Heavy Tau Burden with Subtle Amyloid β Accumulation in the Cerebral Cortex and Cerebellum in a Case of Familial Alzheimer’s Disease with APP Osaka Mutation

Abstract

We previously identified a novel mutation in amyloid precursor protein from a Japanese pedigree of familial Alzheimer’s disease, FAD (Osaka). Our previous positron emission tomography (PET) study revealed that amyloid β (Aβ) accumulation was negligible in two sister cases of this pedigree, indicating a possibility that this mutation induces dementia without forming senile plaques. To further explore the relationship between Aβ, tau and neurodegeneration, we performed tau and Aβ PET imaging in the proband of FAD (Osaka) and in patients with sporadic Alzheimer’s disease (SAD) and healthy controls (HCs). The FAD (Osaka) patient showed higher uptake of tau PET tracer in the frontal, lateral temporal, and parietal cortices, posterior cingulate gyrus and precuneus than the HCs (>2.5 SD) and in the lateral temporal and parietal cortices than the SAD patients (>2 SD). Most noticeably, heavy tau tracer accumulation in the cerebellum was found only in the FAD (Osaka) patient. Scatter plot analysis of the two tracers revealed that FAD (Osaka) exhibits a distinguishing pattern with a heavy tau burden and subtle Aβ accumulation in the cerebral cortex and cerebellum. These observations support our hypothesis that Aβ can induce tau accumulation and neuronal degeneration without forming senile plaques.

Cofilin and Actin Dynamics: Multiple Modes of Regulation and Their Impacts in Neuronal Development and Degeneration

“…Rod formation in culture systems is causative of synaptic deficits, but rods only form in a subset of hippocampal neurons in response to disease-related degenerative factors. However, only a subpopulation of neurons in the hippocampus undergo loss of dendritic spines in a sleep deprivation model in which cognitive deficits are significant [297,298]. Given the importance of cofilin in modulating dynamic actin processes for synaptic function, it is not yet possible to conclude that rods per se are causative with respect to the cognitive dysfunctions that arise.…”

Identifying Mixed Dementia With Lewy Bodies and Alzheimer Disease Using Multitracer PET Imaging

“…Interestingly, apart from the diffuse accumulation in the cortex, tau tracer uptake was also detected in atypical locations such as the basal ganglia, thalamus ( I , white arrows), brainstem, and cerebellum ( H , white arrows), which is unusual in AD. Notwithstanding, the uptake pattern of Aβ and tau in the cortex indicated the presence of an AD-related pathological mechanism in the patient, 7 and the final diagnosis was DLB concurrent with AD. Notably, DLB and AD share numerous overlapping symptoms, 8 and previous efforts have aimed to establish a reliable differential diagnosis.…”

Radiosynthesis and quality control testing of the tau imaging positron emission tomography tracer [18F]PM‐PBB3 for clinical applications

“…Recently, we obtained the 11 C‐labeled 2‐((1 E ,3 E )‐4‐(6‐(methylamino)pyridin‐3‐yl)buta‐1,3‐dienyl)benzo[ d ]thiazol‐6‐ol ([ 11 C]PBB3), which has a 50‐fold higher binding affinity for tau compared with the Aβ deposits, as a clinically used PET tracer for in vivo imaging of tau pathology in the human brain 9–18 . [ 11 C]PBB3 was designed for capturing tau fibrils in a wide range of tauopathies 9 and demonstrated the ability to bind to three‐ and four‐repeat tau aggregates in human brain tissues with higher binding potential than [ 18 F]flortaucipir 19 .…”