Alexandre Gironell

Parkinson's disease-cognitive rating scale: a new cognitive scale specific for Parkinson's disease.

Cognitive defects associated with cortical pathology may be a marker of dementia in Parkinsons disease (PD). There is a need to improve the diagnostic criteria of PD dementia (PDD) and to clarify the cognitive impairment patterns associated with PD. Current neuropsychological batteries designed for PD are focused on fronto‐subcortical deficits but are not sensitive for cortical dysfunction. We developed a new scale, the Parkinsons Disease‐Cognitive Rating Scale (PD‐CRS), that was designed to cover the full spectrum of cognitive defects associated with PD. We prospectively studied 92 PD patients [30 cognitively intact (CogInt), 30 mild cognitive impairment (MCI), 32 PDD] and 61 matched controls who completed the PD‐CRS and neuropsychological tests assessing the cognitive domains included in the PD‐CRS. Acceptability, construct validity, reliability, and the discriminative properties of the PD‐CRS were examined. The PD‐CRS included items assessing fronto‐subcortical defects and items assessing cortical dysfunction. Construct validity, test‐retest and inter‐rater reliability of PD‐CRS total scores showed an intraclass correlation coefficient >0.70. The PD‐CRS showed an excellent test accuracy to diagnose PDD (sensitivity 94%, specificity 94%). The PD‐CRS total scores and confrontation naming item scores‐assessing “cortical” dysfunction—independently differentiated PDD from non‐demented PD. Alternating verbal fluency and delayed verbal memory independently differentiated the MCI group from both controls and CogInt. The PD‐CRS appeared to be a reliable and valid PD‐specific battery that accurately diagnosed PDD and detected subtle fronto‐subcortical deficits. Performance on the PD‐CRS showed that PDD is characterized by the addition of cortical dysfunction upon a predominant and progressive fronto‐subcortical impairment.

Deep brain stimulation of the subcallosal cingulate gyrus: further evidence in treatment-resistant major depression

Deep brain stimulation (DBS) is currently tested as an experimental therapy for patients with treatment-resistant depression (TRD). Here we report on the short- and long-term (1 yr) clinical outcomes and tolerance of DBS in eight TRD patients. Electrodes were implanted bilaterally in the subgenual cingulate gyrus (SCG; Broadman areas 24-25), and stimulated at 135 Hz (90-μs pulsewidth). Voltage and active electrode contacts were adjusted to maximize short-term responses. Clinical assessments included the 17-item Hamilton Depression Rating Scale (HAMD17; primary measure), the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Clinical Global Impression (CGI) Scale. In the first week after surgery, response and remission (HAMD ⩽7) rates were, respectively 87.5% and 50%. These early responses were followed by an overall worsening, with a response and remission rates of 37.5% (3/8) at 1 month. From then onwards, patients showed a progressive improvement, with response and remission rates of 87.5% and 37.5%, respectively, at 6 months. The corresponding figures at 1 yr were 62.5% and 50%, respectively. Clinical effects were seen in all HAMD subscales without a significant incidence of side-effects. Surgical procedure and post-operative period were well-tolerated for all patients. This is the second independent study on the use of DBS of the SCG to treat chronic depression resistant to current therapeutic strategies. DBS fully remitted 50% of the patients at 1 yr, supporting its validity as a new therapeutic strategy for TRD.

Chronic effects of dopaminergic replacement on cognitive function in Parkinson's disease : A two-year follow-up study of previously untreated patients

The cognitive effects of dopaminergic treatment in Parkinsons disease (PD) are still controversial.

Prevalence and correlates of neuropsychiatric symptoms in Parkinson's disease without dementia.

A cross‐sectional study of the profile of psychiatric symptoms and their relationships to medications, executive performance, and excessive daytime somnolence (EDS) was conducted on 1351 consecutive Parkinsons disease patients without dementia (PD‐ND). Ratings were: neuropsychiatric inventory (NPI); hospital anxiety and depression scale (HADS); executive performance (semantic, phonemic, and alternating verbal fluencies); and the Epworth sleepiness scale (ESS). Eighty‐seven percent of the subjects reported at least one psychiatric symptom. The most common were depression (70%), anxiety (69%), apathy (48%), and irritability (47%). Fifty percent of the patients had HADS‐depression scores ranging from possible (8–10; 22%) to probable (≥11; 28%) depression. Executive impairment was found in 41% and EDS in 26% of subjects. All considered variables were significantly more common with longer duration and more severe disease. Only depression appeared to be influenced by type of medication, being less prevalent among patients treated with DAs. Five NPI clusters were identified among patients scoring ≥1 on the NPI (87.3%): patients exhibiting predominantly apathy (12.7%), psychosis (3%), depression (13%), anxiety (15.6%), and “low‐total NPI” (43.2%). Neuropsychiatric symptoms are common in nondemented PD patients suggesting that they are an integral part of PD from the beginning of the disease and appears more related to disease progression than to the type of antiparkinsonian medication. Apathy emerged as an independent construct in PD‐ND, indicating the need to address specific therapeutical approaches targeted toward this particular symptom.

Effects of pallidotomy and bilateral subthalamic stimulation on cognitive function in Parkinson disease

Abstract. Unilateral pallidotomy and bilateral subthalamic deep brain stimulation (STN-DBS) for Parkinson’s disease (PD) have demonstrated a positive effect on motor functions. However, further studies are needed of the unintended cognitive effects accompanying these new surgical procedures. We studied the consequences of unilateral pallidotomy and STN-DBS on cognitive function in a controlled comparative design. Sixteen consecutive PD patients were assessed before and 6 months after unilateral pallidotomy (n = 8) and bilateral STN-DBS (n = 8). The same assessments were performed in a control group of eight non-operated matched PD patients recruited from surgery candidates who refused operation. The neuropsychological battery consisted of test measuring memory, attention, arithmetic, problem solving and language, as well as visuospatial, executive and premotor functions. An analysis of variance (factors time and treatment) was applied. No statistically significant differences were found in the presurgical evaluation of clinical and demographic data for the three treatment groups. The controlled comparison between presurgical and postsurgical performance revealed no significant changes in the cognitive domains tested in the pallidotomy group. The STN-DBS group showed a selective significant worsening of semantic verbal fluency (p = 0.005). This controlled comparative study suggests that neither unilateral pallidotomy nor bilateral STN-DBS have global adverse cognitive consequences, but bilateral STN-DBS may cause a selective decrease in verbal fluency.

Bilateral pallidal stimulation for cervical dystonia: Dissociated pain and motor improvement

Pallidotomy and deep brain stimulation (DBS) of the globus pallidus internus (GPi) has been investigated for medically intractable dystonia.1,2⇓ Attention has mainly focused on motor function; little is known about modification of dystonia-associated pain, which contributes considerably to functional disability.3 We report two patients with idiopathic cervical dystonia (ICD) with only mild motor improvement but marked amelioration of pain symptoms following bilateral DBS of the posteroventral GPi. A 35-year-old woman presented with a 20-year medically intractable segmental ICD and severe pain in her neck and shoulders. At age 34 she experienced reactive depression and attempted suicide. Results of blood analysis—including copper, ceruloplasmin, and acanthocytes—cranial MRI, and muscle biopsy were normal. She received various unsuccessful trials with diazepam, trihexyphenidyl, botulinum toxin, and opioid and nonopioid analgesics. Depressive symptoms improved only mildly with fluoxetine. Preoperative examination disclosed dysphonia, left torticollis and laterocollis, left shoulder elevation, and dystonic postural tremor in both arms (torticollis rating scale of Tsui et al.4 [RST] total score = 21; Hamilton depression score = 36). Palpation over dystonic muscles reproduced the pain that brought the patient to …

Minor hallucinations occur in drug-naive Parkinson's disease patients, even from the premotor phase

The description of minor hallucinatory phenomena (presence, passage hallucinations) has widened the spectrum of psychosis in Parkinsons disease (PD). Minor hallucinatory phenomena seem to antedate the development of more severe hallucinations. Early detection of minor hallucinations may be useful for screening patients with more severe endophenotypes. Motivated by the observation of “de novo,” drug‐naive PD patients reporting minor hallucinations, we aimed to prospectively identify “de novo” untreated PD patients experiencing hallucinatory phenomena, and to compare their clinico‐demographic characteristics with those of untreated PD patients without hallucinations and healthy controls.

Acute effects of immediate and controlled‐release levodopa on mood in Parkinson's disease: A double‐blind study

Mood fluctuations related to levodopa (LD) dosing are well‐known psychiatric complications of Parkinsons disease (PD). No formal studies explored how affective response to LD relates to the type of motor response to oral LD (stable or wearing‐off) and to different pharmacokinetic profiles of oral LD. We used an intrasubject randomized double‐blind crossover design to study 14 patients (7 stable, 7 wearing‐off) who were monitored for motor status, mood, anxiety, and plasma LD levels 1 hour before and 6 hours after an oral dose of immediate‐release (IR) and controlled‐release LD formulations. Analysis of the dose–response curves showed a significant interaction between the type of motor response and the type of LD. Only the wearing‐off patients had a significant mood elevation, and this effect was only significant following challenge with IR LD. Motor status strongly correlated with LD plasma levels and anxiety but not with mood ratings. Mood changes in PD patients are related to the patients type of motor response to oral LD and also to the kinetic profile of the LD formulation used for dopaminergic replacement.

Effects of alprazolam on the acoustic startle response in humans

Abstract In the present study, we assessed the effects of the potent benzodiazepine alprazolam on the human acoustic startle response in healthy volunteers. Eight undergraduate students received single oral doses of placebo and alprazolam 2 mg on 2 separate days, according to a double-blind balanced crossover design. Electromyographic activity of the orbicularis oculi muscle was recorded 5, 7 and 11 h after drug administration. At each recording time, subjects received 21 acoustic stimuli (1 KHz, 116 dB, 50 ms duration) separated by variable intervals (8–30 s, mean 16.5 s). Consistent with previous results obtained for diazepam in humans, alprazolam significantly reduced the amplitude of the startle reflex. A patent increase in onset latency was also observed, this being a novel effect not previously described for benzodiazepines in human studies. Both effects were maximum at 5 h after dosing, the startle response experiencing a recovery as the drug disappeared from systemic circulation. These results indicate a potent inhibitory effect of alprazolam on baseline startle at the dose used, with a robust time-dependent recovery of initial values effectively counteracting between-session habituation.

A double-blind crossover, placebo-controlled study of the adenosine A2A antagonist theophylline in Parkinson's disease.

Blockade of the adenosine A2A receptor potentiates the effects of levodopa in experimental animals and may offer a novel nondopaminergic target for drug therapy in Parkinsons disease (PD). Open-label trials suggest that the nonspecific adenosine antagonist theophylline improves parkinsonian symptoms and increases ON time in advanced patients with PD. In a double-blind, crossover, placebo-controlled trial, the authors investigated the ability of stable plasma levels of theophylline (between 10–20 &mgr;g/mL after 15 days of treatment) to modulate the long-duration response and the short-duration response of levodopa in 10 patients with PD. Although theophylline induced a longer duration of the effect of levodopa in all Unified Parkinsons Disease Rating Scale variables considered, including dyskinesias, maximal levodopa-induced improvement and the duration of the effect of levodopa did not differ significantly from placebo. Only the secondary variable “akinesia” showed a statistical tendency to a more prolonged beneficial response with theophylline during an acute levodopa test (short-duration response), and tremor worsened with theophylline during levodopa withdrawal (long-duration response). No differences were observed during the subacute course of study medication added to levodopa. During this exploratory study, the effects of theophylline were not strong enough to potentiate clearly the antiparkinsonian action of levodopa or to increase ON time in patients with advanced PD.