Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive and fatal motor neuron disease. We carried out two randomized, double-blind, placebo-controlled, multi-centre, multi-national studies with xaliproden (a drug with neurotrophic effect) to assess drug efficacy and safety at two doses. Patients with clinically probable or definite ALS of more than 6 months and less than 5 years duration were randomly assigned to placebo, 1 mg or 2 mg xaliproden orally once daily as monotherapy in Study 1 (n=867); or to the same regimen with addition of riluzole 50 mg bid background therapy in Study 2 (n=1210 patients). The two primary endpoints were defined as: 1. Time to death, tracheostomy, or permanent assisted ventilation (DTP), and 2. Time to vital capacity (VC)<50% or DTP before (log-rank test) and after adjustment using a Cox proportional hazard model for prespecified prognostic factors. Secondary endpoints were rates of change of various functional measures. In Study 1, primary outcome measures did not reach statistical significance. For the 2 mg group, for time to VC<50% analysis (without DTP) a significant 30% RRR was obtained (95% confidence interval [CI]: 8.46, P=0.009). In Study 2, no significant results were obtained. However, there was a trend in favour of add-on 1 mg dose xaliproden vs. placebo (RRR 15% [-6.31, ns] for time to VC<50%; RRR 12% [CI: -6.27, ns] for time to VC<50% or DTP). Adjusted RR ratios were consistently more favourable for the xaliproden groups. Tolerability was good, and dose-dependent side effects were largely associated with the serotonergic properties of xaliproden. An effect of xaliproden on functional parameters, especially VC, was noted. Although this effect did not reach statistical significance, xaliproden had a small effect on clinically noteworthy aspects of disease progression in ALS.

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SynopsisAn examination was made of urinary catecholamine and metabolite outputs in 28 unipolar depressed patients and 25 normal controls. The total group of depressed patients had significantly higher urinary outputs of norepinephrine (NE) and its metabolite normetanephrine (NM), and significantly lower urinary outputs of the dopamine metabolite dihydroxyphenylacetic acid (DOPAC), than controls. Patients who met DSM-III criteria for a major depressive episode with melancholia (N = 8) had significantly higher urinary outputs of normetanephrine than controls, whereas patients with a major depressive episode without melancholia (N = 7) and dysthymic disorder patients (N = 8) had levels comparable with controls. We postulate that the higher urinary outputs of norepinephrine and its metabolite, normetanephrine, reflect dysregulation of the sympathetic nervous system in depression.

Introduction Cerebrospinal fluid (CSF) biomarker ratios were never evaluated in late-onset (>65 years) behavioral variant of frontotemporal lobar degeneration (bvFTLD) versus Alzheimer's disease (AD). Methods A retrospective monocentric study on 44 clinically suspected amnestic AD or bvFTLD patients with onset after 65 years and available CSF and clinical data. Results The final clinical diagnosis was AD (n = 28; 64%), late-onset bvFTLD (n = 14; 32%), and others (n = 2; 4%). Applying the CSF cutoff total-tau/Aβ 1–42 of 1.06, all the bvFTLD were in the FTLD range (<1.06, bvFTLD/FTLD), whereas the AD patients were either in the AD (>1.06, AD/AD) or in the FTLD range (<1.06, AD/FTLD); CSF biomarkers were significantly different in these three groups, but not neuroradiological features or presence of episodic memory deficit. Discussion Late-onset bvFTLD is underdiagnosed. The available CSF biomarker ratio cutoff need further improvement and overestimated late-onset bvFTLD but could potentially differentiate it from AD, notably in case of conflicting results.