Aging gene signature of memory CD8+ T cells is associated with neurocognitive functioning in Alzheimer's disease.

BACKGROUND: Memory CD8+ T cells expand with age. We previously demonstrated an age-associated expansion of effector memory (EM) CD8+ T cells expressing low levels of IL-7 receptor alpha (IL-7Rαlow) and the presence of its gene signature (i.e., IL-7Rαlow aging genes) in peripheral blood of older adults without Alzheimer's disease (AD). Considering age as the strongest risk factor for AD and the recent finding of EM CD8+ T cell expansion, mostly IL-7Rαlow cells, in AD, we investigated whether subjects with AD have alterations in IL-7Rαlow aging gene signature, especially in relation to genes possibly associated with AD and disease severity. RESULTS: We identified a set of 29 candidate genes (i.e., putative AD genes) which could be differentially expressed in peripheral blood of patients with AD through the systematic search of publicly available datasets. Of the 29 putative AD genes, 9 genes (31%) were IL-7Rαlow aging genes (P < 0.001), suggesting the possible implication of IL-7Rαlow aging genes in AD. These findings were validated by RT-qPCR analysis of 40 genes, including 29 putative AD genes, additional 9 top IL-7R⍺low aging but not the putative AD genes, and 2 inflammatory control genes in peripheral blood of cognitively normal persons (CN, 38 subjects) and patients with AD (40 mild cognitive impairment and 43 dementia subjects). The RT-qPCR results showed 8 differentially expressed genes between AD and CN groups; five (62.5%) of which were top IL-7Rαlow aging genes (FGFBP2, GZMH, NUAK1, PRSS23, TGFBR3) not previously reported to be altered in AD. Unbiased clustering analysis revealed 3 clusters of dementia patients with distinct expression levels of the 40 analyzed genes, including IL-7Rαlow aging genes, which were associated with neurocognitive function as determined by MoCA, CDRsob and neuropsychological testing. CONCLUSIONS: We report differential expression of "normal" aging genes associated with IL-7Rαlow EM CD8+ T cells in peripheral blood of patients with AD, and the significance of such gene expression in clustering subjects with dementia due to AD into groups with different levels of cognitive functioning. These results provide a platform for studies investigating the possible implications of age-related immune changes, including those associated with CD8+ T cells, in AD.

Behavioral symptomatology and psychopharmacology of Lewy body dementia.

Lewy body dementia (LBD) is an umbrella term for major neurocognitive disorders caused by Lewy body pathology. Parkinson's disease dementia (PDD) and Dementia with Lewy bodies (DLB) are the two main syndromes in LBD. LBDs typically present with cognitive impairment, cholinergic deficiency, neuropsychiatric symptoms such as visual hallucinations and paranoid delusions, as well as parkinsonian symptoms. Due to the urgency in diagnosing LBD early in the disease course to provide the most optimal management of these syndromes, it is important that clinicians elicit the most clinically significant symptoms during patient encounters. The focus of this chapter is to discuss current LBD classification systems and assessments, neuropathology of LBDs, behavioral symptomatology, contemporary management options, and possible future targets of treatment. PubMed was searched to obtain reviews and studies that pertain to classification, behavioral symptomatology, neurobiology, neuroimaging, and treatment of LBDs. Articles were chosen with a predilection to more recent clinical trials and systematic reviews or meta-analyses. Updates to diagnostic criteria have increased clinical diagnostic sensitivity and specificity. Current therapeutic modalities are limited as there is no current disease-modifying drug available. Cholinesterase inhibitors have been reported to be effective in decreasing neuropsychiatric and cognitive symptoms. Neuroleptics should be avoided unless clinically indicated. There is a paucity of studies investigating treatment options for mood symptoms. Current novel targets of treatment focus on decreasing α-synuclein burden. LBDs are a group of dementia syndromes that affect a significant portion of the elderly population. Early diagnosis and treatment is necessary to improve patient quality of life with current treatment options more focused on alleviating severe symptomatology rather than modifying disease pathology.

Frontotemporal dementia: latest evidence and clinical implications.

BACKGROUND: Frontotemporal dementia (FTD) describes a cluster of neurocognitive syndromes that present with impairment of executive functioning, changes in behavior, and a decrease in language proficiency. FTD is the second most common form of dementia in those younger than 65 years and is expected to increase in prevalence as the population ages. This goal in our review is to describe advances in the understanding of neurobiological pathology, classification, assessment, and treatment of FTD syndromes. METHODS: PubMed was searched to obtain reviews and studies that pertain to advancements in genetics, neurobiology, neuroimaging, classification, and treatment of FTD syndromes. Articles were chosen with a predilection to more recent preclinical/clinical trials and systematic reviews. RESULTS: Recent reviews and trials indicate a significant advancement in the understanding of molecular and neurobiological clinical correlates to variants of FTD. Genetic and histopathologic markers have only recently been discovered in the past decade. Current therapeutic modalities are limited, with most studies reporting improvement in symptoms with nonpharmacological interventions. However, a small number of studies have reported improvement of behavioral symptoms with selective serotonin reuptake inhibitor (SSRI) treatment. Stimulants may help with disinhibition, apathy, and risk-taking behavior. Memantine and cholinesterase inhibitors have not demonstrated efficacy in ameliorating FTD symptoms. Antipsychotics have been used to treat agitation and psychosis, but safety concerns and side effect profiles limit utilization in the general FTD population. Nevertheless, recent breakthroughs in the understanding of FTD pathology have led to developments in pharmacological interventions that focus on producing treatments with autoimmune, genetic, and molecular targets. CONCLUSION: FTD is an underdiagnosed group of neurological syndromes comprising multiple variants with distinct neurobiological profiles and presentations. Recent advances suggest there is an array of potential novel therapeutic targets, although data concerning their effectiveness are still preliminary or preclinical. Further studies are required to develop pharmacological interventions, as there are currently no US Food and Drug administration approved treatments to manage FTD syndromes.

Is there Progress? An Overview of Selecting Biomarker Candidates for Major Depressive Disorder.

Major depressive disorder (MDD) contributes to a significant worldwide disease burden, expected to be second only to heart disease by 2050. However, accurate diagnosis has been a historical weakness in clinical psychiatry. As a result, there is a demand for diagnostic modalities with greater objectivity that could improve on current psychiatric practice that relies mainly on self-reporting of symptoms and clinical interviews. Over the past two decades, literature on a growing number of putative biomarkers for MDD increasingly suggests that MDD patients have significantly different biological profiles compared to healthy controls. However, difficulty in elucidating their exact relationships within depression pathology renders individual markers inconsistent diagnostic tools. Consequently, further biomarker research could potentially improve our understanding of MDD pathophysiology as well as aid in interpreting response to treatment, narrow differential diagnoses, and help refine current MDD criteria. Representative of this, multiplex assays using multiple sources of biomarkers are reported to be more accurate options in comparison to individual markers that exhibit lower specificity and sensitivity, and are more prone to confounding factors. In the future, more sophisticated multiplex assays may hold promise for use in screening and diagnosing depression and determining clinical severity as an advance over relying solely on current subjective diagnostic criteria. A pervasive limitation in existing research is heterogeneity inherent in MDD studies, which impacts the validity of biomarker data. Additionally, small sample sizes of most studies limit statistical power. Yet, as the RDoC project evolves to decrease these limitations, and stronger studies with more generalizable data are developed, significant advances in the next decade are expected to yield important information in the development of MDD biomarkers for use in clinical settings.

A review of the relationship between proinflammatory cytokines and major depressive disorder.

BACKGROUND: Determining etiological factors and reviewing advances in diagnostic modalities sensitive and specific to Major Depressive Disorder (MDD) is of importance in its evaluation and treatment. The inflammatory hypothesis is one of the most prevalent topics concerning MDD and may provide insight into the pathogenesis of depression, development of biomarkers, and ultimately production of more effective depression therapies. METHOD: We reviewed several studies to evaluate contemporary concepts concerning proinflammatory cytokines and their relationship to various depressive disorders, the use of anti-inflammatory therapies in MDD treatment, and the application of neuroimaging in conjunction with cytokine profiles from both plasma and CSF as possible diagnostic tools. RESULTS: Proinflammatory cytokines in both plasma and CSF have been found to influence the progression and severity of depressive disorders in different populations. Studies have shown elevated serum levels of IL-1, IL-6, TNF-α, CRP, and MCP-1 in depressed patients, but have presented mixed results with IL-8 serum levels, and with IL-6 and MCP-1 CSF levels. Anti-inflammatory treatment of MDD may have adjuvant properties with current depression medications. MRI and NIRS neuroimaging confirm neurological abnormalities in the presence of elevated proinflammatory cytokines in depressed or stressed patients. LIMITATIONS: Heterogeneity of MDD and limited CSF cytokine research complicate the study of MDD pathogenesis. CONCLUSION: There is significant evidence that inflammatory processes influence the development and progression of MDD. Future studies with larger arrays of cytokine profiles aided by neuroimaging may provide more sensitive and specific modes of diagnostics in determining MDD etiology and provide guidance in individual therapies.