Resting-state fMRI sheds light on neural substrates of cognitive decline in Parkinson disease

Neurology11月25日号に掲載されたOlde Dubbelinkの論文は、Parkinson病55例を対象としてfMRI検査を行い、3年間で認知機能の低下とともに、頭頂、側頭葉、後頭葉において進行性に機能的結合が消失していくことを示した論文であり、興味ある論文である

Imaging distinct strains of tau fibrils in Alzheimer\u27s disease and related neurodegenerative disorders

Deposition of fibrillary tau aggregates in the brain is characteristic of Alzheimer’s disease (AD) and allied disorders including frontotemporal lobar degeneration (FTLD), and has been reported to be tightly associated with neuronal loss in these illnesses. We recently developed an imaging agent, PBB3, applicable to positron emission tomography (PET) for humans and transgenic mouse models of tau pathologies. Preclinical and clinical PET studies have demonstrated that PBB3 retention in the brain reflects tau deposition in AD and familial and sporadic FTLDs. Our results have also supported the utility of PBB3-PET as an objective index for progression of AD, and have indicated that PBB3-positive tau deposition may precede reduction of regional cerebral glucose metabolism in transition from prodromal to severe AD. Notably, PET images of diverse tau-positive diseases highlight the view that isoform composition, mutation and even minor fibril strains of tau could determine mechanisms of tau-induced neurotoxicity, reactivity of tau with PET ligands and subcellular and regional localizations of pathological tau assemblies. Hence, reactivity with PBB3 and other PET ligands would help to identify a tau strain accumulating in each individual, facilitating a strain-specific anti-tau therapy as personalized medicine. Finally, 18F-fluorinated PBB3 derivatives with a longer radioactive half-life are being developed for wider availability and better dynamic range, potentially offering robust clarification of roles played by distinct tau fibril strains in neurodegeneration.Brain Conference 201

Imaging diverse tau fibril strains in tauopathies

Visualization of fibrillar tau aggregates in Alzheimer’s disease (AD) and other tauopathies including frontotemporal lobar degeneration (FTLD) provides insights into roles of tau deposition in neurodegeneration, and a diagnostic adjunct to these illnesses. We recently developed a positron emission tomographic (PET) imaging agent for tau lesions, PBB3, and demonstrated its capability in detecting tau accumulation in diverse tauopathies. PBB3-PET also indicated spreading of tau pathology from the hippocampal formation to extensive neocortical areas in transition from normal aging to advanced AD. In FTLD patients, distributions of PBB3 retention differed between progressive supranuclear palsy (PSP) and corticobasal syndrome, and were also distinct from those in AD. Furthermore, PET and autoradiography with PBB3 have revealed regionality of PBB3-positive tau deposition in a manner characteristic of familial tau gene mutations. Notably, PBB3 and various other tau ligands displayed differential reactivity with tau aggregates in FTLDs. These data support the presence of distinct strains of tau fibrils presumably attributed to different isoform compositions and mutations of tau as well as interactions of tau with non-tau aggregates, and the same non-mutant tau isoforms may also produce minor conformational variations in PSP and corticobasal degeneration. These strains define regional, cellular and subcellular localization of tau inclusions, and would be identified in living brains using a set of tau PET ligands. PBB3 may be utilized as a versatile ligand reacting with tau lesions in the vast majority of tauopathies, and development of its fluorinated derivatives aimed at a wider use is in progress.9th International Conference on Frontotemporal Dementia

Noninvasive k3 estimation method for slow dissociation PET ligands: application to [11C]Pittsburgh compound B.

Background: Recently, we reported an information density theory and an analysis of three-parameter plus shorter scan than conventional method (3P+) for the amyloid-binding ligand [11C]Pittsburgh compound B (PIB) as anexample of a non-highly reversible positron emission tomography (PET) ligand. This article describes an extension of 3P + analysis to noninvasive ‘3P++’ analysis (3P + plus use of a reference tissue for input function).Methods: In 3P++ analysis for [11C]PIB, the cerebellum was used as a reference tissue (negligible specific binding). Fifteen healthy subjects (NC) and fifteen Alzheimer\u27s disease (AD) patients participated. The k3 (index of receptordensity) values were estimated with 40-min PET data and three-parameter reference tissue model and were compared with that in 40-min 3P + analysis as well as standard 90-min four-parameter (4P) analysis with arterial input function. Simulation studies were performed to explain k3 biases observed in 3P++ analysis.Results: Good model fits of 40-min PET data were observed in both reference and target regions-of-interest (ROIs). High linear intra-subject (inter-15 ROI) correlations of k3 between 3P++ (Y-axis) and 3P + (X-axis) analyses wereshown in one NC (r2 = 0.972 and slope = 0.845) and in one AD (r2 = 0.982, slope = 0.655), whereas inter-subject k3 correlations in a target region (left lateral temporal cortex) from 30 subjects (15 NC + 15 AD) were somewhat lower(r2 = 0.739 and slope = 0.461). Similar results were shown between 3P++ and 4P analyses: r2 = 0.953 for intra-subject k3 in NC, r2 = 0.907 for that in AD and r2 = 0.711 for inter-30 subject k3. Simulation studies showed that such lowerinter-subject k3 correlations and significant negative k3 biases were not due to unstableness of 3P++ analysis but rather to inter-subject variation of both k2 (index of brain-to-blood transport) and k3 (not completely negligible) inthe reference region.Conclusions: In [11C]PIB, the applicability of 3P++ analysis may be restricted to intra-subject comparison such as follow-up studies. The 3P++ method itself is thought to be robust and may be more applicable to other non-highly reversible PET ligands with ideal reference tissue

Quantification of putaminal dopamine transporter in patients with REM sleep behavior disorder and Parkinson’s disease

not available第18回国際パーキンソン病・運動障害疾患会議（MDS2014

In vivo tau PET imaging using [11C]PBB3 in Alzheimer’s disease and non-Alzheimer’s disease tauopathies.

Objectives:[11C]PBB3 is a novel tau imaging PET ligand, which could visualize the tau deposition in Alzheimer’s disease (AD) and non-AD tauopathies. The aim of the present study was to investigate characteristics of [11C]PBB3 binding and its relation with clinical aspects in cognitively healthy subjects and patients with cognitive impairments.Methods:Participants included 15 AD patients, 15 mild cognitive impairments (MCI) patients, few patients with corticobasal syndrome (CBS), progressive supranuclear palsy (PSP) and frontotemporal dementia (FTD) and 23 healthy controls (HCs). We performed [11C]PBB3 PET and [11C]PIB PET. Standardized uptake value ratio (SUVR) was calculated for each PET image using the cerebellar cortex as reference region. Results:All HCs and patients with non-AD tauopaties were PIB-negative, and all AD patients and 9 of 15 MCI patients were PIB-positive. [11C]PBB3 was highly accumulated in the medial temporal cortex of all AD and PIB-positive MCI patients, in which binding of [11C]PIB was minimal. Distribution of [11C]PBB3 accumulation observed in AD and PIB-positive MCI patients extended to the entire limbic system and subsequently to the neocortex as a function of the disease severity. Mean cortical [11C]PBB3 binding showed significantly positive correlation with dementia severity among AD and PIB-positive MCI patients. Furthermore, [11C] PBB3 was also accumulated in lesions associated with neurological symptoms in CBS, PSP and FTD patients, as well as some PIB-negative MCI patients and HCs. Conclusions:The present study demonstrated the spread of [11C]PBB3 binding reflect the dementia severity in AD and MCI due to AD patients. Furthermore, [11C]PBB3 binding could explain the neurological manifestations in CBS, PSP and FTD patients.Research support: “Integrated research on neuropsychiatric disorders”, “J-AMP”, Young Scientists 21791158, Scientific Research (B) 23390235, Core Research for Evolutional Science and Technology and Scientific Research on Innovative Areas 23111009 from the MEXT, Japan, Comprehensive Research on Dementia (No. 11103404) from MHLW, and the Mochida Memorial Foundation for Medical and Pharmaceutical Research.Society of Nuclear Medicine and Molecular Imaging 201

PET monitoring of donepezil therapy in patients with Alzheimers

The 12th International Symposium on Radiopharmacolog