta and non-motor symptoms severity. Principal Component Analysis showed that molecular and clinical parameters were independent of each other in de novo PD patients. Receiver operating characteristic curve analysis reported an accurate diagnostic performance of oligomeric a-synuclein and MAP-LC3beta. The diagnostic accuracy of total a-synuclein increased when it was combined with other salivary biomarkers targeting different molecular pathways. INTERPRETATION: Our study proposes a novel biomarker panel using saliva, a non-invasive biofluid, in de novo PD patients, with implications in understanding the molecular pathways involved in PD pathogenesis and the relevance of different molecular pathways in determining clinical PD subtypes. ANN NEUROL 2023;93:446-459.

Relationship between risk and protective factors and clinical features of Parkinson's disease.

BACKGROUND: Non-genetic risk factors play a relevant role in Parkinson's disease (PD) development but the relationship between these factors and PD clinical features is unknown. OBJECTIVE: The aim of the present multicenter study was to investigate possible relationship between risk factors and clinical motor and non-motor features in a large sample of PD patients. METHODS: Six hundred ninety-four patients with PD participated. Patients underwent a clinical evaluation assessing motor symptoms and motor complications as well as non-motor symptoms severity. Information regarding pharmacological treatment was also collected. Risk and protective factors were previously identified in the present population and included coffee consumption, cigarette smoking, and physical activity as protective factors and a family history of PD, dyspepsia, exposure to toxic agents and general anesthesia as risk factors. Multiple regression models were used to investigate the relationship between risk factors and clinical variables. RESULTS: Coffee consumption predicted older age at onset (B: 0.527; CI: 0.195; 0.858) and milder motor symptom severity (B: 1.383; CI: 2.646; -0.121). Non-motor symptom severity was more severe in patients with dyspepsia before PD (B: 13.601; CI 5.019; 22.182) and milder in patients who performed physical activity before PD (B: 11.355; CI: 16.443; -6.266). We found no relationship between risk factors and motor complications, motor subtype and pharmacological treatment. CONCLUSIONS: Risk and protective factors of PD development may influence PD clinical features. This finding may represent the first step in the development of new preventive approaches able to delay disease onset and mitigate the extent of clinical manifestations.

No evidence of iron deposition in essential tremor: a susceptibility-weighted imaging study.

OBJECTIVE: To evaluate the role of iron deposition in subcortical nuclei of patients with essential tremor (ET). METHODS: Twenty-three patients with ET underwent a standardized 3T-MRI protocol. We specifically assessed iron deposition using susceptibility-weighted angiography (SWAN) images in seven specific regions of interest (ROIs): the thalamus, putamen, globus pallidus, caudate nucleus, substantia nigra, red nucleus, and dentate nucleus. Tremor in ET patients was clinically assessed using the Fahn-Tolosa-Marin Tremor Rating Scale (FTM-TRS). ET patient data were compared with data obtained from 23 Parkinson's disease (PD) patients and 14 healthy subjects (HS). RESULTS: No differences in iron deposition in the seven ROIs were found between ET patients and HS. Conversely, PD patients showed increased iron deposition in the substantia nigra in comparison with both ET patients and HS. CONCLUSIONS: Our results indicate the absence of iron deposition in subcortical nuclei of ET patients, which is generally considered a marker of neurodegeneration.

The Pathophysiological Correlates of Parkinson's Disease Clinical Subtypes.

BACKGROUND: Possible pathophysiological mechanisms underlying Parkinson's disease (PD) clinical subtypes are unknown. The objective of this study was to identify pathophysiological substrate of PD subtypes using neurophysiological techniques. METHODS: One hundred de novo PD patients participated. We collected patient demographic and clinical data, which were used to perform a hierarchical cluster analysis. The neurophysiological assessment tested primary motor cortex excitability and plasticity using transcranial magnetic stimulation. To evaluate motor performance, we performed a kinematic analysis of fast index finger abduction. To investigate sensory function and sensorimotor mechanisms, we measured the somatosensory temporal discrimination threshold at rest and during movement, respectively. RESULTS: Hierarchical cluster analysis identified 2 clinical clusters. Cluster I ("mild motor-predominant") included patients who had milder motor and nonmotor symptoms severity than cluster II patients, who had a combination of severe motor and nonmotor manifestations (diffuse malignant). We observed that the diffuse malignant subtype had increased cortical excitability and reduced plasticity compared with the mild motor-predominant subtype. Kinematic analysis of motor performance demonstrated that the diffuse malignant subtype was significantly slower than the mild motor-predominant subtype. Conversely, we did not observe any significant differences in sensory function or sensorimotor integration between the two PD subtypes. CONCLUSIONS: De novo PD subtypes showed different patterns of motor system dysfunction, whereas sensory function and sensorimotor integration mechanisms did not differ between subtypes. Our findings suggest that the subtyping of PD patients is not a mere clinical classification but reflects different pathophysiological mechanisms. Neurophysiological parameters may represent promising biomarkers to evaluate PD subtypes and their progression. © 2020 International Parkinson and Movement Disorder Society.

Risk factors of Parkinson disease: Simultaneous assessment, interactions, and etiologic subtypes.

OBJECTIVE: To perform a simultaneous evaluation of potential risk/protective factors of Parkinson disease (PD) to identify independent risk/protective factors, to assess interaction among factors, and to determine whether identified risk factors predict etiologic subtypes of PD. METHODS: We designed a large case-control study assessing 31 protective/risk factors of PD, including environmental and lifestyle factors, comorbid conditions, and drugs. The study enrolled 694 patients with PD and 640 healthy controls from 6 neurologic centers. Data were analyzed by logistic regression models, additive interaction models, and cluster analysis. RESULTS: The simultaneous assessment of 31 putative risk/protective factors of PD showed that only coffee consumption (odds ratio [OR] 0.6; 95% confidence interval [CI] 0.4-0.9), smoking (OR 0.7, 95% CI 0.6-0.9), physical activity (OR 0.8, 95% CI 0.7-0.9), family history of PD (OR 3.2, 95% CI 2.2-4.8), dyspepsia (OR 1.8, 95% CI 1.3-2.4), and exposure to pesticides (OR 2.3, 95% CI1.3-4.2), oils (OR 5.6, 95% CI 2.3-13.7), metals (OR 2.8, 95% CI 1.5-5.4), and general anesthesia (OR 6.1, 95% CI 2.9-12.7) were independently associated with PD. There was no evidence of interaction among risk/protective factors, but cluster analysis identified 4 subtypes with different risk factor profiles. In group 1, all patients had a family history of PD, while dyspepsia or exposure to toxic agents was present in 30% of patients. In groups 2 and 3, a family history of PD was lacking, while exposure to toxic agents (group 2) and dyspepsia (group 3) played major roles. Group 4 consisted of patients with no risk factors. CONCLUSIONS: This study demonstrated that 9 factors independently modify PD risk by coexisting in the same patient rather than interacting with others. Our study suggests the need for future preventive strategies aimed at reducing the coexistence of different risk factors within the same participant.

Modifiable risk and protective factors in disease development, progression and clinical subtypes of Parkinson's disease: What do prospective studies suggest?

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, ß2-adrenoreceptor antagonists) or protective (smoking, caffeine and tea intake, physical activity, gout, vitamin E intake, non-steroidal anti-inflammatory drugs and ß2-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.

Epileptic seizures heralding a relapse in high grade gliomas.

PURPOSE: Seizures are a common clinical symptom in high-grade gliomas (HGG). The aim of the study was to investigate the relationship between seizures and HGG relapse (HGG-R). METHODS: We retrospectively evaluated 145 patients who were surgically treated for HGG-R. By analyzing clinical characteristics in these patients (all operated and treated by the same protocol), we identified 37 patients with seizures during follow-up. This cohort was divided into four subgroups according to a) presence or absence of seizures at the time of diagnosis and b) temporal relationship between seizure occurrence and HGG-R during follow-up: subgroup A (25pts) had seizures at follow-up but not at onset, subgroup B (12pts) had seizures both at follow-up and onset, subgroup C (30pts) had seizures before MRI-documented HGG-R, and subgroup D (7pts) had seizures after MRI-documented HGG-R. RESULTS: Although the datum was not statistically significant, survival was longer in patients with seizures during follow-up than in those without seizures (59.3% vs 51.4% alive at 2 years). In 30 patients (subgroup C) seizures heralded HGG-R. In a correlation analysis for this last subgroup, the time interval between seizure and the HGG-R was significantly associated with the number of chemotherapy cycles (r=0.470; p=0.009) and follow-up duration (r=0.566; p=0.001). A linear regression model demonstrated a reciprocal association between the above factors and that it may be possible to estimate the timing of HGG-R by combining these data. CONCLUSIONS: Seizures may herald HGG-R before MRI detection of relapse, thus suggesting that seizures should always be considered a red flag during follow-up.

Intradetrusorial Botulinum Toxin in Patients with Multiple Sclerosis: A Neurophysiological Study.

Patients with multiple sclerosis (MS) often complain of urinary disturbances characterized by overactive bladder syndrome and difficulties in bladder emptying. The aim of the study was to investigate the pathophysiology of bladder dysfunction and the neurophysiological effects of intradetrusorial incobotulinum toxin A (BoNT/A) in patients with MS having both brain and spinal MS-related lesions. Twenty-five MS patients with neurogenic detrusor overactivity (NDO) underwent clinical evaluation and soleus Hoffmann reflex (H reflex) study during urodynamics. Of the 25 patients, 14 underwent a further session one month after intradetrusorial BoNT/A injection. Eighteen healthy subjects acted as the control. In healthy subjects, the H reflex size significantly decreased at maximum cystometric capacity (MCC), whereas in MS patients with NDO, the H reflex remained unchanged. In the patients who received intradetrusorial BoNT/A, clinical and urodynamic investigations showed that NDO improved significantly. Volumes at the first, normal and strong desire to void and MCC increased significantly. Despite its efficacy in improving bladder symptoms and in increasing volumes for first desire, normal and strong desire to void, BoNT/A left the H reflex modulation during bladder filling unchanged. In the MS patients we studied having both brain and spinal MS-related lesions, the H reflex size remained unchanged at maximum bladder filling. Since this neurophysiological pattern has been previously found in patients with spinal cord injury, we suggest that bladder dysfunction arises from the MS-related spinal lesions. BoNT/A improves bladder dysfunction by changing bladder afferent input, as shown by urodynamic findings on bladder filling sensations, but its effects on H reflex modulation remain undetectable.

Extrarolandic electroclinical findings in the evolution of adult-onset Rasmussen's encephalitis.

Rasmussen's encephalitis (RE) is a rare immunomediated disorder characterized by unilateral hemispheric atrophy, drug-resistant focal epilepsy, and progressive neurological deficits. Its onset typically occurs in childhood, though it has also been reported in adult age (A-RE) with atypical clinical features. The aim of this study was to describe the electroclinical features in a group of seven patients with A-RE. We retrospectively studied seven women aged 23-43years (mean: 32.1years) with a diagnosis of RE according to commonly accepted diagnostic criteria. All the patients were clinically evaluated and underwent prolonged video-EEG monitoring, laboratory investigations, and high-resolution MRI follow-up. All the patients displayed an ictal electroclinical pattern whose evolution varied. We identified an early phase characterized by polymorphic ictal electroclinical manifestations (temporal semiology in five cases, frontal in one, and parietal in the remaining case) and a late phase clinically characterized by viscerosensitive phenomena followed by somatosensitive signs, experiential symptoms, and motor signs in all the cases. In the late phase, the ictal EEG pattern was characterized by monomorphic, pseudorhythmic, repetitive slow-wave theta activity over the frontal and central regions, with ipsilateral propagation and/or secondary spreading to contralateral perisylvian structures. Patients were treated with a combination of AEDs and immunotherapy (steroids and IVIg); epilepsy surgery was performed in 3 cases. Our results show that A-RE is characterized by early and late clinical- and EEG-different features which may reflect a progressive involvement of a specific "extrarolandic" network in the advanced phase of the disease and may suggest that the electroclinical expression of RE varies according to the different stages of the pathological process.

Botulinum toxin type A in patients with Parkinson's disease and refractory overactive bladder.

PURPOSE: In this 6-month followup study we investigated the effect of intradetrusor injection of 100 U botulinum toxin type A in patients with Parkinson's disease and refractory detrusor overactivity. MATERIALS AND METHODS: Eight patients with Parkinson's disease and detrusor overactivity refractory to anticholinergics were injected with 100 U botulinum toxin type A. Daytime and nighttime urinary frequency, and urinary incontinence episodes were recorded. Patients also completed a standardized quality of life questionnaire on incontinence and a visual analog scale on the impact of bladder problems on daily life activities, and underwent urodynamic assessment, including pressure flow studies. Clinical and urodynamic assessment was performed before, and 1, 3 and 6 months after injection. RESULTS: In all patients 100 U botulinum toxin type A induced decreased daytime and nighttime urinary frequency, a decreased number of urinary incontinence episodes, increased quality of life scores and, as shown by increased maximum cystometric capacity, improved urodynamic findings. In 2 patients with Parkinson's disease post-void residual urine volume developed. CONCLUSIONS: Intradetrusor injection of 100 U botulinum toxin type A induced clinical and urodynamic improvement in overactive bladder symptoms that lasted at least 6 months in patients with Parkinson's disease.

Botulinum toxin A for overactive bladder and detrusor muscle overactivity in patients with Parkinson's disease and multiple system atrophy.

PURPOSE: Urinary disturbances are common in patients with Parkinson's disease and multiple system atrophy. We investigated the effectiveness and safety of botulinum toxin type A injected into the detrusor muscle in patients with Parkinson's disease and multiple system atrophy who had refractory overactive bladder symptoms and detrusor overactivity. MATERIALS AND METHODS: All participants underwent clinical and urodynamic assessment, and completed a quality of life questionnaire before botulinum toxin type A treatment, and 1 and 3 months thereafter. Four patients with Parkinson's disease and 2 with multiple system atrophy were enrolled in the study. All patients received 200 U botulinum toxin type A injected into the detrusor muscle at 20 sites under cystoscopic guidance at a single session on an inpatient basis. Outcome measures were clinical assessment (a voiding diary including daytime and nighttime urinary frequency, and episodes of urgency and urge urinary incontinence), urodynamic assessment (including first volume and maximum pressure of uninhibited detrusor contractions, and maximum cystometric capacity) and pressure flow studies. RESULTS: One and 3 months after botulinum toxin type A injection all patients reported that daytime and nighttime urinary frequency had decreased and quality of life scores improved. No patients had further episodes of urgency and urge urinary incontinence during the 5-month followup. Urodynamics showed improvement in all urinary function variables tested. No systemic side effects were recorded during or after treatment. In all patients post-void urinary residual volume increased and intermittent catheterization was required only in those with multiple system atrophy. CONCLUSIONS: The new beneficial effect that we report in a small study sample encourages larger trials to confirm botulinum toxin type A injection into the detrusor muscle as an effective and safe treatment for refractory overactive bladder symptoms and detrusor overactivity related to Parkinson's disease and multiple system atrophy.