Cerebral blood flow and Aβ-amyloid estimates by WARM analysis of [¹¹C]PiB uptake distinguish among and between neurodegenerative disorders and aging

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 [C]Pittsburgh Compound B ([C]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 [C]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 [C]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 [C]PiB's binding potentials (BP) and correlated surrogate cerebral blood flow (sCBF) estimates, based on the [C]PiB images, compared to estimates by conventional Standard Uptake Value Ratio (SUVR) of [C]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 [C]PiB binding potential (BP) by WARM exceeded the power of SUVR that in turn exceeded the power of sCBF estimates. Differences of [C]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 [C]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 [C]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

The hypoxia imaging agent Cu ii(atsm) is neuroprotective and improves motor and cognitive functions in multiple animal models of Parkinson's disease

Parkinson's disease (PD) is a progressive, chronic disease characterized by dyskinesia, rigidity, instability, and tremors. The disease is defined by the presence of Lewy bodies, which primarily consist of aggregated α-synuclein protein, and is accompanied by the loss of monoaminergic neurons. Current therapeutic strategies only give symptomatic relief of motor impairment and do not address the underlying neurodegeneration. Hence, we have identified Cu II(atsm) as a potential therapeutic for PD. Drug administration to four different animal models of PD resulted in improved motor and cognition function, rescued nigral cell loss, and improved dopamine metabolism. In vitro, this compound is able to inhibit the effects of peroxynitrite-driven toxicity, including the formation of nitrated α-synuclein oligomers. Our results show that Cu II(atsm) is effective in reversing parkinsonian defects in animal models and has the potential to be a successful treatment of PD

MR-less high dimensional spatial normalization of (11)C PiB PET images on a population of elderly, mild cognitive impaired and alzheimer disease patients

beta - amyloid (A beta) plaques are one of the neuropathological hallmarks of Alzheimer's disease (AD) and can be quantified using the marker C-11 PiB. As C-11 PiB PET images have limited anatomical information, an Magnetic Resonance Image, (MRI) is usually acquired to perforin the spatial normalization needed for population anaysis. We designed and evaluated a, high dimensional spatial normalization approach that, only use, the, C-11 PiB PET image. The non-rigid registration (NRR) is based oil free form deformation (FFD) modelled using B-splines. To compensate for the limited anatomical information, the FFD is constrained to an allowable transform space using a model trained from MR registrations. A beta deposition is dependent on (diseases staging, so a spatially normalized C PiB PET appearance model selects and refines the atlas. The approach was compared with MR NRR using data from healthy elderly, mild Cognitive impaired and Alzheimer disease participants. Using segmentation propagation, an average, Dice similarity coefficient, of 0.64 and 0.73 was obtained for white and gray matter. The R-squared correlation between the uptake obtained in the frontal, parietal, occipital and temporal was 0.789, 0.843, 0.871 and 0.964. These are very promising results, considering the low of C-11 PiB PET images

Correlation of memory dysfunction and amyloid burden in mild cognitive impairment

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Nicotinic receptors are not responsible for improved cognitive performance by galantamine in early Alzheimer's disease: A 2-[18F]F-A-85380 PET study

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Correlation between amyloid burden and memory impairment: A¹¹C-PIB PET cross sectional study

Objectives: Mild cognitive impairment (MCI) carries a high risk of conversion to Alzheimer's disease (AD). The relationship between brain beta-amyloid (A?) burden and cognitive function has not been explored in subjects with MCI. We examined this relationship using in-vivo amyloid-imaging tracer 11C-PIB. Methods: 32 healthy controls (HC) (age 71 � 7; MMSE >28), 35 MCI subjects (age 71 � 9; MMSE 26.8 � 2) and 40 subjects with mild to moderate AD (age 74 � 10; MMSE 21.7 � 4) underwent 11C-PIB PET. All subjects underwent MMSE and California Verbal Learning Test II (CVLT II). A? burden was quantified using Standardized Uptake Value normalized to cerebellar cortex (SUVR) 40-70 post-injection. The neocortical SUVR was used for analysis. Results: Neocortical SUVR was 1.40 � 0.33 in HC, 1.84 � 0.59 in MCI and 2.42 � 0.33 in AD and correlated negatively across all subjects with MMSE (r = -0.56, P < 0.001). When groups were analysed separately, only the MCI cohort showed a correlation with cognition (MMSE: r = -0.33, P < 0.05; CVLT: r = -0.53, P < 0.001). Cognitive performance did not correlate with level of PIB retention in other groups. At a SUVR threshold of 1.6 (the 75th percentile of HC), cortical PIB binding was present in 100% of AD, 60% of MCI and 23% of HC. In MCI, but not in HC, PIB positive subjects performed worse than PIB negative subjects on cognitive performance (CVLT II-long delay: 3.60 � 4.51 vs. 7.21 � 4.35; p = 0.026). Correlation between A? and memory impairment in MCI persisted after excluding the PIB negative subjects (CVLT r = -0.49, P < 0.01). Conclusions: Our data supports a pathogenic role for A? accumulation in AD by showing a relationship to mild cognitive impairment. This relationship is lost in later stages of disease as dementia develops suggesting a maximum or equilibrium level of A? plaque can be reached early in the pathological course of AD. These findings may have implications for anti-amyloid therapy.7 page(s

Amyloid burden in ageing subjects with and without cognitive decline

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Relationship between nicotinic receptors and cognitive function in early Alzheimer's disease: A 2-[F-18]fluoro-A-85380 PET study

Neuronal nicotinic acetylcholine receptors (nAChRs) are critical for higher order cognitive processes. Post-mortem studies suggest reductions in nAChRs (particularly the α4β2 subtype) with ageing and in Alzheimer's disease (AD). This study aimed to; (1) quantify nAChR distribution in vivo with 2-[18F]fluoro-A-85380 (2-FA) in 15 early AD patients compared to 14 age-matched, healthy controls (HC) and (2) correlate nAChR distribution with cognitive performance in both groups. All participants were non-smokers and underwent cognitive testing along with a dynamic PET scan after injection of 200 MBq of 2-FA. Brain regional 2-FA binding was assessed through a simplified estimation of Distribution Volume (DVS). The AD group differed significantly from HC on all cognitive measures employed, with impairments on measures of attention, working memory, language, executive function, visuospatial ability, verbal learning and verbal memory (p &lt; .05). Contrary to post-mortem data this study found no evidence of in vivo nAChR loss in early AD despite significant cognitive impairment. Furthermore, no correlation between nAChR and cognitive performance was found for either group. The findings of the current study suggest preservation of nAChRs early in AD supporting previous studies. It is possible that while the clinical 2-FA PET method described here may be insensitive in detecting changes in early AD, such changes may be detected in more advanced stages of the illness.9 page(s