Cesare Iani

Non-motor functions in parkinsonian patients implanted in the pedunculopontine nucleus: Focus on sleep and cognitive domains

Between 2005 and 2007, six patients affected by idiopathic Parkinsons disease (IPD) were submitted to the bilateral implantation (and subsequent deep brain stimulation - DBS) of the pedunculopontine nucleus (PPN) plus the subthalamic nucleus (STN). This review synthesizes the effects of PPN low-frequency stimulation on non-motor functions, focusing on patient sleep quality and cognitive performance. If not associated to STN-DBS, PPN-DBS promoted a modest amelioration of patient motor performance. However, during PPN-DBS, they experienced on the one hand a significant improvement in executive functions and working memory, on the other hand a beneficial change in sleep architecture. Overall, the limited sample hampers definite conclusions. Yet, although the PPN-DBS induced motor effects are quite disappointing (discouraging extended trials based upon the sole PPN implantation), the neuropsychological profile supports the contention by which in selected PD patients, with subtle cognitive deficits or vanished efficacy of previous implanted STN, PPN-DBS might still represent a reliable and compassionate option.

Low frequency rTMS of the SMA transiently ameliorates peak-dose LID in Parkinson’s disease

OBJECTIVEnTo determine whether low-frequency repetitive transcranial magnetic stimulation (rTMS) may modulate l-DOPA-induced dyskinesia (LID) in dyskinetic Parkinsons disease (PD) patients. LID is a severe motor complication in advanced PD patients. The neural mechanisms involved in LID are not clear, and it is apparent that both an excessive decrease in internal pallidus firing and a modification and overactivation of cortical motor and premotor areas are involved in its pathogenesis.nnnMETHODSnUsing low frequency 1Hz repetitive rTMS we investigated whether decrease of excitability of the supplementary motor area (SMA) may result in modification of LID in PD patients. Furthermore we tested whether it was possible to enhance and/or prolong the beneficial effects of the treatment with repeated sessions of stimulation.nnnRESULTSnWe observed that 1Hz rTMS induced a transient reduction of dyskinesias. A single session of rTMS improved LID, while repeated sessions of stimulation failed to enhance and/or prolong the beneficial effects of the procedure, without causing motor deterioration or other adverse effects.nnnCONCLUSIONSnThese results suggest that LID may depend on an increased excitability of the SMA.nnnSIGNIFICANCEnSMA rTMS is effective in reducing transiently LID, although cannot yet be considered clinically useful.

Treatment of the Symptoms of Huntington's Disease : Preliminary Results Comparing Aripiprazole and Tetrabenazine

Aripiprazole (AP), a dopamine (DA) D2 receptor partial agonist, has recently been used to reduce schizophrenic symptoms, while tetrabenazine (TBZ), a DA depletor, has been used to treat hyperkinesias in Huntingtons disease (HD). The aim of this study is to define the role of AP on chorea, motor performance, and functional disability, and to compare the effects of AP vs. TBZ in a small study of six patients with HD. Both AP and TBZ increased the Unified Huntingtons Disease Rating Scale (UHDRS) chorea score in a similar way. However, AP caused less sedation and sleepiness than TBZ and was better tolerated by the patients on the trial. Moreover, AP showed a slight but not significant improvement of depression in the patients as compared to TBZ. A larger group of patients and a longer period of observation are an important prerequisite for further evaluations of APs therapeutic use.

Metabolic changes induced by theta burst stimulation of the cerebellum in dyskinetic Parkinson's disease patients.

BACKGROUNDnCerebellar repetitive transcranial magnetic stimulation may be effective in reducing peak-dose levodopa induced dyskinesia in Parkinsons disease patients. It was proposed that the antidyskinetic effect could be due to modulation of cerebello-thalamo-cortical pathways. However the neural basis for these clinical effects have not yet been demonstrated.nnnMETHODSnWe investigated the effects of repeated sessions of cerebellar continuous theta burst stimulation in Parkinsons disease patients with levodopa induced dyskinesia on brain metabolism by means of positron emission tomography scan with fluorodeoxyglucose ((18)F-FDG) to characterize the specific cerebral network activated by cerebellar stimulation in these patients.nnnRESULTSnWe found that five days of bilateral cerebellar continuous theta burst stimulation (cTBS) were effective in reducing levodopa induced dyskinesia. Clinical changes were paralleled by a reduction of (18)F-FDG metabolism in the cerebellum as revealed by positron emission tomography imaging. We found a global decrease in the metabolism of the bilateral cerebellar hemispheres, and a significant decrease in (18)F-FDG uptake in correspondence of bilateral dentate nucleus.nnnCONCLUSIONSnOur study demonstrates the antidyskinetic effect of cerebellar cTBS in Parkinsons disease patients with levodopa induced dyskinesia, is paralleled by modulation of the activity of the pathways connecting the cerebellar cortex with the deep cerebellar nuclei, confirming the hypothesis that the motor cerebellar circuit is involved in the generations of levodopa induced dyskinesia.

Theta Burst Stimulation Modulates Cerebellar-Cortical Connectivity in Patients with Progressive Supranuclear Palsy

BACKGROUNDnProgressive Supranuclear Palsy (PSP) is an atypical degenerative Parkinsonism characterized by postural instability, supranuclear gaze palsy and frontal deficits. Recent imaging studies revealed that the volume of cerebellar peduncles and midbrain were reduced in PSP. Transcranial magnetic stimulation (TMS) studies demonstrated a cerebellar involvement in PSP showing an impairment of functional connectivity between the cerebellar hemisphere (Cb) and the contralateral primary motor cortex (M1) (cerebellar brain inhibition-CBI).nnnOBJECTIVEnTo investigate the plasticity of the cerebello-thalamo-cortical circuits in ten PSP patients after two-week course of cerebellar intermittent theta burst stimulation (iTBS), a form of repetitive TMS.nnnMETHODSnBefore and after the iTBS sessions we measured functional connectivity between Cb and contralateral M1 (CBI), short intracortical inhibition (SICI) and intracortical facilitation (ICF) and short latency afferent inhibition (SLAI) in contralateral M1. We also performed resting state functional magnetic resonance (rs-fMRI) and we administered clinical rating scale (PSP-RS).nnnRESULTSnAt baseline PSP patients had decreased efficiency of CBI, SICI and SLAI in comparison to PD patients and healthy subjects. Cerebellar iTBS increased the deficient functional cerebellar-motor connectivity as assessed by CBI. No effect was seen for SICI/ICF and SLAI circuits. Following iTBS there was an increased signal in the head of the caudate nucleus bilaterally as shown by rs-fMRI. Moreover, PSP-RS showed an improvement of dysarthria in all patients.nnnCONCLUSIONSniTBS enhanced functional connectivity between the cerebellar hemisphere, the caudate nucleus and the cortex, that was paralleled by some clinical improvement. Future randomized, sham-stimulation controlled studies are warranted to support the clinical efficacy of this technique.

Effects of inhibitory rTMS on bladder function in Parkinson's disease patients†

Patients affected by Parkinsons disease (PD) may present with lower urinary tract (LUT) dysfunction characterized by involuntary detrusor overactivity. We evaluated possible impact of a 2‐week course of low frequency 1 Hz repetitive transcranial magnetic stimulation (rTMS) on LUT behavior in eight advanced PD patients complaining of urinary disturbances. We tested the effects of rTMS measuring urodynamic examination and the International Prostate Symptoms Score (IPSS) questionnaire, used for evaluation of subjective LUTS. rTMS was able to improve temporarily LUT behavior in PD patients, increasing bladder capacity and the first sensation of filling phase. Moreover, a reduction of IPSS score was noticed, due to an improvement on filling phase symptoms. The beneficial effects assessed with the IPSS lasted for up to 2 weeks after the end of the stimulation. rTMS seems to be an effective, noninvasive alternative treatment for PD patients with urinary disturbances.

Bladder symptoms assessed with overactive bladder questionnaire in Parkinson's disease.

In Parkinsons disease (PD) the urinary dysfunction manifests primarily with symptoms of overactive bladder (OAB). The OAB questionnaire (OAB‐q) is a measure designed to assess the impact of OAB symptoms on health‐related quality of life. In this study, we quantified the urinary symptoms in a large cohort of PD patients by using the OAB‐q short form. Possible correlations between the OAB‐q and clinical features were tested. Three hundred and two PD patients were enrolled in the study. Correlations between the OAB‐q and sex, age, Unified Parkinsons Disease Rating Scale part III (UPDRS‐III), Hoehn‐Yahr (H‐Y) staging, disease duration, and treatment were analyzed. Data were compared with a large cohort of 303 age‐matched healthy subjects. The OAB‐q yielded significantly higher scores in PD patients than in healthy subjects. In the group of PD patients, all the variables tested were similar between men and women. Pearsons coefficient showed a significant correlation between mean age, disease duration, mean OAB‐q scores, UPDRS‐III scores, and H‐Y staging. A multiple linear regression analysis showed that OAB‐q values were significantly influenced by age and UPDRS‐III. No statistical correlations were found between OAB‐q scores and drug therapy or the equivalent levodopa dose, whilst the items relating to the nocturia symptoms were significantly associated with the equivalent levodopa dose. Our findings suggest that bladder dysfunction assessed by OAB‐q mainly correlates with UPDRS‐III scores for severity of motor impairment, possibly reflecting the known role of the decline in nigrostriatal dopaminergic function in bladder dysfunction associated with PD and patients age. Our study also suggests that the OAB‐q is a simple, easily administered test that can objectively evaluate bladder function in patients with PD.

Rasagiline effect on bladder disturbances in early mild Parkinson's disease patients

Rasagiline was administered in mild PD patients com plaining for incomplete compensation of motor symptoms and bladder disturbances. Its urodyn amic and motor effects were studied. Results demonstrated that rasagiline significantly ameliorated urodynamic and urologic questioner scores. We speculate that urinary effect was due to an increase of dopamine post-synaptic concentration at central level. Introduction It is well known that bladder dysfunction is one of the most common autonomic disorders complained by Parkinsons disease (PD) patients, th e incidence being estimated as 55–80% according to the stage of disease. Neurogenic bladder control involves almost all aspe cts of the nervous system: cortical (anterior cingulate cortex, prefrontal cortex and insula) pon tine function, spinal connections between pons and the sacral cord, and peripheral nerves [1]. Dop amine seems to play a pivotal role in central bladder control, either in normal animals, or Parki nson’s disease animal models or in patients affected by the disease [2], [3]. In PD patients, i t was pointed out that l-dopa chronic administratio n improves bladder capacity and volume at which mictu rition reflex is activated [3], possibly by the combined stimulation of both D1 and D2 receptors. On these basis we wanted to evaluate rasagiline eff ect on LUT behavior in a group of mild PD patients complaining of urologic disturbances. We c hosed rasagiline a new generation MAO inhibitor in humans, following the referred bladder isturbances amelioration reported by the same patients when treated with rasagiline, administered to improve motor performances. Materials and Methods Twenty patients affected by idiopathic PD (table 1) according with the Brain Bank Criteria were enrolled for the present study. The study was appro ved by our local ethics committee, and all participants provided informed consent. Patients we re not blind to the treatment Only mild patients with Hoehn and Yahr score < 2.5 were included in the study. All of the subjects were evaluated with a first uro dynamic session executed in the morning under the usual antiparkinsonian treatment (Dopamine agon ists mean daily dose: rotigotine 10mg +.2.0; pramipexole 2.5mg + 1.0; ropinirole: 16mg + 2.5) Mo reover the IPSS questionnaire (International Prostate Symptoms Score questionnaire) [3], was administered. Following the first evaluating section, subjects ad de on their usual dopaminergic therapy a morning dose of Rasagiline (1mg) for the sequent tw o months and at the end of this period all were re-evaluated in a second section of evaluation (IPS S + urodynamic), executed in the morning. M AN US CR IP T AC CE PT ED ACCEPTED MANUSCRIPT Moreover, all patients underwent a clinical evaluat ion using the Unified Parkinson’s Disease Rating Scale (UPDRS) (Section III; normal 0 to worst 108) performed in coincidence with any of the two testing conditions. Urodynamic evaluation, performed by two urologists blind to the assumed drugs, was constituted by a medium filling, 50mL/minute water cystometry , followed by pressure/flow study with triated pelvic floor EMG. The procedure was conducted accor ding to ICS17 indications.13 A 6-French transurethral double-lumen catheter was used. The f ollowing urodynamic variables were evaluated: volume variables: first sensation of bladder filling, neurogenic de trusor overactive contractions threshold (NDOC-t), bladder capacity, and post-void residual urine, all expressed in milliliters; pressure variables: neurogenic detrusor overactive contractions ampli tude (NDOC-a) and detrusor pressure at maximum flow (Pdet@Qmax), expressed in centimeters of water. Moreover, maximum flow (Qmax; mL/second) was evaluated. All variables were defined according to ICS standardization [3]. Results Results are reported in table 2. Rasagiline adminis trat on significantly ameliorated bladder volume measurements in comparison to baseline. The post ho c analysis showed a significant (p< 0.001) increment of bladder capacity of about 16%, and fir st desire to void (34%) while significantly decreased residual volume (-53%). Lower urinary tract symptoms in basal condition wer e mild to moderate in all patients, according to the IPSS questionnaire score (mean: 12.3 + 2.1).The total IPSS score was significantly changed on rasagiline treatment in comparison ( p < 0.0005) to baseline (Wilcoxon test); in particula r, filling (irritative) symptoms were significantly decreased by rasagiline administration, whereas obstructive (voiding) symptoms were unchanged . The UPDRS (Sect ion III) score obtained on rasagiline showed a trend to amelioration although not signifi cant in comparison to the baseline condition (Wilcoxon test) (table 1). Discussion In the present study we observed an urodynamic and cli ical amelioration of LUT symptoms following rasagiline treatment in a group of mild P arkinsons disease patients. An improvement although not significant was observed on motor symp to s scored with UPDRS section III. The reported urodynamic and IPSS data are on line with previous studies performed on animals and human beings demonstrating that dopaminergic stimul ation obtained with l-dopa or some of the dopamine agonists, produces a bladder function amel ioration. M AN US CR IP T AC CE PT ED ACCEPTED MANUSCRIPT We hypothesis that the reported bladder amelioratio n was due to an increase of dopamine synaptic cerebral concentration by selective doses of rasagi line, as supported by previous studies on animals, showing that, when administered over a period of ab ut 2 weeks to non-lesioned rats increased extracellular levels of DA [4]. The mechanism may b e through the accumulation of βphenylethylamine in brain tissue which in turn rele as s DA. Chronic treatment with MAO-B inhibitors may therefore lead to accumulation of β-phenylethylamine and, in turn, to a nonexocytotic release of DA. Concerning the site of action of rasagiline, accord ing to the physiological studies on voiding function, it is possible hypothesize that anterior cingulate cortex and insula may play a relevant ro le because involved in bladder inhibitory control. Pre vious imaging studies [5] demonstrated a relevant density of D1 receptors at these sites D1 receptors activation has been also described as relevant for bladder inhibitory control [3]. Thus, it is reasonable to hypothesize that rasagiline by increasing dopamine synaptic concentration in insul a and cingulated cortex allows the transmitter to interact with D1 receptors despite the lower affini ty they show. In conclusion our data reporting a significant blad der function amelioration in patients treated with rasagiline, are in line with the common parkinsonia n p tients experience of the minctionary symptoms amelioration when adequately treated with l-dopa, and with the reports describing a significant LUT improvement in PD patients when sub mitted to chronic l-dopa therapy [3]. M AN US CR IP T AC CE PT ED ACCEPTED MANUSCRIPT References [1] Fowler CJ, Griffiths DJ. A decade of functional brain imaging applied to bladder control. Neurourology and urodynamics 2010; 29:49-55. [2] Winge K, Werdelin LM, Nielsen KK, Stimpel H. Ef fects of dopaminergic treatment on bladder function in Parkinsons disease. Neurourol Urodyn. 2004;23(7):689-96. [3] Brusa L, Petta F, Pisani A, Moschella V, Iani C , Stanzione P, Miano R, Finazzi-Agrò E. Acute vs chronic effects of l-dopa on bladder funct ion in patients with mild Parkinson disease. Neurology. 2007;68(18):1455-9. [4] Lamensdorf I, Youdim MB, Finberg J. Effect of l ong-term treatment with selective monoamine oxidase A and B inhibitors on dopamine release from at striatum in vivo. J Neurochem 1996; 67:1532-9. [5] Cannon DM, Klaver JM, Peck SA, Rallis-Voak D, E rickson K Drevets W. Dopamine type I receptors binding in major depressive disorder asse ssed using Positron emission Tomagraphy and 11CNNC-112. Neuropharmacology 1009; 34, 127787 M AN US CR IP T AC CE PT ED ACCEPTED MANUSCRIPT Table 2. Urodynamic variables and lower urinary tract symptoms scored according to International Prostate Symptoms Score questionnaire Urodynamic Variables Baseline condition Rasagiline condition Volumes First sensation, mL 118 + 53 158 + 42 * NDOC threshold, mL 170 + 86 188 + 73 Bladder capacity, mL 290 + 98 337 + 115 * Residual urine, mL 47 + 23 25 + 15 * Two-way ANOVA Main factor treatment: p ˂0.001 Post hoc: * p ˂0.001 vs basal condition Pressure NDOC amplitude, cm H2O 55 ± 40 51 ± 42 Pdet at Qmax, cmH2O 30 ± 16 32 ±12 Two-way ANOVA Main factor treatm ent: n.s Flow Qmax, mL/s 15 ± 2 13 ± 2 One-way ANOVA Main factor treatment: .s. Parkinsonian patients (n =20). NDOC= neurogenic detrusor overactive contractions; ANOVA=analysis of variance; Pdet@Qmax=detrusor pressure at maximum flow; Qmax=m i um flow; IPSS= International Prostate Symptoms Score. A two-way analysis of variance (ANOVA) for repeated measures, was separately used for volume and pressure variables. In both analysis a first wi thin factor “treatment” with two levels (baseline condition vs rasagiline) was used and a second with in factor “variables” with two levels for pressure measurements, or with four levels for volu me measurements was utilized. Maximal flow (Qmax) was studied with a one-way ANOVA with the me ntioned within factor “treatment.” The Greenhouse–Geisser correction was used when require d. Th post hoc Tukey test was used when allowed M AN US CR IP T AC CE PT ED ACCEPTED MANUSCRIPT Table 1 Patients’ clinical and demographic charact eristics Age (years) Mean± SD 67± 3.2 Sex 7M; 13 F Disease duration (years) Mean± SD 5±2.1 Hoehn and Yahr stage 2.3 ± 0.8 UPDRS section III basal condition 28 ± 10 UPDRS section III Rasagiline condition 23 ± 17 Inclusion criteria were urinary symptoms such as ur gency and increased daytime/nighttime frequency defined according to th e International Continence Society (ICS) standardization. Exclusion criteria were consumption of any drug acting on the