Staging of tau distribution by positron emission tomography may be useful in clinical staging of Alzheimer disease

Aohara, Kenta; Minatani, Shinobu; Kimura, Hiroko; Takeuchi, Jun; Takeda, Akitoshi; Kawabe, Joji; Wada, Yasuhiro; Mawatari, Aya; Watanabe, Yasuyoshi; Shimada, Hitoshi; Higuchi, Makoto; Suhara, Tetsuya; Itoh, Yoshiaki

doi:10.1111/ncn3.12366

Cited by 6 publications

(13 citation statements)

References 33 publications

(67 reference statements)

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“…Previous clinical trials targeting accumulated Aβ were mostly successful in reducing Aβ but failed to improve the clinical outcomes and even worsened the outcomes in some studies [ 18 ]. In contrast, in the present and previous studies, we demonstrated that tau accumulates more widely as the disease progresses in SAD [ 15 ]. The burden of tau was also heavy in FAD (Osaka) without amyloid accumulation.…”

Section: Discussioncontrasting

confidence: 99%

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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

Shimada

Minatani

Takeuchi

et al. 2020

IJMS

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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.

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Section: Discussioncontrasting

confidence: 99%

“…We previously reported that in SAD, tau accumulation spreads from the parahippocampal gyrus to the cerebral cortex with advancing phases of AD, whereas Aβ distribution is already advanced in the clinically earliest stage [ 15 ]. Similar reports supporting our data have been recently published by Jack et al [ 16 ].…”

Section: Discussionmentioning

confidence: 99%

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

Shimada

Minatani

Takeuchi

et al. 2020

IJMS

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“…Similar to a case in the present study, Spitzer et al also reported a 35‐year‐old woman with HDLS whose tau levels in the cerebrospinal fluid were moderately elevated 22 . We previously reported that tau accumulation spreads with disease progression in a large series of Alzheimer's disease 6 . Further studies are warranted to confirm the current hypothesis.…”

Section: Discussionsupporting

confidence: 90%

“…Pathologically, the spheroids in HDLS contain abnormal proteins, such as phosphorylated neurofilament and amyloid precursor protein 3,4 . The accumulation and spread of abnormal proteins, including amyloid β, tau, and α‐synuclein, is currently considered a cardinal mechanism involved in the development of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease 6,7 . A similar spreading mechanism may be involved in HDLS.…”

Section: Introductionmentioning

confidence: 99%

Progression of cortical dysfunction in CSF1R‐related leukoencephalopathy detected using single‐photon emission computed tomography

Sakaguchi

Hasegawa

Minatani

et al. 2021

Neurology & Clinical Neurosc

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Background Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a rare autosomal dominant disease progressively affecting cognitive and motor functions, most often caused by mutations in the colony‐stimulating factor 1 receptor gene (CSF1R). Aim To elucidate the mechanism of disease progression, changes in white matter lesions and cortical cerebral blood flow (CBF) were evaluated in cases during various stages of the disease. Methods All patients were diagnosed with HDLS by confirming mutations in CSF1R. Regional CBF was evaluated using single‐photon emission computed tomography and was analyzed semiquantitatively. Results Three cases (2 males and 1 female, ages 51, 53, and 48 years on admission, disease duration from 1 to 8 years) were registered. All cases exhibited different CSF1R mutations and progressive frontal dysfunction. Scores of the Frontal Assessment Battery and time in the Trail Making Test worsened as the disease progressed, whereas the Mini‐Mental State Examination score remained relatively stable. MRI revealed progressive white matter lesions in the frontal lobe and atrophy of the anterior body of the corpus callosum. Regional CBF was low in the medial frontal cortex in the early case, and the area of hypoperfusion spread to the lateral frontal cortex and parietal cortex as the disease progressed. CBF was maintained in the basal ganglia, thalamus, and occipital lobes. Conclusions Hypoperfusion was initially observed in the medial frontal lobe and spread to the lateral frontal lobe and parietal lobe with disease progression. Spreading of accumulated abnormal proteins induced by mutation in CSF1R may be involved as a molecular mechanism of disease progression.

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“…Clinical studies using a limited number of patients indicated sensitive detection of tau pathology by 11 C-PBB3 in patients with AD, with evidence of association between 11 C-PBB3 uptake and disease progression [ 18 , 19 ]. The 11 C-PBB3 distribution among cognitively normal and AD groups could mirror the pathological staging [ 20 ]. It was reported that in contrast to a relatively low 11 C-PIB uptake in the hippocampus as a cortical association area in AD, 11 C-PBB3 provided a robust signal in this region [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Quantitative analysis of regional distribution of tau pathology with 11C-PBB3-PET in a clinical setting

et al. 2022

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Purpose The recent developments of tau-positron emission tomography (tau-PET) enable in vivo assessment of neuropathological tau aggregates. Among the tau-specific tracers, the application of 11C-pyridinyl-butadienyl-benzothiazole 3 (11C-PBB3) in PET shows high sensitivity to Alzheimer disease (AD)-related tau deposition. The current study investigates the regional tau load in patients within the AD continuum, biomarker-negative individuals (BN) and patients with suspected non-AD pathophysiology (SNAP) using 11C-PBB3-PET. Materials and methods A total of 23 memory clinic outpatients with recent decline of episodic memory were examined using 11C-PBB3-PET. Pittsburg compound B (11C-PIB) PET was available for 17, 18F-flurodeoxyglucose (18F-FDG) PET for 16, and cerebrospinal fluid (CSF) protein levels for 11 patients. CSF biomarkers were considered abnormal based on Aβ42 (< 600 ng/L) and t-tau (> 450 ng/L). The PET biomarkers were classified as positive or negative using statistical parametric mapping (SPM) analysis and visual assessment. Using the amyloid/tau/neurodegeneration (A/T/N) scheme, patients were grouped as within the AD continuum, SNAP, and BN based on amyloid and neurodegeneration status. The 11C-PBB3 load detected by PET was compared among the groups using both atlas-based and voxel-wise analyses. Results Seven patients were identified as within the AD continuum, 10 SNAP and 6 BN. In voxel-wise analysis, significantly higher 11C-PBB3 binding was observed in the AD continuum group compared to the BN patients in the cingulate gyrus, tempo-parieto-occipital junction and frontal lobe. Compared to the SNAP group, patients within the AD continuum had a considerably increased 11C-PBB3 uptake in the posterior cingulate cortex. There was no significant difference between SNAP and BN groups. The atlas-based analysis supported the outcome of the voxel-wise quantification analysis. Conclusion Our results suggest that 11C-PBB3-PET can effectively analyze regional tau load and has the potential to differentiate patients in the AD continuum group from the BN and SNAP group.

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Staging of tau distribution by positron emission tomography may be useful in clinical staging of Alzheimer disease

Cited by 6 publications

References 33 publications

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

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

Progression of cortical dysfunction in CSF1R‐related leukoencephalopathy detected using single‐photon emission computed tomography

Quantitative analysis of regional distribution of tau pathology with 11C-PBB3-PET in a clinical setting

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