Therapeutic choices and disease activity after 2 years of treatment with cladribine: An Italian multicenter study (CladStop).

BACKGROUND AND PURPOSE: Cladribine tablets, a purine analogue antimetabolite, offer a unique treatment regimen, involving short courses at the start of the first and second year, with no further treatment needed in years 3 and 4. However, comprehensive evidence regarding patient outcomes beyond the initial 24 months of cladribine treatment is limited. METHODS: This retrospective, multicenter study enrolled 204 patients with multiple sclerosis who had completed the 2-year course of cladribine treatment. The primary outcomes were therapeutic choices and clinical disease activity assessed by annualized relapse rate after the 2-year treatment course. RESULTS: A total of 204 patients were enrolled; most patients (75.4%) did not initiate new treatments in the 12 months postcladribine. The study found a significant reduction in annualized relapse rate at the 12-month follow-up after cladribine completion compared to the year prior to starting therapy (0.07 ± 0.25 vs. 0.82 ± 0.80, p < 0.001). Furthermore, patients with relapses during cladribine treatment were more likely to start new therapies, whereas older patients were less likely. The safety profile of cladribine was favorable, with lymphopenia being the primary registered adverse event. CONCLUSIONS: This study provides insights into therapeutic choices and disease activity following cladribine treatment. It highlights cladribine's effectiveness in reducing relapse rates and disability progression, reaffirming its favorable safety profile. Real-world data, aligned with previous reports, draw attention to ocrelizumab and natalizumab as common choices after cladribine. However, larger, prospective studies for validation and a more comprehensive understanding of cladribine's long-term impact are necessary.

A case of early disease rebound after fingolimod discontinuation in a patient with multiple sclerosis and SARS-CoV-2 infection.

Fingolimod is approved in Italy as a second-line therapy for relapsing-remitting multiple sclerosis (RRMS). Discontinuation of fingolimod may elevate the risk of relapses, typically manifesting after a relatively prolonged drug-free interval and often necessitating high doses of intravenous steroids for management. Similar to other viruses, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can act as a trigger for MS relapses. In this context, we present a case of rebound following fingolimod discontinuation during a SARS-CoV-2 infection. Notably, the rebound occurred shortly after stopping the medication and responded effectively to low doses of oral steroids. Our case is discussed in light of existing literature, with speculation on potential mechanisms governing this unconventional disease course rebound. We also consider the possibility that SARS-CoV-2 infection might have contributed to or even triggered the MS relapse.

Antibody response elicited by the SARS-CoV-2 vaccine booster in patients with multiple sclerosis: Who gains from it?

BACKGROUND AND PURPOSE: Although two doses of COVID-19 vaccine elicited a protective humoral response in most persons with multiple sclerosis (pwMS), a significant group of them treated with immunosuppressive disease-modifying therapies (DMTs) showed less efficient responses. METHODS: This prospective multicenter observational study evaluates differences in immune response after a third vaccine dose in pwMS. RESULTS: Four hundred seventy-three pwMS were analyzed. Compared to untreated patients, there was a 50-fold decrease (95% confidence interval [CI] = 14.3-100.0, p < 0.001) in serum SARS-CoV-2 antibody levels in those on rituximab, a 20-fold decrease (95% CI = 8.3-50.0, p < 0.001) in those on ocrelizumab, and a 2.3-fold decrease (95% CI = 1.2-4.6, p = 0.015) in those on fingolimod. As compared to the antibody levels after the second vaccine dose, patients on the anti-CD20 drugs rituximab and ocrelizumab showed a 2.3-fold lower gain (95% CI = 1.4-3.8, p = 0.001), whereas those on fingolimod showed a 1.7-fold higher gain (95% CI = 1.1-2.7, p = 0.012), compared to patients treated with other DMTs. CONCLUSIONS: All pwMS increased their serum SARS-CoV-2 antibody levels after the third vaccine dose. The mean antibody values of patients treated with ocrelizumab/rituximab remained well below the empirical "protective threshold" for risk of infection identified in the CovaXiMS study (>659 binding antibody units/mL), whereas for patients treated with fingolimod this value was significantly closer to the cutoff.

Breakthrough SARS-CoV-2 infections in MS patients on disease-modifying therapies.

BACKGROUND: Patients with multiple sclerosis (pwMS) treated with anti-CD20 or fingolimod showed a reduced humoral response to SARS-CoV-2 vaccines. OBJECTIVE: In this study we aimed to monitor the risk of breakthrough SARS-CoV-2 infection in pwMS on different disease-modifying therapies (DMTs). METHODS: Data on the number of vaccinated patients and the number of patients with a breakthrough infection were retrospectively collected in 27 Italian MS centers. We estimated the rate of breakthrough infections and of infection requiring hospitalization per DMT. RESULTS: 19,641 vaccinated pwMS were included in the database. After a median follow-up of 8 months, we observed 137 breakthrough infections. Compared with other DMTs, the rate of breakthrough infections was significantly higher on ocrelizumab (0.57% vs 2.00%, risk ratio (RR) = 3.55, 95% CI = 2.74-4.58, p < 0.001) and fingolimod (0.58% vs 1.62%, RR = 2.65, 95% CI = 1.75-4.00, p < 0.001), while there were no significant differences in any other DMT group. In the ocrelizumab group the hospitalization rate was 16.7% versus 19.4% in the pre-vaccination era (RR = 0.86, p = 0.74) and it was 3.9% in all the other DMT groups versus 11.9% in the pre-vaccination period (RR = 0.33, p = 0.02). CONCLUSIONS: The risk of breakthrough SARS-CoV-2 infections is higher in patients treated with ocrelizumab and fingolimod, and the rate of severe infections was significantly reduced in all the DMTs excluding ocrelizumab.

Plasma redox and inflammatory patterns during major depressive episodes: a cross-sectional investigation in elderly patients with mood disorders.

BACKGROUND: While both depression and aging have been associated with oxidative stress and impaired immune response, little is known about redox patterns in elderly depressed subjects. This study investigates the relationship between redox/inflammatory patterns and depression in a sample of elderly adults. METHODS: The plasma levels of the advanced products of protein oxidation (AOPP), catalase (CAT), ferric reducing antioxidant power (FRAP), glutathione transferase (GST), interleukin 6 (IL-6), superoxide dismutase (SOD), total thiols (TT), and uric acid (UA) were evaluated in 30 patients with mood disorders with a current depressive episode (depressed patients, DP) as well as in 30 healthy controls (HC) aged 65 years and over. Subjects were assessed with the Hamilton Depression Rating Scale (HAM-D), the Hamilton Rating Scale for Anxiety (HAM-A), the Geriatric Depression Rating Scale (GDS), the Scale for Suicide Ideation (SSI), the Reason for Living Inventory (RFL), the Activities of Daily Living (ADL), and the Instrumental Activity of Daily Living (IADL). RESULTS: DP showed higher levels than HC of AOPP and IL-6, while displaying lower levels of FRAP, TT, and CAT. In the DP group, specific correlations were found among biochemical parameters. SOD, FRAP, UA, and TT levels were also significantly related to psychometric scale scores. CONCLUSION: Specific alterations of redox systems are detectable among elderly DP.

Efficacy of fingolimod after switching from interferon ß-1a in an adolescent with multiple sclerosis: case report.

Pediatric-onset multiple sclerosis (POMS) accounts for approximately 2-10% of all cases of multiple sclerosis (MS) and is associated with higher levels of disease activity than adult-onset MS, including higher rates of clinical relapse and a greater incidence of new T2 lesions on magnetic resonance imaging (MRI). First-line therapy for POMS usually includes interferon ß or glatiramer acetate; however, there is limited evidence from randomized trials regarding the safety and efficacy of these disease-modifying drugs in pediatric patients. Fingolimod represents a second-line therapy option for relapsing-remitting MS in pediatric patients. Here, we report the case of a 14-year-old girl with a diagnosis of POMS who started interferon ß-1a as first-line therapy and then switched to fingolimod after 12 months due to radiologic progression and clinical relapse. The patient subsequently experienced clinical stability and showed minimal radiologic activity on follow-up MRI. Our case demonstrates the real-world clinical effectiveness and safety of fingolimod in pediatric MS and is in line with the results of previous randomized and observational studies.

Pharmacogenetics of myotonic hNav1.4 sodium channel variants situated near the fast inactivation gate.

Sodium channel myotonia and paramyotonia congenita are caused by gain-of-function mutations in the skeletal muscle voltage-gated sodium channel hNav1.4. The first-line drug is the sodium channel blocker mexiletine; however, some patients show side effects or limited responses. We previously showed that two hNav1.4 mutations, p.G1306E and p.P1158L, reduce mexiletine potency in vitro, whereas another sodium channel blocker, flecainide, is less sensitive to mutation-induced gating defects. This observation was successfully translated to p.G1306E and p.P1158L carriers. Thus, the aim of this study was to perform a pharmacological characterization of myotonic Nav1.4 mutations clustered near the fast inactivation gate of the channel. We chose seven mutations (p.V1293I, p.N1297S, p.N1297K, p.F1298C, p.G1306E, p.I1310N, and p.T1313M) from the database of Italian and French networks for muscle channelopathies. Recombinant hNav1.4 mutants were expressed in HEK293T cells for functional and pharmacological characterization using the patch-clamp technique. All the studied mutations impair the kinetics and/or voltage dependence of fast inactivation, which is likely the main mechanism responsible for myotonia. The severity of myotonia is well-correlated to the enhancement of window currents generated by the intersection of the activation and fast inactivation voltage dependence. Five of the six mutants displaying a significant positive shift of fast inactivation voltage dependence reduced mexiletine inhibition in an experimental condition mimicking myotonia. In contrast, none of the mutations impairs flecainide block nor does p.T1313M impair propafenone block, indicating that class Ic antiarrhythmics may constitute a valuable alternative. Our study suggests that mutation-driven therapy would be beneficial to myotonic patients, greatly improving their quality of life.

NEDA-3 achievement in early highly active relapsing remitting multiple sclerosis patients treated with Ocrelizumab or Natalizumab.

BACKGROUND: in the early stages of Multiple Sclerosis (MS), initiating high-efficacy disease-modifying therapy (HE DMTs) may represent an optimal strategy for delaying neurological damage and long-term disease progression, especially in highly active MS patients (HAMS). Natalizumab (NAT) and Ocrelizumab (OCR) are recognized as HE DMTs with significant anti-inflammatory effects. This study investigates NEDA-3 achievement in treatment-naïve HAMS patients receiving NAT or OCR over three years. METHODS: we retrospectively enrolled treatment-naïve HAMS patients undergoing NAT or OCR, collecting demographic, clinical, and instrumental data before and after treatment initiation to compare with propensity score analysis disease activity, time to disability worsening, and NEDA-3 achievement. RESULTS: we recruited 281 HAMS patients with a mean age of 32.7 years (SD 10.33), treated with NAT (157) or OCR (124). After three years, the Kaplan-Meier probability of achieving NEDA-3 was 66.0 % (95 % CI: 57.3 % - 76.0 %) with OCR and 68.2 % (95 % CI: 59.9 % - 77.7 %) with NAT without significant differences between the two groups (p = 0.27) DISCUSSION AND CONCLUSION: starting HE DMT with monoclonal antibodies for HAMS could achieve NEDA-3 in a high percentage of patients without differences between NAT or OCR.

Restless Legs Syndrome and fatigue in multiple sclerosis: A cross-sectional clinical study.

BACKGROUND: Restless Legs Syndrome is a sleep-related sensorimotor disorder with a higher prevalence in Multiple Sclerosis (MS) patients than in the general population. Our aim was to determine the prevalence of RLS in a group of relapsing-remittent multiple sclerosis (RRMS) patients, and to investigate whether RLS is associated with MS-related disability, sleep quality, mood disorders and fatigue. METHODS: In this retrospective, mono-centric, observational study, 92 RRMS patients were recruited (median age 46.5 years, 68.5% female patients). Data on MS clinical and radiological variables were collected. Patients underwent a subjective evaluation with standardized questionnaires on sleep fatigue and mood, which were evaluated by an expert neurologists specialized in sleep disorders about the occurrence of RLS. RESULTS: Prevalence of RLS in our sample was of 47.8%. Patients with RLS had a significantly higher rate of worse sleep quality and fatigue, compared to non RLS subjects (respectively 56.8% vs. 35.4%, p=0.04 and 54.4% vs 22.7%, p=0.002). Univariate analysis showed that RLS was significantly more frequent in fatigued patients (66.7% vs 38.5% RLS- patients, p=0.009). Multivariate analysis showed that fatigue correlated with MS-related disability (OR 1.556, p=0.011), poor sleep quality (OR 1.192, p 0.036), and mood disorders (OR 1.096, p 0.046). RLS appears to independently increase the risk of fatigue of 50%, without reaching clear statistical significance (OR 1.572, p 0,0079). CONCLUSION: Our study confirms the high prevalence of RLS in patients with multiple sclerosis and highlights the potential impact of RLS on fatigue and its strict interaction with sleep quality.

Quantitative T1 mapping detects blood-brain barrier breakdown in apparently non-enhancing multiple sclerosis lesions.

OBJECTIVES: The disruption of the blood-brain barrier (BBB) is a key and early feature in the pathogenesis of demyelinating multiple sclerosis (MS) lesions and has been neuropathologically demonstrated in both active and chronic plaques. The local overt BBB disruption in acute demyelinating lesions is captured as signal hyperintensity in post-contrast T1-weighted images because of the contrast-related shortening of the T1 relaxation time. On the contrary, the subtle BBB disruption in chronic lesions is not visible at conventional radiological evaluation but it might be of clinical relevance. Indeed, persistent, subtle BBB leakage might be linked to low-grade inflammation and plaque evolution. Here we hypothesised that 3D Quantitative Transient-state Imaging (QTI) was able to reveal and measure T1 shortening (ΔT1) reflecting small amounts of contrast media leakage in apparently non-enhancing lesions (ANELs). MATERIALS AND METHODS: Thirty-four patients with relapsing remitting MS were included in the study. All patients underwent a 3 T MRI exam of the brain including conventional sequences and QTI acquisitions (1.1 mm isotropic voxel) performed both before and after contrast media administration. For each patient, a ΔT1 map was obtained via voxel-wise subtraction of pre- and post- contrast QTI-derived T1 maps. ΔT1 values measured in ANELs were compared with those recorded in enhancing lesions and in the normal appearing white matter. A reference distribution of ΔT1 in the white matter was obtained from datasets acquired in 10 non-MS patients with unrevealing MR imaging. RESULTS: Mean ΔT1 in ANELs (57.45 ± 48.27 ms) was significantly lower than in enhancing lesions (297.71 ± 177.52 ms; p < 0. 0001) and higher than in the normal appearing white matter (36.57 ± 10.53 ms; p < 0.005). Fifty-two percent of ANELs exhibited ΔT1 higher than those observed in the white matter of non-MS patients. CONCLUSIONS: QTI-derived quantitative ΔT1 mapping enabled to measure contrast-related T1 shortening in ANELs. ANELs exhibiting ΔT1 values that deviate from the reference distribution in non-MS patients may indicate persistent, subtle, BBB disruption. Access to this information may be proved useful to better characterise pathology and objectively monitor disease activity and response to therapy.

Abducens nerve palsy in a congenital anomalous neurovascular development of the sixth cranial nerve and anterior inferior cerebellar artery: A case report.

Abducens nerve palsy is a common ocular motor paralysis with a broad set of etiopathogenetic causes. Magnetic resonance imaging is a key diagnostic technique to investigate organic causes of sixth nerve palsy, as it allows a detailed representation of the course of the nerve, particularly in its intracisternal tract. Anatomical variants of the sixth cranial nerve comprise duplications and fenestrations in various traits. Anatomical variants of cerebellar arteries have also been described. We report the case of a patient with abducens nerve palsy presumably related to a neurovascular conflict due to a peculiar anatomical variant, which consists in a cerebellar artery passing through the intracisternal duplication of the abducens nerve.

Breakthrough SARS-CoV-2 infections after COVID-19 mRNA vaccination in MS patients on disease modifying therapies during the Delta and the Omicron waves in Italy.

BACKGROUND: In this study we aimed to monitor the risk of breakthrough SARS-CoV-2 infection in patients with MS (pwMS) under different DMTs and to identify correlates of reduced protection. METHODS: This is a prospective Italian multicenter cohort study, long-term clinical follow-up of the CovaXiMS (Covid-19 vaccine in Multiple Sclerosis) study. 1855 pwMS scheduled for SARS-CoV-2 mRNA vaccination were enrolled and followed up to a mean time of 10 months. The cumulative incidence of breakthrough Covid-19 cases in pwMS was calculated before and after December 2021, to separate the Delta from the Omicron waves and to account for the advent of the third vaccine dose. FINDINGS: 1705 pwMS received 2 m-RNA vaccine doses, 21/28 days apart. Of them, 1508 (88.5%) had blood assessment 4 weeks after the second vaccine dose and 1154/1266 (92%) received the third dose after a mean interval of 210 days (range 90-342 days) after the second dose. During follow-up, 131 breakthrough Covid-19 infections (33 during the Delta and 98 during the Omicron wave) were observed. The probability to be infected during the Delta wave was associated with SARS-CoV-2 antibody levels measured after 4 weeks from the second vaccine dose (HR=0.57, p < 0.001); the protective role of antibodies was preserved over the whole follow up (HR=0.57, 95%CI=0.43-0.75, p < 0.001), with a significant reduction (HR=1.40, 95%CI=1.01-1.94, p=0.04) for the Omicron cases. The third dose significantly reduced the risk of infection (HR=0.44, 95%CI=0.21-0.90,p=0.025) during the Omicron wave. INTERPRETATION: The risk of breakthrough SARS-CoV-2 infections is mainly associated with reduced levels of the virus-specific humoral immune response. FUNDING: Supported by FISM - Fondazione Italiana Sclerosi Multipla - cod. 2021/Special-Multi/001 and financed or co-financed with the '5 per mille' public funding.

CINRG pilot trial of coenzyme Q10 in steroid-treated Duchenne muscular dystrophy.

INTRODUCTION: Corticosteroid treatment slows disease progression and is the standard of care for Duchenne muscular dystrophy (DMD). Coenzyme Q10 (CoQ10) is a potent antioxidant that may improve function in dystrophin-deficient muscle. METHODS: We performed an open-label, "add-on" pilot study of CoQ10 in thirteen 5-10-year-old DMD patients on steroids. The primary outcome measure was the total quantitative muscle testing (QMT) score. RESULTS: Twelve of 16 children (mean age 8.03 ± 1.64 years) completed the trial. Target serum levels of CoQ10 (≥2.5 µg/ml) were shown to be subject- and administration-dependent. Nine of 12 subjects showed an increase in total QMT score. Overall, CoQ10 treatment resulted in an 8.5% increase in muscle strength (P = 0.03). CONCLUSIONS: Addition of CoQ10 to prednisone therapy in DMD patients resulted in an increase in muscle strength. These results warrant a larger, controlled trial of CoQ10 in DMD.

Strategies for clinical approach to neurodegeneration in Amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and ultimately fatal neurodegenerative disorder of unknown aetiology that involves the loss of upper and lower motor neurons in the cerebral cortex, brainstem and spinal cord. Significant progress in understanding the cellular mechanisms of motor neuron degeneration in ALS has not been matched with the development of therapeutic strategies to prevent disease progression, and riluzole remains the only available therapy, with only marginal effects on disease survival. More recently alterations of mRNA processing in genetically defined forms of ALS, as those related to TDP-43 and FUS-TLS gene mutations have provided important insights into the molecular networks implicated in the disease pathogenesis. Here we review some of the recent progress in promoting therapeutic strategies for neurodegeneration.

Effect of SARS-CoV-2 mRNA vaccination in MS patients treated with disease modifying therapies.

BACKGROUND: In patients with Multiple Sclerosis (pwMS) disease-modifying therapies (DMTs) affects immune response to antigens. Therefore, post-vaccination serological assessments are needed to evaluate the effect of the vaccine on SARS-CoV-2 antibody response. METHODS: We designed a prospective multicenter cohort study enrolling pwMS who were scheduled for SARS-Cov-2 vaccination with mRNA vaccines (BNT162b2, Pfizer/BioNTech,Inc or mRNA-1273, Moderna Tx,Inc). A blood collection before the first vaccine dose and 4 weeks after the second dose was planned, with a centralized serological assessment (electrochemiluminescence immunoassay, ECLIA, Roche-Diagnostics). The log-transform of the antibody levels was analyzed by multivariable linear regression. FINDINGS: 780 pwMS (76% BNT162b2 and 24% mRNA-1273) had pre- and 4-week post-vaccination blood assessments. 87 (11·2%) were untreated, 154 (19·7%) on ocrelizumab, 25 (3·2%) on rituximab, 85 (10·9%) on fingolimod, 25 (3·2%) on cladribine and 404 (51·7%) on other DMTs. 677 patients (86·8%) had detectable post-vaccination SARS-CoV-2 antibodies. At multivariable analysis, the antibody levels of patients on ocrelizumab (201-fold decrease (95%CI=128-317), p < 0·001), fingolimod (26-fold decrease (95%CI=16-42), p < 0·001) and rituximab (20-fold decrease (95%CI=10-43), p < 0·001) were significantly reduced as compared to untreated patients. Vaccination with mRNA-1273 resulted in a systematically 3·25-fold higher antibody level (95%CI=2·46-4·27) than with the BNT162b2 vaccine (p < 0·001). The antibody levels on anti-CD20 therapies correlated to the time since last infusion, and rituximab had longer intervals (mean=386 days) than ocrelizumab patients (mean=129 days). INTERPRETATION: In pwMS, anti-CD20 treatment and fingolimod led to a reduced humoral response to mRNA-based SARS-CoV-2 vaccines. As mRNA-1273 elicits 3·25-higher antibody levels than BNT162b2, this vaccine may be preferentially considered for patients under anti-CD20 treatment or fingolimod. Combining our data with those on the cellular immune response to vaccines, and including clinical follow-up, will contribute to better define the most appropriate SARS-CoV-2 vaccine strategies in the context of DMTs and MS. FUNDING: FISM[2021/Special-Multi/001]; Italian Ministry of Health'Progetto Z844A 5 × 1000'.

Intracellular pathways underlying the effects of lithium.

This is a short overview focusing on the biochemical interactions underlying the protective effects of lithium at the neuronal level. These include lithium modulation of autophagy, growth factors, excitotoxicity, and a variety of mechanisms underlying cell death, neurogenesis, and neuronal differentiation. All these effects represent the result of a multifaceted pharmacology, which is becoming more and more complex. Nonetheless, when trying to dissect the various mechanisms of action of lithium, two primary targets emerge: glycogen synthase kinase 3beta and phosphatidylinositol phosphatase. The numerous lithium effects on biochemical systems are placed downstream of these two main mechanisms. At several steps, these mechanisms interconnect to each other, thus making it difficult to keep distinct the biochemical cascades promoted by lithium. In this way, it is not surprising that, despite being described as different phenomena at the behavioral level, molecular mechanisms underlying the effects of lithium on mood, motor activity, and sensitization overlap with those responsible for neuroprotection and neurorestoration. It is likely that the ancestral role of this ion as a modulator of cell survival, cell growth, movement, and mood is the consequence of a few molecular mechanisms operating in different neuronal networks, where a variety of cascade events take place. This review is an attempt to elucidate the primary effects of lithium to interconnect the simpler targets to the most complex pharmacological effects.

Lack of alpha 1b-adrenergic receptor protects against epileptic seizures.

PURPOSE: The role of alpha 1b-adrenergic receptor (alpha 1b-AR) in relation with neuronal degeneration, drug addiction, and seizure susceptibility has recently emerged. In particular, mice that overexpress alpha 1b-AR undergo spontaneous epileptic seizures and progressive neuronal loss in a variety of brain areas. Therefore, one should expect that the blockade of alpha 1b-AR leads to anticonvulsant and neuroprotective effects. However, the lack of alpha 1b-AR antagonists does not allow testing of this hypothesis. METHODS: The development of alpha 1b-AR knockout (KO) mice led us to measure seizure susceptibility and neurodegeneration following systemic excitotoxins in these mice. RESULTS: We found that alpha 1b-AR KO mice are markedly resistant to kainate- and pilocarpine-induced seizures. Moreover, when marked seizure duration and severity are obtained by doubling the dose of chemoconvulsants in alpha 1b-AR KO, neuronal degeneration never occurs. CONCLUSIONS: These data indicate that alpha 1b-AR per se plays a fundamental role in the mechanisms responsible for seizure onset, severity, and duration, whereas the brain damage observed in alpha 1b-AR-overexpressing mice is likely to be a secondary phenomenon. In fact, the absence of alpha 1b-AR confers resistance to neurotoxicity induced by seizures/chemoconvulsants. These data, although confirming a pivotal role of alpha 1b-AR in modulating seizure threshold and neuronal death, offer a novel target, which may be used to develop novel anticonvulsants and neuroprotective agents.

Effects of Alzheimer's disease and mild cognitive impairment on driving ability: a controlled clinical study by simulated driving test.

OBJECTIVE: To assess the effects of Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI) on simulated car driving ability. METHODS: Twenty patients with a probable AD of mild severity (Clinical Dementia Rating, CDR = 1) were compared with 20 subjects with MCI (CD = 0.5), and a group of age-matched neurologically normal controls on a driving simulation task. Measures of driving competence included the length of run, the number of infractions (omission of stop at pedestrian crossings, speed limits violation), the number of stops at traffic lights, the mean time to collision, and the number of off-road events. Results in the driving competence measures were correlated with scores obtained from simple visual reaction times and mini-mental state examination (MMSE). RESULTS: The patients with mild AD performed significantly worse than MCI subjects and controls on three simulated driving measures, length of run and mean time to collision (p < 0.001), and number of off-road events (p < 0.01). MCI subjects had only a significantly shorter time-to-collision than healthy controls (p < 0.001). Simple visual reaction times were significantly longer (p < 0.001) in patients with AD, compared to MCI and healthy controls, and showed a borderline significant relation (p = 0.05) with simulated driving scores. Driving performance in the three groups did not significantly correlate with MMSE score as measure of overall cognitive function. CONCLUSIONS: Mild AD significantly impaired simulated driving fitness, while MCI limitedly affected driving performance. Unsafe driving behaviour in AD patients was not predicted by MMSE scores.

Genetic or pharmacological blockade of noradrenaline synthesis enhances the neurochemical, behavioral, and neurotoxic effects of methamphetamine.

N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) lesions of the locus coeruleus, the major brain noradrenergic nucleus, exacerbate the damage to nigrostriatal dopamine (DA) terminals caused by the psychostimulant methamphetamine (METH). However, because noradrenergic terminals contain other neuromodulators and the noradrenaline (NA) transporter, which may act as a neuroprotective buffer, it was unclear whether this enhancement of METH neurotoxicity was caused by the loss of noradrenergic innervation or the loss of NA itself. We addressed the specific role of NA by comparing the effects of METH in mice with noradrenergic lesions (DSP-4) and those with intact noradrenergic terminals but specifically lacking NA (genetic or acute pharmacological blockade of the NA biosynthetic enzyme dopamine beta-hydroxylase; DBH). We found that genetic deletion of DBH (DBH-/- mice) and acute treatment of wild-type mice with a DBH inhibitor (fusaric acid) recapitulated the effects of DSP-4 lesions on METH responses. All three methods of NA depletion enhanced striatal DA release, extracellular oxidative stress (as measured by in vivo microdialysis of DA and 2,3-dihydroxybenzoic acid), and behavioral stereotypies following repeated METH administration. These effects accompanied a worsening of the striatal DA neuron terminal damage and ultrastructural changes to medium spiny neurons. We conclude that NA itself is neuroprotective and plays a fundamental role in the sensitivity of striatal DA terminals to the neurochemical, behavioral, and neurotoxic effects of METH.