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Background: Accumulated evidence suggests altered energy metabolism in the brain of tauopathies. In Alzheimer's disease (AD) and progressive supranuclear palsy (PSP), decreased fluorodeoxyglucose (FDG) uptake in the cingulate cortex is considered a marker of neurodegeneration. However, its underlying pathogenesis remains unknown. It is hypothesized that lactate, a glucose metabolite, is produced in astrocytes and subsequently shuttles to neurons as an energy substrate. The current study aims to examine alterations in lactate and glucose concentrations and their association with astrocytic activities in the cingulate cortex of patients with AD and PSP. Method: Thirty AD, 30 PSP, and 30 healthy control (HC) subjects were enrolled. Lactate, glucose, and myoinositol (mI), an astroglial marker, in the anterior cingulate cortex (ACC) and posterior cingulate cortex (PCC) were determined by magnetic resonance spectroscopy (MRS) (3T scanner, SPECIAL sequence, TR/TE 3000/8.5ms, LCModel analysis) (Figure 1). Tau depositions were assessed using PET imaging with 18F‐PM‐PBB3. Result: All the patients with AD and PSP were confirmed to have the typical distribution of tau pathology. Lactate, glucose, and mI levels were higher in the ACC in PSP and AD, and PCC in AD compared to HC (p < 0.05) (Figure 2). In these cortical regions, lactate levels showed a positive correlation with mI levels (p < 0.05) (Figure 3). Lactate levels in the PCC in AD patients showed a positive correlation with Clinical Dementia Rating‐Sum of Boxes (CDR‐SB) scores (p < 0.05) (Figure 4). Moreover, mI levels in the ACC in PSP patients were negatively correlated with Frontal Assessment Battery (FAB) scores (p < 0.05) (Figure 4). Conclusion: We found elevated lactate and glucose levels accompanied by an increased astroglial marker mainly in the PCC in AD and ACC in PSP patients. Moreover, elevated lactate and mI levels in the cingulate cortex reflected the cognitive decline of AD and PSP, respectively. The excess lactate and glucose levels in the disease‐specific regions might reflect decreased energy utilization as shown in previous FDG‐PET studies. Given the residual lactate levels were correlated with mI levels, we speculated that the impaired lactate shuttle of reactivated astrocytes disrupts energy metabolism, leading to cognitive dysfunctions. [ABSTRACT FROM AUTHOR]

Background: Neurodegenerative pathologies, including tau depositions, have been implicated in late‐onset depression (LOD), while there is a lack of in‐vivo evidence for the neuropathological basis of late‐onset bipolar disorder (LOBD) despite postmortem findings of cerebral tau accumulations. The current study aimed to assess tau pathologies in LOBD and LOD patients positron emission tomography (PET) with 18F‐florzolotau, a radioligand for Alzheimer's disease (AD) and non‐AD tau fibrils. Methods: We studied LOBD and LOD patients who developed the first episode of mania or depression after age 45. Twenty‐one patients with LOBD (68.8 ± 9.6 years old; 11 females), 15 patients with LOD (73.0 ± 5.8 years old; 11 females), and 39 age‐matched healthy controls (HCs) (67.1 ± 9.1 years old; 19 females) underwent tau and amyloid PET scans with 18F‐florzolotau and 11C‐PiB, respectively. Amyloid positivity was determined by a visual read of 11C‐PiB‐PET images, and tau depositions were assessed by calculating standardized uptake value ratios (SUVRs) in 52 regions covering the cerebral grey matter and basal ganglia to the optimized reference tissue. All SUVRs were corrected for age and sex and converted to Z‐score relative to HCs. The positivity and topology of tau pathologies were determined according to the presence of a region with a Z‐score ≥ 2.0. Results: 18F‐florzolotau‐PET positivity was observed in 13 LOBD (62%), 7 LOD (47%), and 11 HC (28%) subjects, whereas 4 LOBD, 4 LOD, and no HC individuals were 11C‐PiB‐PET‐positive. A significant difference in the prevalence of tau pathologies was only found between LOBD and HCs (P = 0.043, corrected for multiple comparisons). Tau topologies in the cases with 11C‐PiB‐PET‐positive AD pathologies consisted of predominant frontal (1 LOBD and 3 LODs), lateral temporal (3 LOBDs and 1 LOD), and posterior (1 LOBD) accumulations. Meanwhile, tau pathologies in 11C‐PiB‐negative cases showed predominant frontal (2 LOBDs and 1 LOD), temporal (1 LOBD and 1 LOD), posterior (4 LOBDs and 1 LOD), and basal ganglia (2 LOBDs) localizations. Conclusion: Our findings suggest that a significant subset of LOBD patients harbor tau lesions linked to various AD subtypes and non‐AD tauopathies indicative of distinct early‐stage frontotemporal lobar degeneration subcategories. [ABSTRACT FROM AUTHOR]

Background: Chronic traumatic encephalopathy (CTE), formerly known as "boxer's encephalopathy" is a neurodegenerative disease associated with mild‐repetitive TBI. CTE is characterized by the deposition of hyperphosphorylated tau as neurofibrillary tangles around small blood vessels of the cortex, typically at the sulcal depths. Although tau PET studies on American football players reported findings consistent with neuropathological changes identified by postmortem brains, there are no reports of tau PET studies in boxers, and longitudinal changes of tau depositions following boxing remains unknown. The present study was aimed to characterize cerebral retention patterns of 18F‐florzolotau (18F‐APN‐1607) in the former professional boxers. Method: Twenty‐nine former boxers (43.4 ± 10.3 years) and 27 age‐matched healthy control (HC) subjects underwent PET scans with 18F‐florzolotau and 11C‐PiB. Eleven former boxers underwent a second tau PET scan (average interval: 874days). Standard uptake value ratio (SUVR) with the optimized reference tissue was calculated. Regions of interest were defined on brain regions of the gray matter (GM), white matter (WM) and the gray‐white matter boundary (GWB). Association of regional SUVR values with neurocognitive symptoms and various indexes related boxing was investigated. Result: One boxer was [11C]PiB positive. Former boxers showed higher 18F‐florzolotau retentions than HC subjects in the bilateral frontal GM, right parietal GM, bilateral frontal WM, right parietal WM (P < 0.001). There was a significant correlation between SUVR values in the whole GM and the total number of bouts (p = 0.07,r = 0.40). Subtyping using z‐score heatmap with predetermined criteria revealed heterogeneity in 18F‐florzolotau retention patterns in boxers. Of the 29 boxers, (1) 10 showed increased retention of 18F‐florzolotau in GM (GM dominant), (2) 4 showed increased accumulation mainly in WM (WM dominant), (3) 5 showed increased accumulation in GWB (GWB dominant), and (4) 10 showed no significant increased accumulation in the brain (No tau). These types vary in longitudinal changes of 18F‐florzolotau retention patterns, as well as in clinical features. Conclusion: The present study not only supports pathological heterogeneity of late‐sequalae of professional boxing, but also suggests utility of 18F‐florzolotau PET in detection of late‐life neurodegenerative diseases following mild‐repetitive TBI. [ABSTRACT FROM AUTHOR]

Background: Several blood‐based phosphorylated tau (p‐tau) assays that focus on the N‐terminus have been developed and established as non‐invasive biomarkers for detecting Alzheimer's disease (AD) pathologies from their early stages. However, the p‐tau measured by these assays may not necessarily reflect the accumulation of tau lesions in the brain due to correlation with Aβ burden. Therefore, there remains a significant unmet need to develop blood‐based tau biomarkers that are interchangeable with tau deposits in the brain. Methods: We have devised a novel Simoa assay that can detect N‐ and C‐terminally truncated fragment of p‐tau181 in plasma (QST assay), utilizing an antibody against the mid‐region of tau protein for capture, and an antibody AT270 for detection. The plasma p‐tau181 was measured with both the QST assay and a conventional p‐tau181 Simoa assay (Quanterix) in 164 subjects, including 40 cognitively normal (CN) individuals, 48 with AD continuum, 50 with progressive supranuclear palsy, and 26 with other frontotemporal lobar degeneration, who underwent Aβ (11C‐PiB) and tau (18F‐PM‐PBB3, Florzorotau) positron emission tomography (PET) scans. Subsequently, we conducted a head‐to‐head comparison of p‐tau181 assays in correlation with the imaging biomarker and cognitive dysfunction. Results: QST p‐tau assay demonstrated inferior performance compared to the Quanterix assay in the qualification of Aβ PET (QST assay: AUC = 0.771, Quanterix assay: AUC = 0.867). Neither assay showed a significant correlation with Aβ PET accumulation in the AD group. Meanwhile, the QST assay exhibited excellent correlations with tau PET accumulation in regions indicative of AD including temporal cortex and neocortex (p<0.0005), whereas the Quanterix assay demonstrated non‐linear correlations with tracer binding. In trajectories from CN to AD continuum, the QST assay exhibited a linear association, as well as tau PET accumulation, while the Quanterix assay exhibited a sigmoidal curve association. Conclusions: We have developed a new p‐tau181 assay directly correlated with tau PET accumulation. This quantitative system serves as a promising surrogate marker for tau lesions in the AD brain, which facilitate screening and monitoring of tau deposits in various settings, including developing disease‐modifying therapeutics. [ABSTRACT FROM AUTHOR]

Background: Several cohort studies have recently reported associations between late‐life psychosis and dementia, and postmortem studies have demonstrated that most individuals with late‐onset schizophrenia and delusional disorder had tau pathologies. The present study was aimed to assess the prevalence and topology of tau pathologies by positron emission tomography (PET) with a specific probe, 18F‐PM‐PBB3 (18F‐APN‐1607), in patients with late‐onset psychosis (LOP). Method: We included LOP patients who experienced the first episode of psychosis after 65 years old and excluded those with dementia. Fourteen patients with LOC (74.2 ± 4.0 years old; 7 females and 7 males)and 16 age‐matched healthy controls (HCs) (72.6 ± 5.7 years old; 9 females and 7 males) underwent PET scans with 18F‐PM‐PBB3 and an amyloid‐β probe, 11C‐PiB. The radioprobe retention was calculated as standardized uptake value ratio (SUVR), and the laterality index (LI) of SUVR was estimated as [Left‐Right/(Left+Right)]. We compared 18F‐PM‐PBB3 SUVRs and LIs in the frontal, temporal, parietal, and occipital cortices between patients and HCs using an independent t‐test after Bonferroni correction (p‐value ≤ 0.05/4). Result: All HCs were negative for 11C‐PiB‐PET. By contrast, unequivocally increased 18F‐PM‐PBB3 retentions were found in 4 out of 4 11C‐PiB‐positive patients (100%) and 7 out of 10 11C‐PiB‐negative patients (70%) with variable localizations. Tau topologies in four 11C‐PiB‐positive cases were characteristic of Alzheimer's disease and consisted of limbic predominant (N = 2), medial temporal lobe‐sparing (N = 1), and lateral temporal (N = 1) deposition subtypes. Meanwhile, tau topologies in 7 11C‐PiB‐negative cases were composed of lateral‐posterior diffuse (N = 3), posterior mild (N = 2), lateral temporal local (N = 1), and progressive supranuclear palsy‐like (N = 1) accumulations. None of the target regions exhibited significant differences in 18F‐PM‐PBB3 SUVR between patients and HCs, reflecting the heterogeneous distributions of tau deposits in patients. There was significant rightward lateralization of tau pathologies indicated by a reduced LI in the frontal cortex (P = 0.0093) but not the other cortical regions. Conclusion: Our findings indicate that LOP is associated with tau topologies of diverse Alzheimer's and non‐Alzheimer's disease subtypes. The rightward lateralization of tau pathologies in the frontal cortex might be involved in the development of psychotic manifestations. [ABSTRACT FROM AUTHOR]

Background: Frontotemporal dementia (FTD) is a group of neurodegenerative disorders with diverse clinical and neuropathological features. However, in vivo neuropathological assessments of FTD at an individual level have not hitherto been successful. Here, we aimed to classify patients with FTD based on topologies of tau protein aggregates captured by positron emission tomography (PET) with 18F‐florzolotau, which allows high‐contrast imaging of diverse tau fibrils in Alzheimer's disease (AD) and non‐AD tauopathies. Method: Twenty‐six patients with FTD, consisting of 15 patients with behavioral variant FTD (bvFTD) and 11 patients with other FTD phenotypes, and 20 age‐ and gender‐matched healthy controls were studied. They underwent PET imaging of amyloid and tau depositions with 11C‐PiB and 18F‐florzolotau, respectively. Result: By combining visual and semiquantitative analyses of PET images, the bvFTD patients were classified into the following subgroups: 1) predominant tau accumulations in frontotemporal and frontolimbic cortices resembling three‐repeat tauopathies (n = 3); 2) predominant tau accumulations in subcortical structures accompanied by various degrees of neocortical accumulations resembling four‐repeat tauopathies (n = 4); 3) amyloid and tau accumulations consistent with AD (n = 4); and 4) no overt amyloid and tau pathologies (n = 4). Despite these distinctions, clinical symptoms and localization of brain atrophy were not significantly different among the identified bvFTD subgroups. Patients with other FTD phenotypes were also classified into similar subgroups. Conclusion: To conclude, PET with 18F‐florzolotau potentially enables the characterization of each individual with FTD on a biological basis, thereby possibly contributing to diagnostic and therapeutic approaches to this illness. [ABSTRACT FROM AUTHOR]