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From the Warren Alpert School of Medicine (G.D.S.), Brown University, Providence, RI; Affymax Inc. (M.M.), Palo Alto, CA; Saul Consulting (T.S.), Half-Moon Bay, CA; Acologix Inc. (J.F.), Hayward, CA; Genitope Inc. (J.C.), Fremont, CA; and California-Pacific Medical Center (D.M.), San Francisco.
Address correspondence and reprint requests to Dr. Gerald D. Silverberg, 710 Frenchmans Rd, Stanford, CA 94305
Background: Alzheimer disease (AD) has been associated with abnormal cerebral clearance of macromolecules, such as amyloid and microtubule-associated-protein tau (MAP-
). We hypothesized that improving clearance of macromolecules from the CNS might slow the progression of dementia.
Objective: This prospective, randomized, double-blinded, placebo-controlled trial evaluated the safety and effectiveness of a surgically implanted shunt in subjects with probable AD.
Methods: A total of 215 subjects with probable AD by National Institute of Neurological Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association criteria received either a low-flow ventriculoperitoneal shunt or a sham (occluded) shunt for 9 months. Longitudinal CSF sampling was performed in both active and control subjects. Primary outcome measures were the Mattis Dementia Rating Scale and the Global Deterioration Scale. CSF Aβ(1-42) and MAP- also were assayed.
Results: After a planned interim analysis, the study was halted for futility. Using the intent-to-treat population, no between-group differences were observed in the primary outcome measures. The surgical procedure and device were associated with 12 CNS infections, some temporally associated with CSF sampling. All were treated successfully.
Conclusions: We found no benefit to low-flow CSF shunting in subjects with mild to severe Alzheimer disease. CSF infections, while treatable, occurred more frequently than expected, in some cases likely related to CSF sampling.
GLOSSARY: Aβ = amyloid beta-peptides; AD = Alzheimer disease; ADCS-ADL = AD Cooperative Study Activities of Daily Living; BBB = blood–brain barrier; CP = choroid plexus; FDA = Food and Drug Administration; GDS = Global Deterioration Scale; GEE = Generalized Estimating Equations; IA = interim analysis; ISF = interstitial fluid; ITT = intent-to-treat; LRP-1 = lipoprotein receptor-related protein-1; MAP- = microtubule-associated-protein tau; MDRS = Mattis Dementia Rating Scale; MMSE = Mini-Mental State Examination; NAART = North American Adult Reading Test; NINCDS-ADRDA = National Institutes of Neurological and Communicative Diseases and Stroke–Alzheimer’s Disease and Related Disorders Association; NPH = normal-pressure hydrocephalus; PHF = perihippocampal fissures; RAGE = receptor for advanced glycation end-products; SADAS-Cog = Standardized AD Assessment Scale–Cognitive; SAE = serious adverse events.
e-Pub ahead of print on June 4, 2008, at www.neurology.org.
Disclosure: The authors report no conflicts of interest in the results of this clinical trial. While the trial was being conducted, all authors were associated with the original sponsor of the trial and at that time received salary, equity, or stipends from the original sponsor of the trial. None has received salary, equity, or stipends during or subsequent to the writing of this manuscript, and none hold equity or other interest in the company nor stands to benefit financially from data from this trial. All of the data from this clinical trial were made available to the authors in preparing this manuscript.
Received June 5, 2007. Accepted in final form March 19, 2008.
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