Prediction of future cognitive decline among cognitively unimpaired individuals using measures of soluble phosphorylated tau or tau tangle pathology.

Plasma p-tau217 and Tau-PET are strong prognostic biomarkers in Alzheimer's disease (AD), but their relative performance in predicting future cognitive decline among cognitively unimpaired (CU) individuals is unclear. In this head-to-head comparison study including 9 cohorts and 1534 individuals, we found that plasma p-tau217 and medial temporal lobe Tau-PET signal showed similar associations with cognitive decline on a global cognitive composite test (R2 PET=0.32 vs R2 PLASMA=0.32, pdifference=0.812) and with progression to mild cognitive impairment (Hazard ratio[HR]PET=1.56[1.43-1.70] vs HRPLASMA=1.63[1.50-1.77], pdifference=0.627). Combined plasma and PET models were superior to the single biomarker models (R2=0.36, p<0.01). Furthermore, sequential selection using plasma p-tau217 and then Tau-PET reduced the number of participants required for a clinical trial by 94%, compared to a 75% reduction when using plasma p-tau217 alone. We conclude that plasma p-tau217 and Tau-PET showed similar performance for predicting future cognitive decline in CU individuals, and their sequential use (i.e., plasma p-tau217 followed by Tau-PET in a subset with high plasma p-tau217) is useful for screening in clinical trials in preclinical AD.

Brain 11ß-Hydroxysteroid Dehydrogenase Type 1 Occupancy by Xanamem™ Assessed by PET in Alzheimer's Disease and Cognitively Normal Individuals.

BACKGROUND: 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) regulates intracellular cortisol and its inhibition by the small molecule inhibitor, Xanamem™, may provide a disease-modifying strategy for Alzheimer's disease (AD). Animal models suggest a range of 30-60% enzyme inhibition may suffice to provide neuroprotection. OBJECTIVE: To determine the regional brain occupancy of 11ß-HSD1 by Xanamem™ in cognitively normal participants (CN) and mild cognitive impairment (MCI)/mild AD patients to investigate potential dosing ranges for future efficacy studies. METHODS: Seventeen MCI/AD and 23 CN were included. Regional brain time-activity curves (TAC), standardized uptake values (SUV40-60) and volume of distribution (VT) from Logan plot with image derived input function from 11C-TARACT positron emission tomography (PET) were used to assess the degree of 11ß-HSD1 occupancy by increasing doses of Xanamem™ (5 mg, 10 mg, 20 mg or 30 mg daily for 7 days). RESULTS: All measures showed high 11ß-HSD1 occupancy with Xanamem to similar degree in CN and MCI/AD. The dose-response relationship was relatively flat above 5 mg. Respective median (interquartile range [Q1-Q3]) 11ß-HSD1 occupancy in the MCI/AD and CN groups after treatment with 10 mg Xanamem were 80% [79-81%] and 75% [71-76%] in the neocortex, 69% [64-70%] and 61% [52-63%] in the medial temporal lobe, 80% [79-80%] and 73% [68-73%] in the basal ganglia, and 71% [67-75%] and 66% [62-68%] in the cerebellum. CONCLUSIONS: TAC, SUV40-60, and VT measures indicate Xanamem achieves high target occupancy levels with near saturation at 10 mg daily. These data support exploration of doses of≤10 mg daily in future clinical studies.

Tau, ß-Amyloid, and Glucose Metabolism Following Service-Related Traumatic Brain Injury in Vietnam War Veterans: The Australian Imaging Biomarkers and Lifestyle Study of Aging-Veterans Study (AIBL-VETS).

Traumatic brain injury (TBI) is common among military veterans and has been associated with an increased risk of dementia. It is unclear if this is due to increased risk for Alzheimer's disease (AD) or other mechanisms. This case control study sought evidence for AD, as defined by the 2018 National Institute on Aging - Alzheimer's Association (NIA-AA) research framework, by measuring tau, ß-amyloid, and glucose metabolism using positron emission tomography (PET) in veterans with service-related TBI. Seventy male Vietnam war veterans-40 with TBI (age 68.0 ± 2.5 years) and 30 controls (age 70.1 ± 5.3 years)-with no prior diagnosis of dementia or mild cognitive impairment underwent ß-amyloid (18F-Florbetaben), tau (18F-Flortaucipir), and fluorodeoxyglucose (18F-FDG) PET. The TBI cohort included 15 participants with mild, 16 with moderate, and nine with severe injury. ß-Amyloid level was calculated using the Centiloid (CL) method and tau was measured by standardized uptake value ratios (SUVRs) using the cerebellar cortex as reference region. Analyses were adjusted for age and APOE-e4. The findings were validated in an independent cohort from the Department of Defense-Alzheimer's Disease Neuroimaging Initiative (DOD ADNI) study. There were no significant nor trending differences in ß-amyloid or tau levels or 18F-FDG uptake between the TBI and control groups before and after controlling for covariates. The ß-amyloid and tau findings were replicated in the DOD ADNI validation cohort and persisted when the Australian Imaging Biomarkers and Lifestyle study of aging-Veterans study (AIBL-VETS) and DOD ADNI cohorts were combined (114 TBI vs. 87 controls in total). In conclusion, no increase in the later life accumulation of the neuropathological markers of AD in veterans with a remote history of TBI was identified.

Visual responses in the dorsolateral frontal cortex of marmoset monkeys.

The marmoset monkey (Callithrix jacchus) has gained attention in neurophysiology research as a new primate model for visual processing and behavior. In particular, marmosets have a lissencephalic cortex, making multielectrode, optogenetic, and calcium-imaging techniques more accessible than other primate models. However, the degree of homology of brain circuits for visual behavior with those identified in macaques and humans is still being ascertained. For example, whereas the location of the frontal eye fields (FEF) within the dorsolateral frontal cortex has been proposed, it remains unclear whether neurons in the corresponding areas show visual responses-an important characteristic of FEF neurons in other species. Here, we provide the first description of receptive field properties and neural response latencies in the marmoset dorsolateral frontal cortex, based on recordings using Utah arrays in anesthetized animals. We find brisk visual responses in specific regions of the dorsolateral prefrontal cortex, particularly in areas 8aV, 8C, and 6DR. As in macaque FEF, the receptive fields were typically large (10°-30° in diameter) and the median responses latency was brisk (60 ms). These results constrain the possible interpretations about the location of the marmoset FEF and suggest that the marmoset model's significant advantages for the use of physiological techniques may be leveraged in the study of visuomotor cognition.NEW & NOTEWORTHY Behavior and cognition in humans and other primates rely on networks of brain areas guided by the frontal cortex. The marmoset offers exciting new opportunities to study links between brain physiology and behavior, but the functions of frontal cortex areas are still being identified in this species. Here, we provide the first evidence of visual receptive fields in the marmoset dorsolateral frontal cortex, an important step toward future studies of visual cognitive behavior.

Beneficial effects of garlic on learning and memory deficits and brain tissue damages induced by lead exposure during juvenile rat growth is comparable to the effect of ascorbic acid.

OBJECTIVE: The neuroprotective effects of both garlic and ascorbic acid (AA) have been documented. In this study the effects of garlic and ascorbic acid on memory deficits and brain tissue oxidative damages induced by lead exposure was investigated. METHODS: The juvenile rats were divided and treated: (1) Control, (2) Lead (lead acetate in drinking water, 8 weeks), (3) Lead - Ascorbic Acid (Lead-AA), (4) Lead - Garlic (100 mg/kg, daily, gavage) (Lead-Gar). RESULTS: In Morris water maze (MWM), the escape latency and traveled path in the Lead group were significantly higher while, the time spent in the target quadrant (Q1) was lower than Control. Both Lead-Gar and Lead-AA groups spent more times in Q1than to lead group. There were no significant differences in swimming speed between the groups. In passive avoidance (PA) test, the time latency for entering the dark compartment by Lead group was lower than Control. Treatment of the animals by AA and garlic significantly increased the time latency. In Lead group, the total thiol concentration in brain tissues was significantly lower while, MDA was higher than Control. Treatment by both garlic and AA increased total thiol concentrations and decreased MDA. Both garlic and AA decreased the lead content of brain tissues. CONCLUSION: It is suggested that treatment with garlic attenuates the learning and memory impairments due to lead exposure during juvenile rat growth which is comparable to AA. The possible mechanism may be due to its protective effects against brain tissues oxidative damage as well the lowering effects of brain lead content.

Direct current stimulation of prefrontal cortex modulates error-induced behavioral adjustments.

Commission of errors and conflict between choices might induce behavioral modulations through adjustments in the executive control of behavior and altered patterns of these modulations are detected in neuropsychiatric disorders. We examined the effects of transcranial Direct Current Stimulation (tDCS) applied over the dorsolateral prefrontal cortex (DLPFC) on error- and conflict-induced behavioral modulations. Two separate cohorts of participants performed two clinically relevant tests of executive control, respectively. In the Wisconsin Card Sorting Test (WCST), the relevant rule for matching items frequently changed and therefore participants had to detect these unannounced changes by trial and error and alter their rule-based behavior. In the Stop task, participants had to rapidly respond to a directional go-signal but inhibit their responses when a stop signal appeared after the go-signal. Each participant received tDCS (sham, cathodal or anodal) in three separate sessions. Errors led to a slower response in the next trial (post-error slowing) in both tasks. The tDCS significantly modulated the post-error slowing in both tasks but did not affect the behavioral adjustments induced by the conflict. The modulation of post-error slowing by tDCS were polarity-dependent and also trial specific appearing immediately after errors. In the WCST and Stop task, the post-error slowing may reflect different processes involved in shifting the behavior-guiding rule and adjustments in inhibitory control of responses, respectively, and we found that the effective tDCS polarity differed between the two tasks. Here, we show that in two separate cognitive tasks direct current stimulation of DLPFC significantly modulated error-induced behavioral modulations.

The effect of carvacrol on systemic inflammation in guinea pigs model of COPD induced by cigarette smoke exposure.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a epidemic disease which is mainly due to cigarette smoking. The effect of carvacrol on systemic inflammation in guinea pig model of COPD was examined in the present study. METHODS: Guinea pigs of both sexes were divided into 6 groups, including: control, COPD, COPD+drinking water containing three concentrations of carvacrol and COPD+dexamethasone. Animals were exposed to cigarette smoke for 3 months in order to induce animal model of COPD. Weight changes, serum levels of IL-8 and malondialdehyde (MDA) as well as total and differential white blood cell (WBC) were measured (n=5 for control and COPD groups and n=6 for other groups). RESULTS: Serum levels of IL-8 and MDA, total WBC (p<0.01 for all cases) and eosinophil counts (p<0.05) were increased and weight changes were decreased (p<0.05) in COPD group compared to controls. Serum MDA level and total WBC in treated groups with two higher carvacrol concentrations, eosinophil, neutrophil and lymphocyte percentage in those treated with its high concentration as well as IL-8 level and weight change in treated groups with its all concentrations and in dexamethasone treated group were significantly improved compared to COPD group (p<0.05 to p<0.001). CONCLUSION: These results showed a preventive effect of the carvacrol on all measured parameter in COPD guinea pigs which was comparable to the effect of dexamethasone at used concentrations.

Adipose-derived stromal cell therapy affects lung inflammation and tracheal responsiveness in guinea pig model of COPD.

The effects of adipose derived stromal cells (ASCs) were evaluated on tracheal responsiveness and biochemical parameters in guinea pigs model of chronic obstructive pulmonary disease (COPD). Thirty six guinea pigs were divided into 6 groups including: Control, COPD, COPD+intratracheal delivery of PBS (COPD+ITPBS), COPD+intravenous delivery of PBS (COPD+IVPBS), COPD+intratracheal delivery of ASCs (COPD+ITASC) and COPD+intravenous injection of ASCs (COPD+IVASC). COPD was induced by exposing animals to cigarette smoke for 3 months. Cell therapy was then performed and after 14 days, tracheal responsiveness, concentration of interleukin-8 (IL-8) in serum and broncho-alveolar lavage fluid (BALF), as well as total and differential white blood cells (WBC) counts were evaluated. Tracheal responsiveness, total WBC counts, neutrophil and eosinophil percentage in BALF as well as concentration of IL-8 in serum and BALF significantly increased but lymphocyte percentage decreased in COPD compared to the control group (P<0.05 to p<0.001). Cell therapy was able to restore the tracheal hyper-responsiveness and the increased IL-8 concentration in serum and BALF of COPD-ITASC but not COPD-IVASC animals (P<0.05 for all cases). Total WBC in BALF also showed a significant decrease in both treated groups and the percentages of eosinophils, neutrophils and lymphocytes in BALF were reversed in COPD-ITASC compared to COPD-ITPBS animals (P<0.05 to P<0.001). Therefore, intratracheal cell therapy with ASC can decrease tracheal hyperresponsiveness and lung inflammation in cigarette smoke induced-COPD which may be helpful in attenuation of the severity of disease in patients suffering from COPD.

The effect of safranal, a constituent of Crocus sativus (saffron), on tracheal responsiveness, serum levels of cytokines, total NO and nitrite in sensitized guinea pigs.

BACKGROUND: The effect of safranal (one of the constituents of Crocus sativus) on ovalbumin (OVA) sensitized guinea pigs was examined. METHODS: One group of sensitized guinea pigs were given drinking water alone (group S), three groups drinking water containing three concentrations of safranal and one group contain dexamethasone (S + D). Tracheal responses (TR) of the animals to methacholine as effective concentration causing 50% of maximum response (EC(50) M), TR to 0.1% OVA, relative to contraction induced by 100 µM methacholine, IL-4, IFN-γ, total NO and nitrite levels in serum were measured. RESULTS: The TR to both methacholine and OVA, the level of total NO, nitrite and IL-4 significantly increased but IFN-γ and IFN-γ/IL-4 ratio was decreased in group S compared controls (p < 0.05 to p < 0.001). The TR to both methacholine and OVA in treated animals with dexamethasone and all concentrations of safranal were significantly decreased compared to S group (p < 0.01 to p < 0.001). The level of serum IL-4 in treated guinea pigs was significantly decreased but IFN-γ and IFN-γ/IL-4 ratio was increased compared to S group (p < 0.01 to p < 0.001). The levels of total NO and nitrite were significantly decreased in treated groups compared to sensitized group (p < 0.05 to p < 0.001). CONCLUSION: These results showed a preventive effect for safranal on tracheal responses and serum cytokine, total NO and nitrite levels as well as increased Th1/Th2 balance in sensitized guinea pigs.

The effect of adipose derived stromal cells on oxidative stress level, lung emphysema and white blood cells of guinea pigs model of chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a worldwide epidemic disease and a major cause of death and disability. The present study aimed to elucidate pharmacological effects of adipose derived stromal cells (ASCs) on pathological and biochemical factors in a guinea pig model of COPD. Guinea pigs were randomized into 5 groups including: Control, COPD, COPD + intratracheal delivery of PBS as a vehicle (COPD-PBS), COPD + intratracheal delivery of ASCs (COPD-ITASC) and COPD + intravenous injection of ASCs (COPD-IVASC). COPD was induced by exposing animals to cigarette smoke for 3 months. Cell therapy was performed immediately after the end of animal exposure to cigarette smoke and 14 days after that, white blood cells, oxidative stress indices and pathological changes of the lung were measured. RESULTS: Compared with control group, emphysema was clearly observed in the COPD and COPD-PBS groups (p < 0.001). Lung histopathologic changes of COPD-ITASC and COPD-IVASC groups showed non-significant improvement compared to COPD-PBS group. The COPD-ITASC group showed a significant increase in total WBC compared to COPD-PBS group but there was not a significant increase in this regard in COPD-IVASC group. The differential WBC showed no significant change in number of different types of leukocytes. The serum level of malondialdehyde (MDA) significantly decreased but thiol groups of broncho-alveolar lavage fluid (BALF) increased in both cell treated groups (p < 0.05 for all cases). Weight of animals decreased during smoke exposure and improved after PBS or cell therapy. However, no significant change was observed between the groups receiving PBS and the ones receiving ASCs. CONCLUSION: Cell therapy with ASCs can help in reducing oxidative damage during smoking which may collectively hold promise in attenuation of the severity of COPD although the lung structural changes couldn't be ameliorated with these pharmacological therapeutic methods.

The effect of hydro-ethanolic extract of Achillea millefolium on muscarinic receptors of guinea pig tracheal smooth muscle.

OBJECTIVE: To investigate one possible mechanism for the observed relaxant effect of A. millefolium (Achillea millefolium), in the present study the inhibitory effect of the extract of this plant on muscarinic receptors was examined. MATERIALS AND METHODS: The effects of three concentrations of aqueous-ethanolic extract, 10 nM atropine, and saline on muscarinic receptors were tested in three conditions: In non incubated tracheal smooth muscle (group 1), tracheal chain incubated with propranolol and chlorpheniramine (group 2), and the one incubated with propranolol (group 3). RESULTS: The EC50 obtained in the presence of all three concentrations of the extract were significantly higher compared to saline in groups 2 and 3 (P < 0.001 and P < 0.01 in group 2 and 3 respectively). The EC50 obtained in the presence of all concentrations of the extract in group 2 were significantly improved compared to groups 1 and 3 (P < 0.05 to P < 0.001). The maximum responses to methacholine in presence of only the higher concentration of the extract (0.8 mg/ml) was significantly lower than that of saline in groups 1 (P < 0.05). There was neither significant difference between slopes of methacholine-response curves obtained in the presence of different concentrations of the extract and that of saline nor between the three groups. The values of (CR-1), obtained in the presence of all concentrations of the extract, were significantly lower compared to atropine in the first group but were not significantly different in other groups. The values of (CR-1) obtained in the presence of all concentrations of the extract were significantly improved in groups 2, compared to groups 1 and 3 (P < 0.05 to P < 0.001). CONCLUSION: These results showed an inhibitory effect for the extract of A. millefolium on muscarinic receptors of tracheal smooth muscle. A histamine (H1) receptor blockade was also suggested for the extract.