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 brain lesions (e.g., brain tumors, strokes, encephalomalacia) on concomitant computed tomography (CT) brain scans, other neurologic disorders affecting brain functioning (e.g., multiple sclerosis, head trauma), serious systemic illnesses affecting cognitive functioning, or serious psychiatric disorders affecting cognitive functioning (e.g., schizophrenia, bipolar disorder, brain damage or injury).
The study sample was first divided into 2 groups: positive for PET HM (n=43) or PET NM (n=187), as interpreted by visual inspection of PET scans by radiologists. HM subjects were arranged in groups according to brain regions where HM was detected: Group 1 (parietal), Group 2 (parietal + temporal/frontal), Group 3 (frontal), Group 4 (temporal), Group 5 (focal), and Group 6 (none). The HM subjects were further categorized as amnestic single-domain (n=1), amnestic multi-domain (n=19), non-amnestic single-domain (n=7), non-amnestic multi-domain (n=14), or no signs of MCI (n=2). The NM subjects were also categorized as amnestic single-domain (n=3), amnestic multi-domain (n=27), non-amnestic single-domain (n=50), non-amnestic multi-domain (n=88), or no signs of MCI (n=19).
FDG PET Scans
The narrative reports from the neuroradiology group were divided into 6 groups of hypometabolism: parietal, parietal plus temporal/frontal, frontal, temporal, focal, or none. The original reading of the neuroradiology group was reconfirmed with visual inspection of the DICOM PET images.
The PET scans completed by a private neuroradiology group (MedScan) were conducted with either a whole-body or brain-specific high-resolution PET (Siemens/CTI ECAT HR+, with 4.6×4.6×4.2 mm NEMA; National Electrical Manufacturers Association) using FDG. Methodological details for scanning have been published.18 Prior to PET imaging, a diagnostic quality CT scan of the brain was performed without intravenous contrast, and the patient’s blood glucose level was assessed as being within normal limits. After the CT scan, 14-18 mCi of FDG was administered intravenously. PET scan imaging was performed approximately 50-minutes after the administration of the radioisotope. Forty-seven slices were obtained at approximately 3.3 mm thickness, covering the entire brain parenchyma from the base of the cerebellum to the vertex.
CDs of the DICOM image data of the PET scans were converted to Analyze format utilizing MRIcro,18 which also anonymized the images to which blinded IDs were assigned. The analyzed formatted images were then imported to Statistical Parametric Mapping,19 where they were reviewed to exclude any scans with significant movement artifact, or areas of hypometabolism related to structural brain disorders not evident in the chart review, but observable on CT scan.
EEG, P300, and Evoked Potentials Data
The P300 potential was obtained
