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      ABOUT THE AUTHOR

      Bradley Field Bale, M.D. is among the nation’s leading specialists in preventing heart attacks, stroke and diabetes. His work has been published in numerous medical journals, and his latest book is titled Beat the Heart Attack Gene.

      Chapter 4

      Evoked Potentials and Neuropsychological Tests Validate Positron Emission Topography (PET) Brain Metabolism in Cognitively Impaired Patients

      Eric R. Braverman, M.D., Kenneth Blum, Ph.D., Uma J. Damle, BA, Mallory Kerner, BS, Kristina Dushaj, BA, and Marlene Oscar-Berman, Ph.D.

      ¹ Department of Clinical Neurology, PATH Foundation NY, New York, NY, USA

      ² Department of Psychiatry and McKnight Brain Institute, University of Florida, College of Medicine, Gainesville, FL, USA

      ³ Global Integrated Services Unit, University of Vermont, Center for Clinical & Translational Science, College of Medicine, Burlington, VT, USA

      ⁴Departments of Psychiatry, Neurology, and Anatomy & Neurobiology, Boston University School of Medicine and Boston VA Healthcare System, Boston, MA, USA

      Corresponding Author: Eric R. Braverman, MD; email: [email protected]

      ABSTRACT

      Fluorodeoxyglucose (FDG) positron emission topography (PET) brain hypometabolism (HM) correlates with diminished cognitive capacity and risk of developing dementia. However, because clinical utility of PET is limited by cost, we sought to determine whether a less costly electrophysiological measure, the P300 evoked potential, in combination with neuropsychological test performance, would validate PET HM in neuropsychiatric patients. We found that patients with amnestic and non-amnestic cognitive impairment and HM (n=43) evidenced significantly reduced P300 amplitudes, delayed latencies, and neuropsychological deficits, compared to patients with normal brain metabolism (NM; n=187). Data from patients with missing cognitive test scores (n=57) were removed from the final sample, and logistic regression modeling was performed on the modified sample (n=173, p=.000004). The logistic regression modeling, based on P300 and neuropsychological measures, was used to validate membership in the HM vs. NM groups. It showed classification validation in 13/25 HM subjects (52.0%) and in 125/148 NM subjects (84.5%), correlating with total classification accuracy of 79.8%. In this paper, abnormal P300 evoked potentials coupled with cognitive test impairment validates brain metabolism and mild/moderate cognitive impairment (MCI). To this end, we cautiously propose incorporating electrophysiological and neuropsychological assessments as cost-effective brain metabolism and MCI indicators in primary care. Final interpretation of these results must await required additional studies confirming these interesting results.

      INTRODUCTION

      Dementia is the sixth leading cause of death in the United States, increasing in incidence and prevalence as the “Baby Boomer” generation ages along with longer life expectancies.¹ With the economic burden of dementia consistently rising,² early identification of cognitive decline in primary care settings is imperative.³ Decades of research involving brain electrophysiology have shown that delayed latency in the P300 brain wave (the positive spike in an EEG wave 300 ms after a stimulus) and a lower amplitude in the voltage of the P300 wave, occur in both normal aging, and even more so, in dementia.⁴ However, little is known about the relation of electrophysiological parameters (P300), HM of the brain, and MCI/Alzheimer’s disease (AD) markers such as tau proteins, C-reactive protein, and hippocampal atrophy.^5-7 If a patient diagnosed with clinical MCI is positive for these markers, prodromal AD should be considered. Magnetic resonance imaging or angiogram (MRI, MRA) and PET are useful techniques that permit us to track abnormalities that may be markers of MCI or AD.^8-11 Both P300 and PET can detect early functional changes in MCI before anatomical damage becomes evident on MRI/MRA or neuropsychological profiles. There is also a paucity of information linking scores on the Mini-Mental State Examination (MMSE)¹² and brain HM in early cognitive decline.^13,14 Finally, there are no studies to our knowledge that have evaluated the validation ability of 3 common assessment tools for revealing brain HM: Central Nervous System Vital Signs Memory Test (CNSM); Test of Variables of Attention (TOVA); and Wechsler Memory Scale-III (WMS). Our hypothesis is that evoked potentials and neuropsychological tests can validate PET brain metabolism and MCI, or early stages of Alzheimer’s disease.¹⁵ Therefore, the current retrospective study systematically examined the sensitivity and specificity of using P300, TOVA, and memory tests (WMS, CNSM, and MMSE) as early indicators of HM as measured by PET, in a cohort of patients with amnestic and non-amnestic cognitive impairments presenting to a large medical practice.¹⁶

      METHODS

      Participants

      Of the more than 9,000 outpatients who visited a neuropsychiatric private practice group in Manhattan (1998-2009), 662 receiving a fluorodeoxyglucose (FDG) PET scan expressed interest in enrollment in the study, and signed written informed consent forms. The study sample was further refined by selecting patients (n=240) with data available from P300¹⁷ visual and auditory evoked potentials, TOVA, WMS, MMSE, and CNSM. Subjects enrolled in the study performed testing on arrival and were advised not to take medications 24-hours prior to testing and were asked to refrain from caffeine, nicotine, and alcohol as well. Subjects did not undergo any magnetic resonance (e.g., MRI, MRA). Subjects indicated if they had depressive symptoms (n=124) prior to the study and were evaluated for depression using the Millon Clinical Multiaxial Inventory-III and the Myers-Briggs Type Indicator (MBTI). Fifty-three percent (53.2%) of these subjects (n=66) were found to be clinically depressed. Subjects were excluded (n=10) if they showed evidence of structural

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