Riluzole, a glutamate modulator, slows cerebral glucose metabolism decline in patients with Alzheimer's disease.

Dysregulation of glutamatergic neural circuits has been implicated in a cycle of toxicity, believed among the neurobiological underpinning of Alzheimer's disease. Previously, we reported preclinical evidence that the glutamate modulator riluzole, which is FDA approved for the treatment of amyotrophic lateral sclerosis, has potential benefits on cognition, structural and molecular markers of ageing and Alzheimer's disease. The objective of this study was to evaluate in a pilot clinical trial, using neuroimaging biomarkers, the potential efficacy and safety of riluzole in patients with Alzheimer's disease as compared to placebo. A 6-month phase 2 double-blind, randomized, placebo-controlled study was conducted at two sites. Participants consisted of males and females, 50 to 95 years of age, with a clinical diagnosis of probable Alzheimer's disease, and Mini-Mental State Examination between 19 and 27. Ninety-four participants were screened, 50 participants who met inclusion criteria were randomly assigned to receive 50 mg riluzole (n = 26) or placebo (n = 24) twice a day. Twenty-two riluzole-treated and 20 placebo participants completed the study. Primary end points were baseline to 6 months changes in (i) cerebral glucose metabolism as measured with fluorodeoxyglucose-PET in prespecified regions of interest (hippocampus, posterior cingulate, precuneus, lateral temporal, inferior parietal, frontal); and (ii) changes in posterior cingulate levels of the neuronal viability marker N-acetylaspartate as measured with in vivo proton magnetic resonance spectroscopy. Secondary outcome measures were neuropsychological testing for correlation with neuroimaging biomarkers and in vivo measures of glutamate in posterior cingulate measured with magnetic resonance spectroscopy as a potential marker of target engagement. Measures of cerebral glucose metabolism, a well-established Alzheimer's disease biomarker and predictor of disease progression, declined significantly less in several prespecified regions of interest with the most robust effect in posterior cingulate, and effects in precuneus, lateral temporal, right hippocampus and frontal cortex in riluzole-treated participants in comparison to the placebo group. No group effect was found in measures of N-acetylaspartate levels. A positive correlation was observed between cognitive measures and regional cerebral glucose metabolism. A group × visit interaction was observed in glutamate levels in posterior cingulate, potentially suggesting engagement of glutamatergic system by riluzole. In vivo glutamate levels positively correlated with cognitive performance. These findings support our main primary hypothesis that cerebral glucose metabolism would be better preserved in the riluzole-treated group than in the placebo group and provide a rationale for more powered, longer duration studies of riluzole as a potential intervention for Alzheimer's disease.

Upper extremity motor measures of Tap Test response in Normal Pressure Hydrocephalus.

OBJECTIVE: The Tap Test (TT) is a commonly used method for predicting shunt responsiveness in patients with Normal Pressure Hydrocephalus (NPH). The present study investigates whether measures of upper extremity motor function are useful for assessing response to spinal fluid drainage. METHODS: 42 subjects undergoing evaluations for idiopathic NPH (iNPH) participated in this study. A standardized gait evaluation, a neuropsychological battery, and objective tests of upper extremity motor functions were administered. A Neurologist skilled in NPH assessment independently rated patients as TT Responders (n=26) or Non-Responders (n=16) based on clinical impression of change 2-4h after 40-50 cm(3) drainage of spinal fluid by lumbar puncture (LP). In the subset of subjects who underwent shunt placement, operative outcome was also evaluated. RESULTS: TT Responders improved significantly more than TT Non-Responders in Upper Extremity Coordination/Speed tasks (p<.001). The groups did not differ on other neuropsychological measures post-LP. A possible association was observed between pre- and post-TT changes in Upper Extremity Coordination/Speed and post-shunt improvement. Among Upper Extremity Coordination/Speed measures, Line Tracing displayed the greatest sensitivity (76%) to change post-LP. CONCLUSIONS: Our data suggest that measures of upper extremity motor functions may be useful as measures of Tap Test response in patients with iNPH. These upper extremity motor tasks can be rapidly administered (<5 min) in clinical practice and may provide an additional dimension beyond gait and cognition for evaluating response to LP.

Features of gait most responsive to tap test in normal pressure hydrocephalus.

OBJECTIVE: To identify components of gait associated with a positive tap test (TT) in patients with idiopathic normal pressure hydrocephalus (iNPH). PATIENTS AND METHODS: Thirty-three patients with iNPH underwent clinical evaluation pre- and post-TT and were classified as responders (Rs) or non-responders (NRs). Elements of gait were assessed with a formal standardized Gait Scale and compared between groups. RESULTS: Analysis of pre/post-TT group differences revealed an interaction for Total Gait Score and Walking Score, with improvements in responders only. Total Gait Scores improved by 29% in the Rs and 4.85% in the NRs. Rs showed significant post-TT improvements on a timed 10m walk, turning, and balance. Tandem walking, turning, truck balance and start stop hesitation showed trends toward improvement. CONCLUSIONS: The classic features of gait often used in determining diagnosis of NPH (wide based stride, reduced foot-floor clearance, and small steps) were not helpful in identifying responders to the TT. Walking speed, steps for turning, and tendency towards falling were most likely to improve post-TT. These straightforward measures can readily be adapted into clinical practice to assist in determination of shunt candidacy.

Normal pressure hydrocephalus.

Idiopathic normal pressure hydrocephalus (INPH) is a treatable neurological disorder in older adults involving disturbances of gait/balance, control of micturition, and/or cognition in combination with enlargement of the cerebral ventricles. Diagnosis can be challenging due to its varied presentation and overlap with other disorders common in the elderly. Evidence-based consensus guidelines for diagnosis and treatment of INPH have been created that can assist in clinical management. Diagnosis requires clinical documentation of one or more of the characteristic symptoms of INPH in combination with a brain imaging study demonstrating nonobstructive ventricular enlargement disproportionate to cerebral atrophy. Gait and balance disturbances are the most common presenting findings in INPH and may occur alone or together with cognitive and urinary symptoms. Adjunct tests, particularly those involving transient removal of cerebrospinal fluid via lumbar puncture or lumbar drain, can serve the dual purpose of adding to diagnostic certainty and assisting in prognostication about response to treatment. Prognostication is important because neurosurgical treatment by placement of a ventricular shunt, while effective, carries the risk of potentially significant morbidity. Outcome of shunting in INPH is most often successful when patients are accurately diagnosed, suitably evaluated for surgical candidacy, and managed carefully throughout the preoperative, surgical, and postoperative periods.