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1.  Blood-brain transfer of Pittsburgh compound B in humans 
In the labeled form, the Pittsburgh compound B (2-(4′-{N-methyl-[11C]}methyl-aminophenyl)-6-hydroxy-benzothiazole, [11C]PiB), is used as a biomarker for positron emission tomography (PET) of brain β-amyloid deposition in Alzheimer's disease (AD). The permeability of [11C]PiB in the blood-brain barrier is held to be high but the permeability-surface area product and extraction fractions in patients or healthy volunteers are not known. We used PET to determine the clearance associated with the unidrectional blood-brain transfer of [11C]PiB and the corresponding cerebral blood flow rates in frontal lobe, whole cerebral cortex, and cerebellum of patients with Alzheimer's disease and healthy volunteers. Regional cerebral blood flow rates differed significantly between the two groups. Thus, regional and whole-brain permeability-surface area products were identical, in agreement with the observation that numerically, but insignificantly, unidirectional blood-brain clearances are lower and extraction fractions higher in the patients. The evidence of unchanged permeability-surface area products in the patients implies that blood flow changes can be deduced from the unidirectional blood-brain clearances of [11C]PiB in the patients.
doi:10.3389/fnagi.2013.00070
PMCID: PMC3819578  PMID: 24223554
Alzheimers disease; blood-brain barrier; cerebral blood flow measurement; permeability-surface area product; pittsburgh compound B
2.  Washout allometric reference method (WARM) for parametric analysis of [11C]PIB in human brains 
Rapid clearance and disappearance of a tracer from the circulation challenges the determination of the tracer's binding potentials in brain (BPND) by positron emission tomography (PET). This is the case for the analysis of the binding of radiolabeled [11C]Pittsburgh Compound B ([11C]PIB) to amyloid-β (Aβ) plaques in brain of patients with Alzheimer's disease (AD). To resolve the issue of rapid clearance from the circulation, we here introduce the flow-independent Washout Allometric Reference Method (WARM) for the analysis of washout and binding of [11C]PIB in two groups of human subjects, healthy aged control subjects (HC), and patients suffering from AD, and we compare the results to the outcome of two conventional analysis methods. We also use the rapid initial clearance to obtain a surrogate measure of the rate of cerebral blood flow (CBF), as well as a method of identifying a suitable reference region directly from the [11C]PIB signal. The difference of average absolute CBF values between the AD and HC groups was highly significant (P < 0.003). The CBF measures were not significantly different between the groups when normalized to cerebellar gray matter flow. Thus, when flow differences confound conventional measures of [11C]PIB binding, the separate estimates of CBF and BPND provide additional information about possible AD. The results demonstrate the importance of data-driven estimation of CBF and BPND, as well as reference region detection from the [11C]PIB signal. We conclude that the WARM method yields stable measures of BPND with relative ease, using only integration for noise reduction and no model regression. The method accounts for relative flow differences in the brain tissue and yields a calibrated measure of absolute CBF directly from the [11C]PIB signal. Compared to conventional methods, WARM optimizes the Aβ plaque load discrimination between patients with AD and healthy controls (P = 0.009).
doi:10.3389/fnagi.2013.00045
PMCID: PMC3842163  PMID: 24348416
Alzheimer's disease; CBF; Aβ; PIB; flow normalization; parametric imaging
3.  A comparative clinical, pathological, biochemical and genetic study of fused in sarcoma proteinopathies 
Brain  2011;134(9):2548-2564.
Neuronal intermediate filament inclusion disease and atypical frontotemporal lobar degeneration are rare diseases characterized by ubiquitin-positive inclusions lacking transactive response DNA-binding protein-43 and tau. Recently, mutations in the fused in sarcoma gene have been shown to cause familial amyotrophic lateral sclerosis and fused in sarcoma-positive neuronal inclusions have subsequently been demonstrated in neuronal intermediate filament inclusion disease and atypical frontotemporal lobar degeneration with ubiquitinated inclusions. Here we provide clinical, imaging, morphological findings, as well as genetic and biochemical data in 14 fused in sarcoma proteinopathy cases. In this cohort, the age of onset was variable but included cases of young-onset disease. Patients with atypical frontotemporal lobar degeneration with ubiquitinated inclusions all presented with behavioural variant frontotemporal dementia, while the clinical presentation in neuronal intermediate filament inclusion disease was more heterogeneous, including cases with motor neuron disease and extrapyramidal syndromes. Neuroimaging revealed atrophy of the frontal and anterior temporal lobes as well as the caudate in the cases with atypical frontotemporal lobar degeneration with ubiquitinated inclusions, but was more heterogeneous in the cases with neuronal intermediate filament inclusion disease, often being normal to visual inspection early on in the disease. The distribution and severity of fused in sarcoma-positive neuronal cytoplasmic inclusions, neuronal intranuclear inclusions and neurites were recorded and fused in sarcoma was biochemically analysed in both subgroups. Fused in sarcoma-positive neuronal cytoplasmic and intranuclear inclusions were found in the hippocampal granule cell layer in variable numbers. Cortical fused in sarcoma-positive neuronal cytoplasmic inclusions were often ‘Pick body-like’ in neuronal intermediate filament inclusion disease, and annular and crescent-shaped inclusions were seen in both conditions. Motor neurons contained variable numbers of compact, granular or skein-like cytoplasmic inclusions in all fused in sarcoma-positive cases in which brainstem and spinal cord motor neurons were available for study (five and four cases, respectively). No fused in sarcoma mutations were found in any cases. Biochemically, two major fused in sarcoma species were found and shown to be more insoluble in the atypical frontotemporal lobar degeneration with ubiquitinated inclusions subgroup compared with neuronal intermediate filament inclusion disease. There is considerable overlap and also significant differences in fused in sarcoma-positive pathology between the two subgroups, suggesting they may represent a spectrum of the same disease. The co-existence of fused in sarcoma-positive inclusions in both motor neurons and extramotor cerebral structures is a characteristic finding in sporadic fused in sarcoma proteinopathies, indicating a multisystem disorder.
doi:10.1093/brain/awr160
PMCID: PMC3170529  PMID: 21752791
frontotemporal lobar degeneration; FUS; clinical presentation; neuropathology; biochemistry
4.  Low Residual CBF Variability in Alzheimer’s Disease after Correction for CO2 Effect 
We tested the claim that inter-individual CBF variability in Alzheimer’s disease (AD) is substantially reduced after correction for arterial carbon dioxide tension (PaCO2). Specifically, we tested whether the variability of CBF in brain of patients with AD differed significantly from brain of age-matched healthy control subjects (HC). To eliminate the CO2-induced variability, we developed a novel and generally applicable approach to the correction of CBF for changes of PaCO2 and applied the method to positron emission tomographic (PET) measures of CBF in AD and HC groups of subjects. After correction for the differences of CO2 tension, the patients with AD lost the inter-individual CBF variability that continued to characterize the HC subjects. The difference (ΔK1) between the blood-brain clearances (K1) of water (the current measure of CBF) and oxygen (the current measure of oxygen clearance) was reduced globally in AD and particularly in the parietal, occipital, and temporal lobes. We then showed that oxygen gradients calculated for brain tissue were similar in AD and HC, indicating that the low residual variability of CBF in AD may be due to low functional demands for oxidative metabolism of brain tissue rather than impaired delivery of oxygen.
doi:10.3389/fnene.2012.00008
PMCID: PMC3389721  PMID: 22783187
Alzheimer’s disease; brain energy metabolism; cerebral blood flow; cerebral metabolic rate for oxygen; cerebral vasoreactivity

Results 1-4 (4)