Functional Connectivity Between the Posterior Default Mode Network and Parahippocampal Gyrus Is Disrupted in Older Adults with Subjective Cognitive Decline and Correlates with Subjective Memory Ability.

BACKGROUND: Subjective cognitive decline (SCD) is associated with increased risk of developing Alzheimer's disease (AD). However, the underlying mechanisms for this association remain unclear. Neuroimaging studies suggest the earliest AD-related changes are large-scale network disruptions, beginning in the posterior default mode (pDMN) network. OBJECTIVE: To examine the association between SCD and pDMN network connectivity with medial temporal lobe (MTL) regions using resting-state functional magnetic resonance imaging. METHODS: Forty-nine participants with either SCD (n = 23, 12 females; mean age: 70.7 (5.5)) or who were cognitively unimpaired (CU; n = 26, 16 females, mean age: 71.42 (7.3)) completed the Memory Functioning Questionnaire, a measure of subjective memory, and underwent resting state functional MRI at 3 Tesla. Functional connectivity between the posterior cingulate cortex (PCC), as the key pDMN node, and MTL regions were compared between SCD and CU groups. Further, the association between pDMN-MTL connectivity and the Frequency of Forgetting subscale of the Memory Functioning Questionnaire was examined. RESULTS: Connectivity between the PCC-MTL was observed in the CU group but was absent in SCD (t(47) = 2.69, p = 0.01). Across all participants, self-perception of frequency of forgetting, but not objective memory, was strongly correlated with connectivity between the PCC-left parahippocampal gyrus (r = 0.43, p = 0.002). CONCLUSION: These findings support the hypothesis that increased AD risk in SCD may be mediated by disrupted pDMN-parahippocampal connectivity. In addition, these findings suggest that frequency of forgetting may serve as a potential biomarker of SCD due to incipient AD.

Prefrontal GABA Levels Correlate with Memory in Older Adults at High Risk for Alzheimer's Disease.

γ-Aminobutyric acid (GABA), a primary inhibitory neurotransmitter in the brain, plays a significant role in aging and in neurodegenerative disorders, including Alzheimer's disease (AD). We investigated the relationship between GABA levels in the dorsomedial/dorsoanterolateral prefrontal cortex (DM/DA-PFC) and memory in high-AD risk participants. Thirty-eight participants (14 Cognitively Normal [CN], 11 with Subjective Cognitive Decline (SCD), and 13 Mild Cognitive Impairment [MCI]) underwent magnetic resonance spectroscopy at 3 Tesla. SCD and MCI participants were grouped together to form a single high-AD risk group (N = 24) for the purposes of statistical analyses. Partial correlations of GABA+/Cr level with verbal memory, assessed on California Verbal Learning Test-II, and nonverbal memory, assessed on Brief Visuospatial Memory Test and Rey-Osterrieth test, were examined separately within the high-AD risk and CN groups. GABA+/Cr levels were positively correlated with long-delayed verbal memory (r = 0.69, P = 0.009) and immediate nonverbal memory (r = 0.97, P = 0.03) in high-AD risk, but not in CN participants. These results remained significant after controlling for depression. These preliminary findings, which require replication due to the limited sample sizes, are the first report of an association between GABA+/Cr levels within the DM/DA-PFC and memory performance in high-AD risk individuals.

Cerebrospinal Fluid Correlates of Neuropsychiatric Symptoms in Patients with Alzheimer's Disease/Mild Cognitive Impairment: A Systematic Review.

BACKGROUND: Neuropsychiatric symptoms (NPS) are common, accelerate the conversion to dementia, and are associated with increased caregiver burden in Alzheimer's disease (AD) and mild cognitive impairment (MCI). OBJECTIVE: The aim of this study is to identify potential associations between the core cerebrospinal fluid (CSF) biomarkers (amyloid/tau) and NPS in AD/MCI. METHODS: For this systematic review, four databases, PubMed (1946-2018), Cochrane (2005-2018), EMBASE (1947-2018), and PsycINFO (1806-2018) were searched for relevant observational studies using an extensive list of keywords. English studies were selected for critical appraisal based on our inclusion/exclusion criteria. Inclusion criteria were defined as 1) at least one AD CSF biomarker has been measured; 2) at least one NPS has been assessed; and 3) analysis has been done to examine the association between core AD CSF biomarker and NPS (main outcome). Animal, postmortem, and review studies were excluded. RESULTS: In total, 21 studies qualified for the systematic review. The overall picture regarding the association between NPS and AD CSF biomarkers is conflicting. However, agitation/aggression was significantly and consistently related to core AD CSF biomarkers. Moreover, depression was the only NPS to occasionally be associated with lower core AD CSF pathology. CONCLUSION: Our study has revealed agitation/aggression as the most consistent NPS related to core AD CSF biomarkers. Future studies are required to focus on other neglected NPS domains such as disinhibition. Moreover, why depression was the only NPS inversely associated with core AD CSF pathology remains to be elucidated. Our study also revealed a great degree of heterogeneity, hence calling for a more standardized "objective" approach for the evaluation of NPS.

Psychosis in neurodegenerative disorders: recent developments.

PURPOSE OF REVIEW: This review presents the latest developments covered in the literature regarding psychosis in neurodegenerative disorders and discusses possible future research directions. RECENT FINDINGS: Recent findings in the field of psychosis and neurodegenerative disorders revolve around four main themes. The first theme is the impact of sex on the expression of psychosis in neurodegenerative disorders. The second theme focuses on the relationship between psychosis and neurodegenerative disease biomarkers. The third concerns how psychotic symptoms in neurodegenerative disorders may share common mechanisms with other primary psychotic disorders such as schizophrenia. Finally, there have been some promising developments in the area of therapeutics to treat dementia-related psychosis involving both established and novel treatments. SUMMARY: New findings in the field of neurodegeneration and psychosis parallel new directions in the field of neurodegeneration in general. More specifically, we have seen a shift in focus to issues highlighting the role of sex, biomarkers, translation to other disorders, and therapeutics.

IL-23/IL-17 immune axis in Guillain Barré Syndrome: Exploring newer vistas for understanding pathobiology and therapeutic implications.

Guillain Barré Syndrome (GBS) is a severe disorder of the peripheral nervous system with an inadequately known etiopathology. It is a post infectious immune mediated disorder, characterized by autoantibody production, complement activation as well as T reactivity against gangliosides. However, the precise etiopathogenesis remains poorly understood in a majority of the patients. Th17 cells, a recently identified lineage of Th cells have emerged as a predominant inducer of autoimmunity and inflammation in various immunological disorders. Pathobiological role of Th17 pathway is also becoming increasingly apparent in the nervous system disorders. Two cytokines, such as IL-23, known to determine the pathogenic potential of Th17 cells and IL-17, a prototype effector cytokine of Th17 pathway can form IL-23/IL-17 immune axis. Aberrant functioning of this immune axis has been implicated in many autoimmune diseases. Therapeutic strategies that potentially target this immune axis have shown encouraging results in diseases with immunological underpinnings. Preliminary data obtained both from animal and clinical studies indicate a possible role of this immune axis in GBS. Herein, we explore and highlight the relevance and functional implications of IL-23/IL-17 immune axis in GBS. Understanding this immune axis may shed important insights into the etiology and treatment of GBS.

Brain glutathione levels--a novel biomarker for mild cognitive impairment and Alzheimer's disease.

BACKGROUND: Extant data from in vivo animal models and postmortem studies indicate that Alzheimer's disease (AD) pathology is associated with reduction of the brain antioxidant glutathione (GSH), yet direct clinical evidence has been lacking. In this study, we investigated GSH modulation in the brain with AD and assessed the diagnostic potential of GSH estimation in hippocampi (HP) and frontal cortices (FC) as a biomarker for AD and its prodromal stage, mild cognitive impairment (MCI). METHODS: Brain GSH levels were measured in HP of 21 AD, 22 MCI, and 21 healthy old controls (HC) and FC of 19 AD, 19 MCI, and 28 HC with in vivo proton magnetic resonance spectroscopy. The association between GSH levels and clinical measures of AD progression was tested. Linear regression models were used to determine the best combination of GSH estimation in these brain regions for discrimination between AD, MCI, and HC. RESULTS: AD-dependent reduction of GSH was observed in both HP and FC (p < .001). Furthermore, GSH reduction in these regions correlated with decline in cognitive functions. Receiver operator characteristics analyses evidenced that hippocampal GSH robustly discriminates between MCI and healthy controls with 87.5% sensitivity, 100% specificity, and positive and negative likelihood ratios of 8.76/.13, whereas cortical GSH differentiates MCI and AD with 91.7% sensitivity, 100% specificity, and positive and negative likelihood ratios of 9.17/.08. CONCLUSIONS: The present study provides compelling in vivo evidence that estimation of GSH levels in specific brain regions with magnetic resonance spectroscopy constitutes a clinically relevant biomarker for MCI and AD.