Association Between Amantadine and the Onset of Dementia in Parkinson’s Disease Rivka Inzelberg, MD, 1,2 * Ubaldo Bonuccelli, MD, 3 Edna Schechtman, PhD, 4 Ala Miniowich, MD, 5 Rosa Strugatsky, MD, 1 Roberto Ceravolo, MD, 3 Chiara Logi, MD, 3 Carlo Rossi, MD, 3 Colin Klein, MD, 5 and J. Martin Rabey, MD 5 1 Department of Neurology, Hillel Yaffe Medical Center, Hadera, Israel 2 Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel 3 Department of Neurosciences, University of Pisa, Italy 4 Department of Industrial Engineering and Management, Ben Gurion University, Beer Sheva, Israel 5 Department of Neurology, Asaf Harofe Medical Center, Tzrifin and Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv, Israel Abstract: The objective of this study is to compare the occurrence of dementia among Parkinson’s disease (PD) pa- tients treated with amantadine (AM group) with those never exposed to it (NoAM group). PD dementia shares neuroana- tomical and biochemical similarities with Alzheimer’s disease (AD). Memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist has been shown to be beneficial in AD. Memantine is a dimethyl derivative of amantadine, which also possesses NMDA receptor blocking properties. We hypothesized that amantadine could have a beneficial effect on the occurrence of PD dementia. PD patients attending the Movement Disorders Clinics in Hillel Yaffe, Asaf Harofe Medical Centers (Israel) and Pisa (Italy) were included. Taking the onset of dementia as the endpoint, survival curves for AM and NoAM patients were estimated by the Kaplan–Meier method. The study population consisted of 593 patients (age, 69.5  9.9 years; PD duration, 9.2  6.0 years; 263 patients (44%) amantadine treated). The endpoint of dementia was reached by 116 patients (20%). PD duration until dementia was significantly longer for AM pa- tients (9.1  5.7 years) than for NoAM patients (5.9  4.6 years, P = 0.006). The duration of amantadine exposure pos- itively correlated with PD duration until dementia (P = 0.0001). Survival analysis, taking dementia onset as endpoint, showed slower mental decline in AM patients (Log rank P = 0.0049, Wilcoxon P = 0.0024). Mini-Mental State Examina- tion scores were significantly higher for AM patients than for the NoAM group (P = 0.01). Age of PD onset also signifi- cantly influenced the duration of PD until dementia. Amanta- dine use may delay the onset of dementia in PD patients and may attenuate its severity. © 2006 Movement Disorder Society Key words: Parkinson’s disease; dementia; therapy; aman- tadine; selegiline Contrary to previous assumptions that cognitive dys- function is not an essential feature of the disease, it has been increasingly evident that dementia accompanies Parkinson’s disease (PD). 1 Up to 40% of PD patients develop dementia with disease progression. Reported risk factors include age at study time, age at onset, duration of disease, akinetic–rigid form, depression, and atypical symptoms for PD. 1 Family history of PD might influence the decline toward dementia, 2 although the ApoE4 allele does not constitute a risk factor for PD dementia. 3 Older patients with high severity of PD symp- toms are approximately 10 times more at risk for devel- oping dementia. 4 Dementia increases the risk of death in PD patients. 5 As a consequence, any successful treatment that delays or attenuates the severity of dementia may prolong the survival of PD patients. Although the precise neurochemical basis of PD demen- tia remains unclear, there is substantial evidence that defi- cits of ascending cholinergic pathways may contribute significantly to the cognitive deterioration, similar to the findings described in Alzheimer’s dementia (AD). 6 Cho- *Correspondence to: Dr. Rivka Inzelberg, Department of Neurology, Hillel Yaffe Medical Center, Hadera, 38100, Israel. E-mail: irivka@tx.technion.ac.il Received 12 August 2005; Revised 24 January 2006; Accepted 24 January 2006 Published online 16 May 2006 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.20968 Movement Disorders Vol. 21, No. 9, 2006, pp. 1375–1379 © 2006 Movement Disorder Society 1375