published version features the final layout of the paper including the volume, issue and page numbers. Link to publication General rightsCopyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal.If the publication is distributed under the terms of Article 25fa of the Dutch Copyright Act, indicated by the "Taverne" license above, please follow below link for the End User

Background Clinical staging of Alzheimer disease (AD) may help develop novel treatment in the early stage. Aim We measured the accumulation of amyloid beta (Aβ) and tau with positron emission tomography (PET) in patients with AD to explore its utility for clinical staging. Methods Six patients with AD, two patients with mild cognitive impairment (MCI), and 12 healthy controls (HC) were studied. Aβ and tau accumulation was evaluated with [11C]PiB and [11C]PBB3, respectively. Results PBB3‐PET showed that two cases were in stage I‐II (Braak stage), one case was in stage III‐IV, and three cases were in stage V‐VI. PiB‐PET showed that all cases were in stage C. The duration of the disease correlated positively with PBB3 staging but not with PiB staging. The performance on the Mini‐Mental State Examination (MMSE) tended to decrease with advancing of PBB3 stage but not with PiB stage. PBB3 SUVR and PiB SUVR in all AD signature areas including the parahippocampal gyrus were significantly higher in AD than in HC. A decrease in MMSE is correlated with increases in PBB3 and PiB. Increase in PBB3 started with decrease in MMSE whereas increase in PiB was already observed in the point of highest MMSE, indicating amyloid is already accumulated in the earliest stage. Conclusions The expansion of tau distribution from the parahippocampal gyrus to the cerebral cortex was observed with advancing AD, whereas Aβ distribution was already advanced in the earliest stage. PBB3 may be useful in determining stages in AD based on tau distribution.

No 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.

No abstract

Disposition of amyloid β (Aβ) into the perivascular space of the cerebral cortex has been recently suggested as a major source of its clearance, and its disturbance may be involved in the pathogenesis of cerebral amyloid angiopathy and Alzheimer’s disease. Here, we explored the in vivo dynamics of Aβ in the perivascular space of anesthetized mice. Live images were obtained with two-photon microscopy through a closed cranial window. Either fluorescent-dye-labeled Aβ oligomers prepared freshly or Aβ fibrils after 6 days of incubation at 37 °C were placed over the cerebral cortex. Accumulation of Aβ was observed in the localized perivascular space of the penetrating arteries and veins. Transportation of the accumulated Aβ along the vessels was slow and associated with changes in shape. Aβ oligomers were transported smoothly and separately, whereas Aβ fibrils formed a mass and moved slowly. Parenchymal accumulation of Aβ oligomers, as well as Aβ fibrils along capillaries, increased gradually. In conclusion, we confirmed Aβ transportation between the cortical surface and the deeper parenchyma through the perivascular space that may be affected by the peptide polymerization. Facilitation of Aβ excretion through the system can be a key target in treating Alzheimer’s disease.

Background Heterogeneity in Alzheimer's disease (AD) has been reported on the basis of clinical, neuropathological, and neuroimaging data. However, most of the indices, including cerebral atrophy evaluated using magnetic resonance imaging and amyloid β (Aβ) accumulation detected using positron emission tomography (PET), lack sensitivity, and specificity for categorization. Aim Herein, we used a novel PET ligand for tau to estimate the differential distribution of tau in the subtypes of AD. Methods Patients with posterior cortical atrophy (PCA; n = 3), frontal variant of AD (FAD; n = 1), logopenic variant primary progressive aphasia (LPPA; n = 2), typical AD (TAD; n = 6), and healthy controls (HC; n = 12) were studied. Aβ and tau accumulation were evaluated using [11C]PiB and [11C]PBB3, respectively. Results Amyloid β accumulation was confirmed in all PCA, FAD, LPPA, and TAD cases. Tau accumulation was dominantly high in the occipital lobes in the PCA, strikingly high in the frontal lobes in the FAD, and moderately high in the angular gyrus of the dominant hemisphere in the LPPA. Tau accumulation in TAD cases was significantly higher than age‐dependent tau accumulation in HC in these subtype‐specific regions as well as in AD signature regions. Glucose utilization was reversely correlated with PBB3 accumulation in the subtype‐specific regions. Conclusions Tau accumulates differently in the four subtypes of AD, suggesting that tau pathology may be closely associated with unique clinical features.

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.