Covariance PET patterns in early Alzheimer's disease and subjects with cognitive impairment but no dementia: utility in group discrimination and correlations with functional performance

Abstract

Although multivariate analytic techniques might identify diagnostic patterns that are not captured by univariate methods, they have rarely been used to study the neural correlates of Alzheimer's disease (AD) or cognitive impairment. Nonquantitative PET scans were acquired during rest in 17 probable AD subjects selected for mild severity [mean-modified Mini Mental Status Examination (mMMS) 46/57; SD 5.1], 16 control subjects (mMMS 54; SD 2.5) and 23 subjects with minimal to mild cognitive impairment but no dementia (mMMS 53; SD 2.8). Expert clinical reading had low success in discriminating AD and controls. There were no significant mean flow differences among groups in traditional univariate SPM Voxel-wise analyses or region of interest (ROI) analyses. A covariance pattern was identified whose mean expression was significantly higher in the AD as compared to controls (P = 0.03; sensitivity 76-94%; specificity 63-81%). Sites of increased concomitant flow included insula, cuneus, pulvinar, lingual, fusiform, superior occipital and parahippocampal gyri, whereas decreased concomitant flow was found in cingulate, inferior parietal lobule, middle and inferior frontal, supramarginal and precentral gyri. The covariance analysis-derived pattern was then prospectively applied to the cognitively impaired subjects: as compared to subjects with Clinical Dementia Rating (CDR) = 0, subjects with CDR = 0.5 had significantly higher mean covariance pattern expression (P = 0.009). Expression of this pattern correlated inversely with Selective Reminding Test total recall (r = −0.401, P = 0.002), delayed recall (r = −0.351, P = 0.008) and mMMS scores (r = −0.401, P = 0.002) in all three groups combined. We conclude that patients with AD may differentially express resting cerebral blood flow covariance patterns even at very early disease stages. Significant alterations in expression of resting flow covariance patterns occur even for subjects with cognitive impairment. Expression of covariance patterns correlates with cognitive and functional performance measures, holding promise for meaningful associations with underlying biopathological processes.

Structural and functional biomarkers of prodromal Alzheimer's disease: A high-dimensional pattern classification study

“…The pattern of reduced blood flow measured in our study was asymmetric, and in agreement with the findings of (Minoshima et al, 1994b;Reiman et al, 1996b;Scarmeas et al, 2004) who used PET 15 O imaging in an AD sample. A variety of PET studies in AD have demonstrated asymmetrically reduced blood flow or metabolic activity in AD patients (Foster et al, 1983;Ishii et al, 2005b;Kawachi et al, 2006;Koss et al, 1985;Martin et al, 1986) and in elderly individuals with cognitive decline (Hunt et al, 2007); however the biological underpinnings of these asymmetries are not quite known.…”

“…Two regions of reduced blood flow were also measured, namely the posterior cingulate and a fairly extended area in the left parietal and parieto-temporal cortex. Most of these regions are known to be affected by AD (Ardekani et al, 2007;Chetelat et al, 2002;Convit et al, 1997;Dickerson et al, 2001;Firbank et al, 2007;Fox and Schott, 2004;Fox et al, 1996b;Frisoni et al, 2007;Ishii et al, 2005a;Jack et al, 1999;Karas et al, 2007;Killiany et al, 2000;Krasuski et al, 1998;Matsuda et al, 2002;Pantano et al, 1999;Pennanen et al, 2005b;Thompson et al, 2007); however, it is their combination via high-dimensional pattern classification that leads to high diagnostic accuracy on an individual basis.The pattern of reduced blood flow measured in our study was asymmetric, and in agreement with the findings of (Minoshima et al, 1994b;Reiman et al, 1996b;Scarmeas et al, 2004) who used PET 15 O imaging in an AD sample. A variety of PET studies in AD have demonstrated asymmetrically reduced blood flow or metabolic activity in AD patients (Foster et al, 1983;Ishii et al, 2005b;Kawachi et al, 2006;Koss et al, 1985;Martin et al, 1986) and in elderly individuals with cognitive decline (Hunt et al, 2007); however the biological underpinnings of these asymmetries are not quite known.…”

Multivariate and Univariate Analysis of Continuous Arterial Spin Labeling Perfusion MRI in Alzheimer's Disease

“…In general, multivariate analysis might have increased sensitivity compared to univariate analysis even when the disease-related changes in CBF originate in clearly circumscribed foci and spread spatially during the disease course (Scarmeas et al, 2004). Multivariate analysis can detect these subtle, but robust changes, although univariate analysis might experience overly stringent false-positive corrections that tend to 'correct away' the true effects (as evidenced by the results of our voxelwise analysis.)…”

“…In this study, we focused our analysis in the GM where most of the dementia-related changes are expected to occur (Scarmeas et al, 2004). Although we did not explicitly measure the transit time difference between the groups, we conjecture that the transit times were not significantly different based on the following: (1) There was no significant difference in CASL CBF values acquired with two different PLDs, indicating that the shorter PLD we chose for this study was optimum.…”

“…Perfusion imaging techniques such as H 2 O 15 positron emission tomography (PET), single-photon emission computed tomography (SPECT), dynamic contrast enhanced magnetic resonance imaging (DCE MRI), and arterial spin labeling (ASL) MRI have proven to be indispensable tools in studying brain pathologies such as Alzheimer's disease (AD) (Alsop et al, 2000;Du et al, 2006;Herholz et al, 2002;Johnson et al, 1998;Scarmeas et al, 2004;Silverman et al, 2001). Most AD imaging studies have relied on PET and SPECT and have shown a marked decrease in metabolism and/or regional blood flow in the AD population (Herholz et al, 2002;Johnson et al, 1998;Scarmeas et al, 2004;Silverman et al, 2001). Results from several ASL studies have shown good agreement across techniques (Alsop et al, 2000;Du et al, 2006;Johnson et al, 2005;Sandson et al, 1996).…”