Functional Neural Correlates of Semantic Fluency Task Performance in Mild Cognitive Impairment and Alzheimer’s Disease: An FDG-PET Study

Background: Total score (TS) of semantic verbal fluency test (SVFT) is generally used to interpret results, but it is ambiguous as to specific neural functions it reflects. Different SVFT strategy scores reflecting qualitative aspects are proposed to identify specific cognitive functions to overcome limitations of using the TS. Objective: Functional neural correlates of the TS as well as the other strategy scores in subjects with mild cognitive impairment (MCI) and Alzheimer’s disease (AD) dementia using Fluorine-18-Fluorodeoxyglucose positron emission tomography (FDG-PET). Methods: Correlations between various SVFT scores (i.e., TS, mean cluster size, switching (SW), hard switching, cluster switching (CSW)) and cerebral glucose metabolism were explored using voxelwise whole-brain approach. Subgroup analyses were also performed based on the diagnosis and investigated the effects of disease severity on the associations. Results: Significant positive correlation between TS and cerebral glucose metabolism was found in prefrontal, parietal, cingulate, temporal cortex, and subcortical regions. Significantly increased glucose metabolism associated with the SW were found in similar but smaller regions, mainly in the fronto-parieto-temporal regions. CSW was only correlated with the caudate. In the subgroup analysis conducted to assess different contribution of clinical severity, differential associations between the strategy scores and regional glucose metabolism were found. Conclusion: SW and CSW may reflect specific language and executive functions better than the TS. The SVFT is influenced by brain dysfunction due to the progression of AD, as demonstrated by the SW with larger involvement of temporal lobe for the AD, and CSW with significant association only for the MCI.

Associations between Brain Reserve Proxies and Clinical Progression in Alzheimer’s Disease Dementia

The purpose of this study was to investigate whether brain and cognitive reserves were associated with the clinical progression of AD dementia. We included participants with AD dementia from the Alzheimer’s Disease Neuroimaging Initiative, provided they were followed up at least once, and candidate proxies for cognitive (education for early-life reserve and Adult Reading Test for late-life reserve) or brain reserve (intracranial volume [ICV] for early-life reserve and the composite value of [18F] fluorodeoxyglucose positron emission tomography regions of interest (FDG-ROIs) for late-life reserve) were available. The final analysis included 120 participants. Cox proportional hazards model revealed that FDG-ROIs were the only significant predictor of clinical progression. Subgroup analysis revealed a significant association between FDG-ROIs and clinical progression only in the larger ICV group (HR = 0.388, p = 0.028, 95% CI 0.167–0.902). Our preliminary findings suggest that relatively preserved cerebral glucose metabolism might delay further clinical progression in AD dementia, particularly in the greater ICV group. In addition to ICV, cerebral glucose metabolism could play an important role as a late-life brain reserve in the process of neurodegeneration. Distinguishing between early- and late-life reserves, and considering both proxies simultaneously, would provide a wider range of factors associated with the prognosis of AD dementia.

Sex Differences in the Effect of Diabetes on Cerebral Glucose Metabolism

The neuroimaging literature indicates that brain structure and function both deteriorate with diabetes, but information on sexual dimorphism in diabetes-related brain alterations is limited. This study aimed to ascertain whether brain metabolism is influenced by sex in an animal model of diabetes. Eleven rats (male, n = 5; female, n = 6) received a single intraperitoneal injection of 70 mg/kg streptozotocin (STZ) to develop diabetes. Another 11 rats (male, n = 5; female, n = 6) received the same amount of solvent through a single intraperitoneal injection. Longitudinal positron emission tomography scans were used to assess cerebral glucose metabolism before and 4 weeks after STZ or solvent administration. Before STZ or solvent injections, there was no evidence of sexual dimorphism in cerebral metabolism (p > 0.05). Compared with healthy control animals, rats with diabetes had significantly decreased brain metabolism in all brain regions (all p < 0.05). In addition, female diabetic rats exhibited further reduction in cerebral metabolism, relative to male diabetic rats (p < 0.05). The results of this study may provide some biological evidence, supporting the existence of a sexual dimorphism in diabetes-related complications.

The Associations of Serum Valine with Mild Cognitive Impairment and Alzheimer’s Disease

The introduction of metabolomics makes it possible to study the characteristic changes of peripheral metabolism in Alzheimer’s disease (AD). Recent studies have found that the levels of valine are related to mild cognitive impairment (MCI) and AD, but its characteristics in MCI and AD need to be further clarified. A total of 786 participants from the Alzheimer’s Disease Neuroimaging Initiative-1 (ADNI-1) cohort were selected to evaluate the relationships between serum valine and cerebrospinal fluid (CSF) biomarkers, brain structure (magnetic resonance imaging, MRI), cerebral glucose metabolism (18F-fluorodeoxyglucose-positron emission tomography, FDG-PET), and cognitive declines, through different cognitive subgroups. We found that (1) serum valine was decreased in patients with AD compared with cognitive normal (CN) and stable MCI (sMCI), and in progressive MCI (pMCI) compared with CN; (2) serum valine was negatively correlated with CSF total tau (t-tau) and phosphorylated tau (p-tau) in pMCI; (3) serum valine significantly predicted conversion from MCI to AD; (4) serum valine was related to the rate of change of cerebral glucose metabolism during the follow-up period in pMCI. We speculated serum valine may be a peripheral biomarker of pMCI and AD, and its level predicts the progression of MCI to AD. Our study may help to reveal the metabolic changes during AD disease trajectory and its relationship to clinical phenotype.

Therapeutic Effects of Aripiprazole in the 5xFAD Alzheimer’s Disease Mouse Model

Global aging has led to growing health concerns posed by Alzheimer’s disease (AD), the most common type of dementia. Aripiprazole is an atypical FDA-approved anti-psychotic drug with potential against AD. To investigate its therapeutic effects on AD pathology, we administered aripiprazole to 5xFAD AD model mice and examined beta-amyloid (βA)-induced AD-like phenotypes, including βA production, neuroinflammation, and cerebral glucose metabolism. Aripiprazole administration significantly decreased βA accumulation in the brains of 5xFAD AD mice. Aripiprazole significantly modified amyloid precursor protein processing, including carboxyl-terminal fragment β and βA, a disintegrin and metalloproteinase domain-containing protein 10, and beta-site APP cleaving enzyme 1, as determined by Western blotting. Neuroinflammation, as evidenced by ionized calcium binding adapter molecule 1 and glial fibrillary acidic protein upregulation was dramatically inhibited, and the neuron cell layer of the hippocampal CA1 region was preserved following aripiprazole administration. In 18F-fluorodeoxyglucose positron emission tomography, after receiving aripiprazole, 5xFAD mice showed a significant increase in glucose uptake in the striatum, thalamus, and hippocampus compared to vehicle-treated AD mice. Thus, aripiprazole effectively alleviated βA lesions and prevented the decline of cerebral glucose metabolism in 5xFAD AD mice, suggesting its potential for βA metabolic modification and highlighting its therapeutic effect over AD progression.

A Retrospective Case Series Analysis of the Relationship Between Phenylalanine: Tyrosine Ratio and Cerebral Glucose Metabolism in Classical Phenylketonuria and Hyperphenylalaninemia

We retrospectively examined the relationship between blood biomarkers, in particular the historical mean phenylalanine to tyrosine (Phe:Tyr) ratio, and cerebral glucose metabolism. We hypothesized that the historical mean Phe:Tyr ratio would be more predictive of cerebral glucose metabolism than the phenylalanine (Phe) level alone. We performed a retrospective case series analysis involving 11 adult classical phenylketonuria/hyperphenylalaninemia patients under the care of an Inherited Metabolic &amp; Neuropsychiatry Clinic who had complained of memory problems, collating casenote data from blood biochemistry, and clinical [18F]fluorodeoxyglucose positron emission tomography ([18F]FDG PET). The Phe:Tyr ratio was calculated for individual blood samples and summarized as historical mean Phe:Tyr ratio (Phe:Tyr) and historical standard deviation in Phe:Tyr ratio (SD-Phe:Tyr), for each patient. Visual analyses of [18F]FDG PET revealed heterogeneous patterns of glucose hypometabolism for eight patients. [18F]FDG PET standardized uptake was negatively correlated with Phe in a large cluster with peak localized to right superior parietal gyrus. Even larger clusters of negative correlation that encompassed most of the brain, with frontal peaks, were observed with Phe:Tyr, and SD-Phe:Tyr. Our case series analysis provides further evidence for the association between blood biomarkers, and cerebral glucose hypometabolism. Mean historical blood Phe:Tyr ratio, and its standard deviation over time, appear to be more indicative of global cerebral glucose metabolism in patients with memory problems than Phe.