Repetitive transcranial magnetic stimulation combined with cognitive training is a safe and effective modality for the treatment of Alzheimer's disease: a randomized, double-blind study.

Cortical excitability can be modulated using repetitive transcranial magnetic stimulation (rTMS). Previously, we showed that rTMS combined with cognitive training (rTMS-COG) has positive results in Alzheimer's disease (AD). The goal of this randomized double-blind, controlled study was to examine the safety and efficacy of rTMS-COG in AD. Fifteen AD patients received 1-h daily rTMS-COG or sham treatment (seven treated, eight placebo), five sessions/week for 6 weeks, followed by biweekly sessions for 3 months. The primary outcome was improvement of the cognitive score. The secondary outcome included improvement in the Clinical Global Impression of Change (CGIC) and Neuropsychiatric Inventory (NPI). There was an improvement in the average ADAS-cog score of 3.76 points after 6 weeks in the treatment group compared to 0.47 in the placebo group and 3.52 points after 4.5 months of treatment, compared to worsening of 0.38 in the placebo (P = 0.04 and P = 0.05, respectively). There was also an improvement in the average CGIC score of 3.57 (after 6 weeks) and 3.67 points (after 4.5 months), compared to 4.25 and 4.29 in the placebo group (mild worsening) (P = 0.05 and P = 0.05, respectively). NPI improved non-significantly. In summary, the NeuroAD system offers a novel, safe and effective therapy for improving cognitive function in AD.

Hypoxemia correlates with attentional dysfunction in patients with obstructive sleep apnea.

PURPOSE: Obstructive sleep apnea is associated with cognitive impairment, but whether hypoxemia or repeated arousals and sleepiness are the underlying mechanism is controversial. Studies using a wide range of attention and executive functions tests in patients with severe sleep apnea are lacking. METHODS: In a prospective cohort study, 40 patients aged 30-70 years, diagnosed with obstructive sleep apnea (apnea-hypopnea index ≥5) were recruited. Patients with known cardiovascular, pulmonary, psychiatric, or neurological disease, and or patients receiving anti-psychotic, sedatives, or stimulant medications were excluded. Patients underwent full overnight polysomnography including continuous oxygen saturation measurements followed by extensive neuropsychological testings in attention and executive function domains. The correlation between sleep apnea severity and patients' performance on the neuropsychological tests was examined. RESULTS: The patients' performance on measures of attention and executive function was significantly worse compared to the average in a normal population. Attention, as reflected by the number of omissions and by the reaction time on the Conners' Continuous Performance Test correlated significantly with the apnea-hypopnea index (r = 0.6, p < 0.001 and r = 0.48, p = 0.003, respectively) and with parameters of hypoxemia, namely the average SpO(2) (r = -0.51, p = 0.002 and r = -0.39, p = 0.02, respectively) and the percent time spent with SpO(2) < 90% (r = 0.57, p < 0.001 and r = 0.39, p = 0.02, respectively), but not with the degree of sleepiness. Executive dysfunction did not correlate with sleep parameters. DISCUSSION: Attention is the predominant cognitive function affected in patients with obstructive sleep apnea and correlates primarily with nocturnal hypoxemia rather than daytime sleepiness or sleep fragmentation. Executive functions, while below average in some patients, do not correlate with polysomnographic parameters.

Beneficial effect of repetitive transcranial magnetic stimulation combined with cognitive training for the treatment of Alzheimer's disease: a proof of concept study.

The current drug treatment for Alzheimer's disease (AD) is only partially and temporary effective. Transcranial magnetic stimulation (TMS) is a non-invasive technique that generates an electric current inducing modulation in cortical excitability. In addition, cognitive training (COG) may improve cognitive functions in AD. Our aim was to treat AD patients combining high-frequency repetitive TMS interlaced with COG (rTMS-COG). Eight patients with probable AD, treated for more than 2 months with cholinesterase inhibitors, were subjected to daily rTMS-COG sessions (5/week) for 6 weeks, followed by maintenance sessions (2/week) for an additional 3 months. Six brain regions, located individually by MRI, were stimulated. COG tasks were developed to fit these regions. Primary objectives were average improvement of Alzheimer Disease Assessment Scale-Cognitive (ADAS-cog) and Clinical Global Impression of Change (CGIC) (after 6 weeks and 4.5 months, compared to baseline). Secondary objectives were average improvement of MMSE, ADAS-ADL, Hamilton Depression Scale (HAMILTON) and Neuropsychiatric Inventory (NPI). One patient abandoned the study after 2 months (severe urinary sepsis). ADAS-cog (average) improved by approximately 4 points after both 6 weeks and 4.5 months of treatment (P < 0.01 and P < 0.05) and CGIC by 1.0 and 1.6 points, respectively. MMSE, ADAS-ADL and HAMILTON improved, but without statistical significance. NPI did not change. No side effects were recorded. In this study, rTMS-COG (provided by Neuronix Ltd., Yokneam, Israel) seems a promising effective and safe modality for AD treatment, possibly as good as cholinesterase inhibitors. A European double blind study is underway.

Carotid artery stenting in high risk patients with carotid artery stenosis not eligible for endarterectomy: clinical outcome after 5 years.

BACKGROUND: Carotid artery stenting is used as an alternative to surgical endarterectomy. OBJECTIVES: To determine the outcome of CAS in a retrospective cohort of patients. METHODS: Between July 1999 and March 2003, 56 consecutive patients with carotid artery stenosis who were considered ineligible for surgery were treated (45 males, 11 females, mean age 69). All underwent the procedure prior to the introduction of distal protective devices in Israel. RESULTS: Intraprocedural complications included transient neurological findings in 5 patients (8%), cerebrovascular accident in 2 (3%), hemodynamic changes in 11 (18%), and 4 procedural failures. Post-procedural complications included transient ischemic attack in 3 patients and cardiovascular accident in 6 (10%). At 30 days follow-up, three patients (5%) remained with signs of CVA. Two patients (3%) died during the post-procedural period and 16 (28%) during the 5 year follow-up, one due to recurrent CVA and the remainder to non-neurological causes. Five-year carotid Doppler follow-up was performed in 25 patients (45%), which revealed normal stent flow in 21 (84%), 50-60% restenosis in 3 (12%) and > 70% restenosis in one patient (4%). CONCLUSIONS: This study confirms that stent procedures are beneficial for symptomatic carotid stenosis in patients not eligible for surgery.

Quantitative EEG After Brain Stimulation and Cognitive Training in Alzheimer Disease.

PURPOSE: Medications are the currently accepted symptomatic treatment of Alzheimer disease (AD), but their impact on delaying the progression of cognitive deficits and functional impairment is limited. The authors aimed to explore long-term electrophysiological effects of repetitive transcranial magnetic stimulation interlaced with cognitive training on quantitative electroencephalography (EEG) in patients with AD. METHODS: Quantitative EEG was assessed on non-repetitive transcranial magnetic stimulation interlaced with cognitive training treatment days before treatment and after each treatment phase in seven patients with mild AD. RESULTS: After 4.5 months (54 sessions) of treatment, a significant increase of delta activity over the temporal region was found compared with pretreatment values. Nonsignificant increases of the log EEG power were found for alpha band over the frontal and temporal regions, beta band over the frontal region, theta band over the frontal, temporal, and parieto-occipital regions, and delta band over the frontal and parieto-occipital regions. Nonsignificant decreases were found for alpha over the parieto-occipital region, and for beta over the temporal and parieto-occipital regions. A positive correlation was found between log alpha power over the frontal and temporal regions at 6 weeks and Mini-Mental State Examination (MMSE) scores at 6 weeks and 4.5 months, and between log alpha power over the parieto-occipital regions and MMSE scores at 6 weeks. A negative correlation was found between log alpha power over the frontal and temporal regions at 6 weeks and baseline Alzheimer's Disease Assessment Scale-cognitive subscale scores. CONCLUSIONS: Repetitive transcranial magnetic stimulation interlaced with cognitive training has long-term effects on quantitative EEG in patients with mild AD. Further research on the quantitative EEG long-term effects of transcranial magnetic stimulation interlaced with cognitive training is required to confirm the authors' data.

Long-term follow-up (24 months) of quetiapine treatment in drug-induced Parkinson disease psychosis.

OBJECTIVES: To evaluate the long-term outcome of quetiapine (QTP) use for drug-induced psychosis in Parkinson disease as assessed by the primary caregiver using the Clinical Global Impression Scale. METHODS: Thirty-five patients (mean age+/-SD, 76.1+/-5.9 years; mean disease duration+/-SD, 10.3+/-5.3 years; 19 with dementia) were followed up over a 24-month period. RESULTS: At 6 months, 20 (57%) responded to QTP, of whom 11 (31%) maintained their improvement in the long term (for 24 months). Altogether, 15 patients (43%) responded to QTP in the long term (11 were still on treatment at 24 months, 3 stopped because of improvement and medication was no longer required, and 3 stopped because of financial reasons [one was responding positively by the time of stopping medication]). The medications of nonresponding patients (n=15) were switched to clozapine, with a positive response in 12 patients (80%). CONCLUSIONS: In long-term follow-up, 31% of parkinsonian patients with psychosis treated with QTP were still on QTP therapy at 24 months. For those failing to respond to QTP, clozapine was an effective alternative therapy.

Inhibitors of MAO-A and MAO-B in Psychiatry and Neurology.

Inhibitors of MAO-A and MAO-B are in clinical use for the treatment of psychiatric and neurological disorders respectively. Elucidation of the molecular structure of the active sites of the enzymes has enabled a precise determination of the way in which substrates and inhibitor molecules are metabolized, or inhibit metabolism of substrates, respectively. Despite the knowledge of the strong antidepressant efficacy of irreversible MAO inhibitors, their clinical use has been limited by their side effect of potentiation of the cardiovascular effects of dietary amines ("cheese effect"). A number of reversible MAO-A inhibitors which are devoid of cheese effect have been described in the literature, but only one, moclobemide, is currently in clinical use. The irreversible inhibitors of MAO-B, selegiline and rasagiline, are used clinically in treatment of Parkinson's disease, and a recently introduced reversible MAO-B inhibitor, safinamide, has also been found efficacious. Modification of the pharmacokinetic characteristics of selegiline by transdermal administration has led to the development of a new drug form for treatment of depression. The clinical potential of MAO inhibitors together with detailed knowledge of the enzyme's binding site structure should lead to future developments with these drugs.

Frequent misdiagnosis of adult polyglucosan body disease.

Adult polyglucosan body disease (APBD) is a rare glycogenosis manifesting progressive spastic paraparesis, sensorimotor polyneuropathy and neurogenic bladder. Misdiagnosis of APBD may lead to unnecessary investigations and to potentially harmful therapeutic interventions. To examine the frequency of misdiagnosis of APBD, we retrospectively reviewed the clinical data of 30 patients diagnosed between 1991 and 2013. Diagnosis was based on the combination of typical clinical and imaging findings, reduced glycogen branching enzyme activity, and the presence of p.Y326S GBE1 mutation. Initial symptoms started in the 5th-6th decade with bladder dysfunction (47 %), gait problems (33 %) or both. Diagnosis of APBD was delayed by 6.8 (±4.8) years. Consistent signs at diagnosis were spasticity in the legs (93 %), decreased or absent ankle reflexes (100 %), bilateral extensor plantar response (100 %) and distal sensory deficit (80 %). Nerve conduction study showed invariable sensorimotor polyneuropathy, and MRI demonstrated cervical spinal cord atrophy (100 %) and leukoencephalopathy (97 %). All 30 patients were initially misdiagnosed. Common misdiagnoses included cerebral small vessel disease (27 %), multiple sclerosis (17 %), amyotrophic lateral sclerosis (17 %) and peripheral neuropathies (20 %). Consequently, 27 % received inappropriate therapy. In addition, lower urinary tract symptoms in 60 % of men were attributed solely to prostatic disorders but did not respond to medical treatment or prostatectomy. These findings suggest that despite limited clinical variability, APBD is invariably misdiagnosed and patients are often mistreated. Physicians' unfamiliarity with the typical clinical and imaging features of APBD appears as the main reason for misdiagnosis.

Beneficial effect of donepezil augmentation for the management of comorbid schizophrenia and dementia.

Comorbid schizophrenia and dementia is a common clinical phenomenon; however, management of the coexisting illnesses remains incomplete. Donepezil, a cholinesterase inhibitor, may be beneficial for the management of symptoms of Alzheimer's disease, a disease in which cholinergic pathways in the cerebral cortex and basal forebrain are well known to be compromised. Furthermore, impaired cognition in elderly schizophrenic patients has been observed to be more than two thirds; however, there are no published controlled studies reporting the use of cholinesterase inhibitors in the management of schizophrenia in patients with associated dementia. In this study, six patients with chronic schizophrenia and comorbid dementia were administered donepezil, 5 mg, in single-blind fashion as augmentation to their standard antipsychotic medication for a 4-week period. Patients were evaluated with the Mini Mental State Examination (MMSE); Alzheimer's Disease Assessment Scale, Cognitive subscale; Positive and Negative Symptom Scale (PANSS); and the Clinical Global Impression (CGI) scales. A significant improvement was noted in MMSE scores (P < 0.01) and for CGI scores (P < 0.01). In addition, three patients demonstrated improvement on the PANSS. Donepezil appears to be an effective treatment for the management of symptoms of dementia accompanying patients with comorbid schizophrenia and dementia. Since cholinergic dysfunction may be present in some patients with schizophrenia, the authors' findings further demonstrate the possibility that this disorder may be managed with cholinergic medications as augmenting agents, at least in this specific subpopulation of patients with comorbid dementia. To confirm the findings of this preliminary trial, further investigation is mandated with a larger sample of subjects in the context of a double-blind medication trial.

Rapid improvement of tardive dyskinesia with tetrabenazine, clonazepam and clozapine combined: a naturalistic long-term follow-up study.

Tardive dyskinesia (TD) is a complex involuntary movement disorder affecting about 23% of neuroleptic-treated patients. Our objective was to retrospectively analyze a combination of tetrabenazine (TBZ), clonazepam (CLONAZ) and clozapine (CLOZ) used simultaneously for TD in psychotic patients. Six patients with severe, unsuccessfully controlled TD were referred for treatment (mean age 51.5 years; three male; four schizophrenics; one bipolar disease; one borderline personality disorder). They were being treated with neuroleptics (classic, three; risperidone, two; olanzapine, one) and developed severe neck and buccolingual dyskinesias. At our clinic, all of them were treated simultaneously with TBZ (mean dose 141.6 mg); CLONAZ (mean dose 4.3 mg); and CLOZ (mean dose 125 mg). In parallel, we stopped the offending medication. With 1 week, we observed a very impressive improvement in symptoms and within 1 month all the patients were free of symptoms. The mean observation period was 4 years. The combination of TBZ, CLONAZ and CLOZ is a rapid and beneficial option for the management of TD. An augmentation effect probably played a role in the rapid alleviation of symptomatology.

A molecular signature in blood identifies early Parkinson's disease.

BACKGROUND: The search for biomarkers in Parkinson's disease (PD) is crucial to identify the disease early and monitor the effectiveness of neuroprotective therapies. We aim to assess whether a gene signature could be detected in blood from early/mild PD patients that could support the diagnosis of early PD, focusing on genes found particularly altered in the substantia nigra of sporadic PD. RESULTS: The transcriptional expression of seven selected genes was examined in blood samples from 62 early stage PD patients and 64 healthy age-matched controls. Stepwise multivariate logistic regression analysis identified five genes as optimal predictors of PD: p19 S-phase kinase-associated protein 1A (odds ratio [OR] 0.73; 95% confidence interval [CI] 0.60-0.90), huntingtin interacting protein-2 (OR 1.32; CI 1.08-1.61), aldehyde dehydrogenase family 1 subfamily A1 (OR 0.86; 95% CI 0.75-0.99), 19 S proteasomal protein PSMC4 (OR 0.73; 95% CI 0.60-0.89) and heat shock 70-kDa protein 8 (OR 1.39; 95% CI 1.14-1.70). At a 0.5 cut-off the gene panel yielded a sensitivity and specificity in detecting PD of 90.3 and 89.1 respectively and the area under the receiving operating curve (ROC AUC) was 0.96. The performance of the five-gene classifier on the de novo PD individuals alone composing the early PD cohort (n = 38), resulted in a similar ROC with an AUC of 0.95, indicating the stability of the model and also, that patient medication had no significant effect on the predictive probability (PP) of the classifier for PD risk. The predictive ability of the model was validated in an independent cohort of 30 patients at advanced stage of PD, classifying correctly all cases as PD (100% sensitivity). Notably, the nominal average value of the PP for PD (0.95 (SD = 0.09)) in this cohort was higher than that of the early PD group (0.83 (SD = 0.22)), suggesting a potential for the model to assess disease severity. Lastly, the gene panel fully discriminated between PD and Alzheimer's disease (n = 29). CONCLUSIONS: The findings provide evidence on the ability of a five-gene panel to diagnose early/mild PD, with a possible diagnostic value for detection of asymptomatic PD before overt expression of the disorder.

Measles-vaccinated Israeli boy with subacute sclerosing panencephalitis.

Subacute sclerosing panencephalitis is a rare neurologic disorder of childhood and adolescence. We describe a 16-year-old boy who manifested the disease despite proper vaccinations. He was hospitalized because of bedwetting, involuntary limb movements, abnormal speech, and balance disturbances. Immunoglobulin G antibodies against measles were strongly positive, with a high relative cerebrospinal fluid/serum ratio. Polymerase chain reaction for measles produced negative results. Electroencephalography registered slow activity with high voltage discharges every few seconds, and with triphasic complex morphology. Magnetic resonance imaging revealed diffuse white matter changes, mostly around the posterior regions and lateral ventricles. Treatment with valproic acid, levetiracetam, carbamazepine, and intravenous immunoglobulin G was ineffective. Inosiplex and interferon-ß-1a were also administrated. The patient became comatose, with generalized myoclonic jerks, and died 1 year later. An autopsy was not performed. This patient illustrates that subacute sclerosing panencephalitis should be suspected among young vaccinated subjects.

Distal lesion of the lateral femoral cutaneous nerve.

We report three patients with a typical clinical picture of unilateral meralgia paresthetica in whom routine nerve conduction studies were normal. However, cortical somatosensory evoked potentials were absent after lateral femoral cutaneous nerve (LFCN) stimulation on the affected side. After stimulation of the LFCN in the anterosuperior iliac spine (ASIS) region and recording the responses distal to conventional sites (20 cm from the ASIS), sensory nerve action potentials (SNAPs) were absent in the symptomatic leg, but present in the normal leg. We suggest that thigh paresthesias may be caused by a distal LFCN lesion. Eliciting this requires recording SNAPs distal to conventional sites.

Effect of quetiapine in psychotic Parkinson's disease patients: a double-blind labeled study of 3 months' duration.

This double-blind randomized study examined the effect of quetiapine (QTP) on drug-induced psychosis (DIP) in Parkinson's disease (PD). Conventional antipsychotic drugs are associated with adverse extrapyramidal effects. QTP is a new atypical antipsychotic drug used in the treatment of psychosis in PD. A total of 58 consecutive psychotic PD patients (mean age, 75 +/- 8.3 years; mean disease duration, 10.5 +/- 6.4 years; 29 with dementia) were randomly assigned to 2 groups: 30 were treated with QTP (mean dose, 119.2 +/- 56.4 mg) and 28 received placebo for 3 months. The motor part of the Unified Parkinson's Disease Rating Scale, the Brief Psychiatric Rating Scale, the Mini-Mental State Examination, the Hamilton Rating Scale for Depression, the Epworth Sleepiness Score, and the Clinical Global Impression Scale were administered before and during the study. No significant difference was found between the groups in all parameters. There were 32 PD patients (55%) completed the 3-month study (15 [26%] QTP and 17 [29%] placebo). Treatment was interrupted in 15 patients in the QTP and 11 in the placebo groups. This double-blind study did not show a beneficial effect of QTP for the treatment of DIP in PD. The high rate of withdrawal probably influenced the results. Larger double-blind studies are required.

Neurochemical evidence for agmatine modulation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity.

Agmatine treatment is known to exert neuroprotective effects in several models of neurotoxic and ischemic brain and spinal cord injuries. Here we sought to find out whether agmatine treatment would also prove to be neuroprotective in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. Concomitant daily treatment (intraperitoneal injections) with agmatine (100 mg/kg for 5 days) and MPTP (40 mg/kg for 2 days) exacerbated MPTP-related toxicity as evidenced by a larger reduction in dopamine uptake into striatal synaptosomes (42.4% as compared to 58.3% of control, respectively). In contrast, agmatine treatment commencing after MPTP, produced partial protection (31%) against MPTP dopaminergic toxicity. The findings implicate agmatine in mechanisms regulating MPTP neurotoxicity, but underscore the characteristic neuroprotective efficacy of agmatine when applied after the insult.

Medial dorsal superficial peroneal nerve studies in patients with polyneuropathy and normal sural responses.

We studied medial dorsal superficial peroneal (MDSP) nerves in 52 patients with clinical evidence of mild chronic sensorimotor polyneuropathy and normal sural nerve responses, in order to assess the diagnostic sensitivity and usefulness of MDSP nerve testing in electrodiagnostic practice. To determine the effect of age on MDSP nerve parameters, 98 normal subjects were also examined. Electrodiagnostic evaluation involved studies of motor nerve conduction in tibial, peroneal, and median nerves; sensory nerve conduction in sural, MDSP, median, and radial nerves; tibial and peroneal nerve F waves; H reflexes from the soleus muscles; and needle electromyography of gastrocnemius and abductor hallucis muscles. Among the patients, 49% had low-amplitude sensory responses in MDSP nerves and 57% had either slowing of sensory conduction velocity or no sensory responses on proximal stimulation. MDSP nerve amplitude, tibial nerve motor velocity, and H reflexes were the most sensitive for detection of mild chronic symmetrical axonal sensorimotor polyneuropathy. MDSP nerve testing should be included in the routine electrodiagnostic evaluation of patients with suspected polyneuropathy and normal sural nerve responses.