No abstract

Numerous serum and plasma based biomarkers of systemic inflammation have been linked to both neuropsychiatric disorders and Alzheimer’s disease. The present study investigated the relationship of clinical biomarkers of cardiovascular risk (cholesterol, triglycerides and homocysteine) and a panel of markers of systemic inflammation (CRP, TNF-α, IL1-ra, IL-7, IL-10, IL-15, IL18) and microvascular pathology (ICAM-1, VCAM-1) to neuropsychiatric symptoms in a sample with mild Alzheimer’s disease. Biomarker data was analyzed on a sample of 194 diagnosed with mild to moderate probable Alzheimer’s disease. The sample was composed of 127 females and 67 males. The presence of neuropsychiatric symptoms was gathered from interview with caretakers/family members using the Neuropsychiatric Inventory. For total sample IL15, VCAM (Vascular Adhesion Molecule) and triglycerides were significantly and negatively related to number of neuropsychiatric symptoms and total cholesterol and homocysteine were positively related and as a group accounted for 16.1% of the variance. When stratified by gender different patterns of significant biomarkers were found with relationships more robust for males for both total symptoms and symptom clusters. A combination of biomarkers of systemic inflammation, microvascular pathology and clinical biomarkers of cardiovascular risk can account for a significant portion of the variance in the occurrence of neuropsychiatric symptoms in Alzheimer’s disease supporting a vascular and inflammatory component of psychiatric disorders found in Alzheimer’s disease. Gender differences suggest distinct impact of specific risks with total cholesterol a measure of cardiovascular risk being the strongest marker for males and IL-15 a marker of inflammation being the strongest for females.

Mounting evidence supports immune dysfunction in psychiatric conditions such as post-traumatic stress disorder (PTSD). The association of immunomodulatory mechanisms with PTSD-relevant behavior and physiology is not well understood. Communication between neurons and microglia, resident immune cells of the central nervous system, is crucial for optimal regulation of behavior and physiology. In this regard, the fractalkine CX3CL1, secreted from neurons and its target, the microglial CX3CR1 receptor represent a primary neuron-microglia inter-regulatory system important for synaptic plasticity and function. The current study investigated the impact of CX3CR1 deficiency on behaviors relevant to PTSD, such as fear acquisition and memory, acoustic startle response and anxiety-like behavior. Morphological analysis of microglia and neuronal activation within PTSD-relevant forebrain nuclei regulating stress and fear behaviors was also conducted. CX3CR1-deficient (CX3CR1) mice elicited increased fear acquisition as well as reinstatement of fear as compared to wild type (CX3CR1) mice. Conditioned fear and extinction were not significantly different between genotypes. No significant differences were observed in unconditioned acoustic startle response between genotypes. CX3CR1 mice showed reduced anxiety-like behaviors as compared with CX3CR1 mice. Morphological assessment of microglia showed region-selective effects of CX3CR1 deficiency, primarily within hypothalamic and cortical areas. Lastly, CX3CR1 mice elicited elevated neuronal activity in the PVN and the ventral tegmental-interpeduncular area following reinstatement of fear. Collectively, our data suggest that impaired CX3CR1 function may evoke region-selective alterations in forebrain circuits regulating stress, anxiety and fear, impacting behaviors relevant to disorders such as PTSD.

Inhalation of carbon dioxide (CO2) is frequently employed as a biological challenge to evoke intense fear and anxiety. In individuals with panic disorder, CO2 reliably evokes panic attacks. Sensitivity to CO2 is highly heterogeneous among individuals, and although a genetic component is implicated, underlying mechanisms are not clear. Preclinical models that can simulate differential responsivity to CO2 are therefore relevant. In the current study we investigated CO2-evoked behavioral responses in four different rat strains: Sprague-Dawley (SD), Wistar (W), Long Evans (LE) and Wistar-Kyoto, (WK) rats. We also assessed tryptophan hydroxylase 2 (TPH-2)-positive serotonergic neurons in anxiety/panic regulatory subdivisions of the dorsal raphe nucleus (DR), as well as dopamine β hydroxylase (DβH)-positive noradrenergic neurons in the locus coeruleus, implicated in central CO2-chemosensitivity. Behavioral responsivity to CO2 inhalation varied between strains. CO2-evoked immobility was significantly higher in LE and WK rats as compared with W and SD cohorts. Differences were also observed in CO2-evoked rearing and grooming behaviors. Exposure to CO2 did not produce conditioned behavioral responses upon re-exposure to CO2 context in any strain. Reduced TPH-2 positive cell counts were observed specifically in the panic-regulatory dorsal raphe ventrolateral (DRVL)-ventrolateral periaqueductal grey (VLPAG) subdivision in CO2-sensitive strains. Conversely, DβH positive cell counts within the LC were significantly higher in CO2-sensitive strains. Collectively, our data provide evidence for strain dependent, differential CO2-sensitivity and potential differences in monoaminergic systems regulating panic and anxiety. Comparative studies between CO2-vulnerable and resistant strains may facilitate the mechanistic understanding of differential CO2-sensitivity in the development of panic and anxiety disorders.

Functional impairment is common in Alzheimer’s disease, and related to increased caregiver burden and institutionalization. There is a dearth of research investigating the relationship between specific biomarkers and basic activities of daily living such as toileting, feeding, dressing, grooming, bathing, and ambulating. The present study examined the relationship between serum based biomarkers and specific activities of daily living in a sample of Alzheimer’s disease patients Data were collected from 196 participants enrolled in the Texas Alzheimer’s Research and Care Consortium Project and diagnosed with Alzheimer’s. Basic activities of daily living were measured using the Lawton-Brody Physical Self-Maintenance Scale. A panel of 22 biomarkers previously found to be related to AD pathology was used for the analysis. Stepwise regression modeling was used to assess the link between the biomarkers and basic ADLs. Results were also examined by gender. Nine of the 22 biomarkers were significantly related to basic ADLS. When stratified by gender, the biomarkers accounted for 32% of the variance in the male’s scores and 27% in females. The pattern of significant biomarkers differed by gender with IL-7 and Tenascin C significantly related to basic activities of daily living for females and IL-15 significantly related to basic activities of daily living for males. The results of this study indicated that a small number of serum based biomarkers are related to basic ADLs, and these biomarkers differed by gender.