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Objective: Increasing evidence suggests that reactive astrocytes are associated with Alzheimer's disease (AD). However, its underlying pathogenesis remains unknown. Given the role of astrocytes in energy metabolism, reactive astrocytes may contribute to altered brain energy metabolism. Astrocytes are primarily considered glycolytic cells, suggesting a preference for lactate production. This study aimed to examine alterations in astrocytic activities and their association with brain lactate levels in AD. Methods: The study included 30 AD and 30 cognitively unimpaired participants. For AD participants, amyloid and tau depositions were confirmed by positron emission tomography using [11C]PiB and [18F]florzolotau, respectively. Myo‐inositol, an astroglial marker, and lactate in the posterior cingulate cortex were quantified by magnetic resonance spectroscopy. These magnetic resonance spectroscopy metabolites were compared with plasma biomarkers, including glial fibrillary acidic protein as another astrocytic marker, and amyloid and tau positron emission tomography. Results: Myo‐inositol and lactate levels were higher in AD patients than in cognitively unimpaired participants (p < 0.05). Myo‐inositol levels correlated with lactate levels (r = 0.272, p = 0.047). Myo‐inositol and lactate levels were positively associated with the Clinical Dementia Rating sum‐of‐boxes scores (p < 0.05). Significant correlations were noted between myo‐inositol levels and plasma glial fibrillary acidic protein, tau phosphorylated at threonine 181 levels, and amyloid and tau positron emission tomography accumulation in the posterior cingulate cortex (p < 0.05). Interpretation: We found high myo‐inositol levels accompanied by increased lactate levels in the posterior cingulate cortex in AD patients, indicating a link between reactive astrocytes and altered brain energy metabolism. Myo‐inositol and plasma glial fibrillary acidic protein may reflect similar astrocytic changes as biomarkers of AD. ANN NEUROL 2024;95:104–115 [ABSTRACT FROM AUTHOR]

INTRODUCTION: Recently, an increasing number of tau tracers have become available. There is a need to standardize quantitative tau measures across tracers, supporting a universal scale. We developed several cortical tau masks and applied them to generate a tau imaging universal scale. METHOD: One thousand forty‐five participants underwent tau scans with either 18F‐flortaucipir, 18F‐MK6240, 18F‐PI2620, 18F‐PM‐PBB3, 18F‐GTP1, or 18F‐RO948. The universal mask was generated from cognitively unimpaired amyloid beta (Aβ)− subjects and Alzheimer's disease (AD) patients with Aβ+. Four additional regional cortical masks were defined within the constraints of the universal mask. A universal scale, the CenTauRz, was constructed. RESULTS: None of the regions known to display off‐target signal were included in the masks. The CenTauRz allows robust discrimination between low and high levels of tau deposits. DISCUSSION: We constructed several tau‐specific cortical masks for the AD continuum and a universal standard scale designed to capture the location and degree of abnormality that can be applied across tracers and across centers. The masks are freely available at https://www.gaain.org/centaur‐project. [ABSTRACT FROM AUTHOR]

Background Central serotonin (5-hydroxytryptamine [5-HT]) neurotransmission has been implicated in the etiology of depression. Most antidepressants ameliorate depressive symptoms by increasing 5-HT at synaptic clefts, but their effect on 5-HT receptors has yet to be clarified. 11C-WAY-100635 and 18F-MPPF are positron emission tomography (PET) radioligands for 5-HT1A receptors. While binding of both ligands reflects 5-HT1A receptor density, 18F-MPPF biding may also be affected by extracellular 5-HT concentrations. This dual-tracer PET study explored the neurochemical substrates underlying antidepressant effects in patients with depression. Methods Eleven patients with depression, including 9 treated with antidepressants, and 16 age- and sex-matched healthy individuals underwent PET scans with 11C-WAY-100635 and 18F-MPPF. Radioligand binding was determined by calculating the nondisplaceable binding potential (BP ND). Results Patients treated with antidepressants showed significantly lower 18F-MPPF BP ND in neocortical regions and raphe nuclei, but not in limbic regions, than controls. No significant group differences in 11C-WAY-100635 BP ND were found in any of the regions. Significant correlations of BP ND between 11C-WAY-100635 and 18F-MPPF were observed in limbic regions and raphe nuclei of healthy controls, but no such associations were found in antidepressant-treated patients. Moreover, 18F-MPPF BP ND in limbic regions was significantly correlated with the severity of depressive symptoms. Conclusions These results suggest a diversity of antidepressant-induced extracellular 5-HT elevations in the limbic system among depressive patients, which is associated with the individual variability of clinical symptoms following the treatment. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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]