Cerebral Blood Flow and Aβ-Amyloid Estimates by WARM Analysis of [11C]PiB Uptake Distinguish among and between Neurodegenerative Disorders and Aging

Abstract

Background: We report results of the novel Washout Allometric Reference Method (WARM) that uses estimates of cerebral blood flow and amyloid load from the same [11C]Pittsburgh Compound B ([11C]PiB) retention maps in brain to distinguish between patients with different forms dementia, including Alzheimer’s disease, and healthy volunteers. The method introduces two approaches to the identification of brain pathology related to amyloid accumulation, (1) a novel analysis of amyloid binding based on the late washout of the tracer from brain tissue, and (2) the simultaneous estimation of absolute cerebral blood flow indices (sCBF) from the early accumulation of the tracer in brain tissue.Objective: We tested the hypothesis that a change of cerebral blood flow is correlated with the degree of tracer [11C]PiB retention, reflecting dendritic spine pathology and consequent inhibition of brain energy metabolism and reduction of blood flow by neurovascular coupling in neurodegenerative disorders, including Alzheimer’s disease.Methods: Previously reported images of [11C]PiB retention in brain of 29 subjects with cognitive impairment or dementia [16 Alzheimer’s Disease (AD), eight subjects with dementia with Lewy bodies (DLB), five patients with frontotemporal lobar degeneration (FTLD), five patients with mild cognitive impairment, and 29 age-matched healthy control subjects (HC)], underwent analysis of PiB delivery and retention by means of WARM for quantitation of [11C]PiB’s binding potentials (BPND) and correlated surrogate cerebral blood flow (sCBF) estimates, based on the [11C]PiB images, compared to estimates by conventional Standard Uptake Value Ratio (SUVR) of [11C]PiB retention with cerebellum gray matter as reference. Receiver Operating Characteristics (ROC) revealed the power of discrimination among estimates.Results: For AD, the discriminatory power of [11C]PiB binding potential (BPND) by WARM exceeded the power of SUVR that in turn exceeded the power of sCBF estimates. Differences of [11C]PiB binding and sCBF measures between AD and HC both were highly significant (p < 0.001). For all the dementia groups as a whole, sCBF estimates revealed the greatest discrimination between the patient and HC groups. WARM resolves a major issue of amyloid load quantification with [11C]PiB in human brain by determining absolute sCBF and amyloid load measures from the same images. The two parameter approach provides key discriminary information in AD for which [11C]PiB traditionally is used, as well as for the distinct flow deficits in FTLD, and the marked parietal and occipital lobe flow deficits in DLB.Conclusion: We conclude that WARM yields estimates of two important variables that together discriminate among patients with dementia, including AD, and healthy volunteers, with ROC that are superior to conventional methods of analysis. The distinction between estimates of flow and amyloid load from the same dynamic emission tomograms provides valuable pathogenetic information.

Diagnostic manifestations of total hemispheric glucose metabolism ratio in neuronal network diaschisis: diagnostic implications in Alzheimer’s disease and mild cognitive impairment

“…The basal ganglia and thalami of patients with AD or MCI, in general, had a higher index of glucose metabolism compared to the cortex. The finding is consistent with the common observation of reduced glucose consumption in patients with AD or MCI, in addition to the hemispheric imbalance revealed by the THGr index [25][26][27][28]. Also, while the decline of metabolism initially may affect only one hemisphere, it progresses to involve both hemispheres but to different degrees.…”

“…We included the FDG-PET/CT brain images of 23 patients (17 females) with a final diagnosis of AD (n=15) or MCI (n=8), aged 50 to 78 y (mean age 63.7 y). The AD and MCI patients had a mean MMSE score of 20.5 (range: [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] and 24.9 (range: [16][17][18][19][20][21][22][23][24][25][26][27][28][29], and a mean CAMCOG score of 70.0 (range: 40-98) and 83.8 (range: 60-98), respectively. Ten age-matched HIs aged 43 to 75 y (mean age 62.5 y) were also included (5 females).…”

Brain Amyloid PET Tracer Delivery is Related to White Matter Integrity in Patients with Mild Cognitive Impairment

“…For example, early kinetic parameters, such as the unidirectional influx constant (K1), have been shown to be correlated with cerebral blood flow (CBF) and glucose metabolism . Moreover, dynamic data fitted using the simplified reference tissue model (SRTM) have shown that the kinetic parameter R1–the ratio of K1 in target versus a reference tissue is also highly correlated with CBF and glucose metabolism . Associations of early [ 11 C]‐PIB standardized uptake value (SUV) and R1 have recently been validated both with a measure of CBF, [ 15 O]‐water PET, and cerebral glucose metabolism measured with fludeoxyglucose PET .…”

Early Phase PIB‐PET as a Surrogate for Global and Regional Cerebral Blood Flow Measures

“…The potential of the initial phase of the amyloid study to reflect cerebral blood flow (CBF) has been recognized. Reports have compared CBF to estimates derived from the summed early phase [ 11 C]PIB images (6 minutes, 1‐4 minutes), and WARM (washout allometric reference method) and the normalized CBF (to cerebellum) to the R1 parameter from the standard reference tissue model . These techniques are generally computationally demanding (eg, R1 or WARM) or produce relative CBF measures only .…”