Shedding Light on the Effects of Blood Pressure on Cognitive Decline and Dementia Risk by Way of Neurobiological Evidence.

Midlife cerebrovascular risk factors increase risk of late life cognitive impairment and dementia, while their presence in patients with dementia may lead to cognitive improvement or stabilization in late life. Defining the best measure of blood pressure (BP) to be associated with cognitive decline remains debatable, also due to possible bidirectionality. BP variability, pulse pressure, systolic and diastolic BP have been associated with cognitive status, dementia risk and Alzheimer's disease biomarkers. Proper BP control notwithstanding, BP variability increases risk for pathophysiological change in the Alzheimer's disease continuum, implying the need for selection of anti-hypertensive drugs with neurobiological evidence of benefits.

[Better assessment, better care: Quetci, a questionnaire for assessing cognitive disorders in nursing practice]. / Mieux évaluer, mieux soigner : le Quetci, un questionnaire d'évaluation des troubles cognitifs IDE.

Cognitive disorders can have significant repercussions on the quality of care and daily life for patients. We have developed a new tool specifically designed for nursing practice to identify these problems in patients with brain tumors. The Cognitive Impairment Assessment Questionnaire for nursing practice is an objective, quick and easy-to-administer tool that is readily accepted by patients.

Risks and benefits of hormone therapy after menopause for cognitive decline and dementia: A conceptual review.

OBJECTIVE: The effects on the brain of hormone therapy after the onset of menopause remain uncertain. The effects may be beneficial, neutral, or harmful. We provide a conceptual review of the evidence. METHODS: We 1) provide a brief history of the evidence, 2) discuss some of the interpretations of the evidence, 3) discuss the importance of age at menopause, type of menopause, and presence of vasomotor symptoms, and 4) provide some clinical recommendations. RESULTS: The evidence and the beliefs about hormone therapy and dementia have changed over the last 30 years or more. Five recent observation studies suggested that hormone therapy is associated with an increased risk of dementia, and the association appears not to change with the timing of initiation of therapy. These harmful associations may be explained by a causal effect of hormone therapy on the brain or by several confounding mechanisms. We suggest that the use of hormone therapy should be customized for different subgroups of women. It may be important to subgroup women based on age at onset of menopause, type of menopause, and presence or absence of vasomotor symptoms. In addition, the effects may vary by type, dose, route, and duration of administration of estrogens and by the concurrent use of progestogens. DISCUSSION: The relation of hormone therapy with the risk of dementia is complex. Hormone therapy may have beneficial, neutral, or harmful effects on the brain. Hormone therapy should be guided by the clinical characteristics of the women being treated.

Cancer-related cognitive impairment and wellbeing in patients with newly diagnosed aggressive lymphoma compared to population norms and healthy controls: an exploratory study.

PURPOSE: There has been little dedicated research on cancer-related cognitive impairment in patients with aggressive lymphoma. We describe and compare patients' cognitive function with that of healthy controls and patients' wellbeing and distress with general population values. We also explore associations between patients' neuropsychological test performance and self-reported cognitive function and distress. METHODS: Secondary analysis of data from a feasibility study of 30 patients with newly diagnosed aggressive lymphoma and 72 healthy controls. Patients completed neuropsychological tests and self-report measures before and 6-8 weeks after chemotherapy. Healthy controls completed neuropsychological tests and the FACT-Cog at enrolment and 6 months later. Mixed models were used to analyze neuropsychological test and FACT-Cog scores. One-sample t-tests were used to compare patients' self-reported wellbeing and distress with population norms. Associations were explored with Kendall's Tau b. RESULTS: Patients and healthy controls were well matched on socio-demographics. Differences between neuropsychological test scores were mostly large-sized; on average, patients' scores on measures of information processing speed, executive function, and learning and memory were worse both before and after chemotherapy (all p ≤ 0.003). The same pattern was observed for impact of perceived cognitive impairment on quality-of-life (both p < 0.001). Patients' physical and emotional wellbeing scores were lower than population norms both before and after chemotherapy (all p ≤ 0.018). Associations between neuropsychological performance and other measures were mostly trivial (all p > 0.10). CONCLUSION: For many patients with aggressive lymphoma, impaired neuropsychological test performance and impact of perceived impairments on quality-of-life precede chemotherapy and are sustained after chemotherapy. Findings support the need for large-scale longitudinal studies with this population to better understand targets for interventions to address cognitive impairments.

Lower glomerular filtration rate after mild stroke induces cognitive impairment by causing endothelial dysfunction.

The incidence of post stroke cognitive impairment (PSCI) is high in patients with mild stroke (MIS), and the risk factors and mechanism are uncertain. Increased cystatin C (CysC) levels after stroke may reflect lower glomerular filtration rate (GFR) and renal impairment. Previous studies have suggested endothelial dysfunction (ED) is closely related to renal impairment and cognitive impairment, respectively. We aimed to observe whether lower GFR estimated by CysC after MIS leaded to a high incidence of PSCI, and the role of ED in this process. 256 patients were enrolled in this prospective observational study. Renal function was assessed using GFR estimated by serum CysC. Endothelial function was evaluated by reactive hyperemia index (RHI) which calculated automatically by peripheral arterial tonometry (PAT). The cognitive function at baseline and 3 months was evaluated by MoCA score, and MoCA score ≤ 26 indicates the presence of PSCI. Spearman correlation analysis and linear regression were conducted to explore the factors affecting ED. Univariate and multivariate analysis was used to identify the independent risk factors of PSCI. The receiver operating characteristic (ROC) curve was applied to explore the optimal cutoff value of the independent risk factors levels for predicting PSCI. A total of 141 patients (55.1%) suffered from ED. Multiple linear regression analysis showed that there was a strong linear correlation between eGFRcys and RHI (p < 0.001). At the three-month follow-up, a total of 150 (58.6%) patients had been diagnosed with PSCI. Multivariate logistic regression analysis showed that RHI was an independent factor affecting the occurrence of PSCI (p < 0.05). ROC curve showed that the area under the curve was 0.724, and the optimal cut-off value of RHI was 1.655, with the sensitivity and specificity for PSCI were 72.7% and 73.6%, respectively. The lower eGFRcys level after MIS was significantly associated with ED, and ED may mediate the higher incidence of PSCI at 3 months after MIS.

Serum soluble alpha-klotho klotho and cognitive functioning in older adults aged 60 and 79: an analysis of cross-sectional data of the National Health and Nutrition Examination Survey 2011 to 2014.

OBJECTIVES: Klotho, consisting of membrane klotho and soluble alpha-klotho, is found to be associated with better cognitive outcomes in small samples of the aged population. We aimed to examine the association of serum soluble alpha-klotho with cognitive functioning among older adults using a nationally representative sample of U.S. older adults. METHOD: A total of 2,173 U.S. older adults aged 60-79 years in the National Health and Nutrition Examination Survey from 2011 to 2014 were included in this cross-sectional analysis. Serum soluble alpha-klotho was measured in the laboratory and analyzed with an ELISA kit. Cognitive function was measured using the Consortium to Establish a Registry for Alzheimer's Disease Word Learning subtest (CERAD-WL) immediate and delayed memory, the Animal fluency test (AFT), and the Digit Symbol Substitution Test (DSST). Test-specific and global cognition z-scores were calculated based on sample means and standard deviations. Multivariable linear regression models were applied to examine the association of quartiles and continuous value of serum soluble alpha-klotho with test-specific and global cognition z-scores. Subgroup analysis was conducted by sex. The following covariates were included in the analysis- age, sex, race/ethnicity, education, depressive symptoms, smoking status, body mass index (BMI), physical activity, stroke, prevalent coronary heart disease, total cholesterol, and systolic blood pressure. All the information was self-reported or obtained from health exams. RESULTS: Serum soluble alpha-klotho level in the lowest quartile was associated with lower z-scores for DSST (beta [ß] =-0.13, 95% confidence interval [CI]: -0.25, -0.01). For subgroup analysis, serum soluble alpha-klotho level in the lowest quartile was associated with lower z-scores for DSST (ß=-0.16, 95% CI: -0.32, -0.003) and global cognition (ß=-0.14, 95% CI: -0.28, -0.01) among female participants. No association was found between continuous serum soluble alpha-klotho and cognitive functioning among the participants. CONCLUSIONS: Lower serum soluble alpha-klotho quartile was associated with poorer cognitive functioning among older women. Future studies are expected to examine the longitudinal association between klotho levels and cognitive outcomes.

Pituitary neuroendocrine tumor: A neuropsychological comparison with intra-axial tumor.

OBJECTIVE: Despite pituitary neuroendocrine tumor (PitNET) being extra-axial tumors without direct damage to brain tissue, patients with PitNET exhibit neuropsychological impairments. However, it remains unclear whether there are neuropsychological differences between PitNET and intra-axial tumors that directly destroy the brain parenchyma. This prospective study aims to clarify this distinction to inform decision-making for intracranial tumors of diverse origins. METHODS: A total of 146 patients with PitNET, 74 patients with glioma representing intra-axial tumors, and 52 age-, sex-, and education-matched healthy controls were recruited. All patients received standard treatment and postoperative rehabilitation. Clinical data were meticulously collected, and neuropsychological tests were administered to all participants both before and 3 months after surgery. RESULTS: Both PitNET and glioma patients experience the dual burden of cognitive and affective deficits. However, the feature of these deficits differs substantially. In PitNET patients, the deficits are relatively mild and focal, whereas in glioma patients, they are severe and extensive. Specifically, PitNET patients exhibit deficits in memory, anxiety, and negative affect. In contrast, glioma patients display deficits in executive function, attention, anxiety, positive/negative affect, and empathy. Notably, except for persistent memory deficits, the majority of neuropsychological scores declines in PitNET patients are restorable and can reach improvement within a short period after standard surgical therapy and perioperative management. Conversely, glioma patients not only fail to show improvements but also demonstrate worsening in terms of general cognition and memory postoperatively. INTERPRETATION: As an extra-axial tumor, PitNET may exhibit distinctive cognitive and affective functioning compared to intra-axial tumors, highlighting the need for specific treatment approaches for PitNET patients.

Verbal fluency predicts work resumption after awake surgery in low-grade glioma patients.

BACKGROUND: Resuming professional activity after awake surgery for diffuse low-grade glioma (DLGG) is an important goal, which is not reached in every patient. Cognitive deficits can occur and persist after surgery. In this study, we analyzed the impact of mild cognitive impairments on the work resumption. METHODS: Fifty-four surgeries (including five redo surgeries) performed between 2012 and 2020 for grade 2 (45) and 3 (nine) DLGG in 49 professionally active patients (mean age 40 [range 23-58.) were included. We retrospectively extracted the results of semantic and phonemic verbal fluency tests from preoperative and 4-month postoperative cognitive assessments. Patients were interviewed about their working life after surgery, between April and June 2021. RESULTS: Patients (85%) returned to work, most within 3 to 6 months. Patients (76%) reported subjective complaints (primarily fatigue). Self-reported symptoms and individual and clinical variables had no impact on the work resumption. Late-postoperative average Z-scores in verbal fluency tasks were significantly lower than preoperative for the entire cohort (Wilcoxon test, p < 0.001 for semantic and p = 0.008 for phonemic fluency). The decrease in Z-scores was significantly greater (Mann Whitney U-test, semantic, p = 0.018; phonemic, p = 0.004) in the group of patients who did not return to work than in the group of patients who did. CONCLUSION: The proportion of patients returning to work was comparable to similar studies. A decrease in verbal fluency tasks could predict the inability to return to work.

Cognitive Impairment and Depression in Mastocytosis: A Synthesis of the Literature.

PURPOSE OF REVIEW: Symptoms of depression and cognitive dysfunction are commonly reported in mastocytosis. The aims of this review paper are to summarize the current literature on cognitive dysfunction and depressive symptoms, elucidate some of the mechanistic pathways underlying depressive symptoms in mastocytosis, identify gaps in the literature, and offer guidance for future research in this area. RECENT FINDINGS: The study of cognition and depression in mastocytosis is in its infancy and the methodological flaws of the current literature limit interpretability. There is preliminary evidence that some individuals with mastocytosis might experience mild deficits in memory. On average, depression symptom scores fell within the mild to moderate or sub-syndromal range. Regrettably, only one study utilized a standardized diagnostic instrument to assess major depressive disorder. The authors' tendency to inaccurately equate depressive symptoms with a diagnosis of major depressive disorder presents a notable issue. The prevalence of cognitive deficits and depression appears to be similar to other chronic illnesses. Future work needs to better characterize cognition and characterize "depression" in this population.

QEEG findings in nonsyndromic sagittal craniosynostosis.

Despite the undertaken treatment, children with nonsyndromic sagittal craniosynostosis (NSC) are burdened with problems with speech development, visuospatial and other cognitive deficits. The electroencephalographic assessment has not influenced the diagnostics and treatment strategy of craniosynostosis so far but the introduction of quantitative EEG (QEEG) protocols renewed an interest in the functional aspect of this disease. In this study we retrospectively assessed the QEEG records of 25 children with NSC aged 1-18 months (mean age 9.62 months) before and after surgery. In each case, the amplitude, interhemispheric (ICoh) and intrahemispheric (HCoh) coherence indices were calculated. Obtained data were compared to age-matched control group of 25 normocephalic children. Children with NSC presented significantly lower values of amplitudes and intrahemispheric coherence in occipital, posterior parietal and posterior temporal regions than normocephalic children. The values of amplitudes, ICoh and HCoh in pre- and postoperative QEEG records mostly remained unchanged, with a slight improvement in HCoh in centro-parietal area. These findings suggest that NSC children present their own QEEG profile. The operative treatment improves an intrahemispheric connectivity, but there still exists a significant difference in the occipitotemporal, frontotemporal and centro-frontal areas, which may be considered as a functional substrate of reported speech and neurocognitive problems. QEEG findings in nonsyndromic sagittal craniosynostosis.

Sleep and cognition in South African patients with non-functioning pituitary adenomas.

Strong lines of evidence in the neuroscience literature indicate that (a) healthy sleep facilitates cognitive processing, and (b) sleep disruption is associated with cognitive dysfunction. Despite the fact that patients with pituitary disease often display both disrupted sleep and cognitive dysfunction, few previous studies investigate whether these clinical characteristics in these patients might be related. Hence, we explored whether sleep disruption in patients with pituitary disease mediates their cognitive dysfunction. We recruited 18 patients with non-functioning pituitary adenomas (NFPA) and 19 sociodemographically matched healthy controls. They completed the Global Sleep Assessment Questionnaire (thus providing self-report data regarding sleep disruption) and were administered the Brief Test of Adult Cognition by Telephone, which assesses cognitive functioning in the domains of processing speed, working memory, episodic memory, inhibition, and reasoning. We found no significant differences in cognition between patients and controls. Furthermore, spectra of sleep disturbance did not differ significantly between patients and controls. Our data suggest that NFPA patients' cognition and sleep quality is relatively intact, and that sleep disruption does not mediate cognitive dysfunction. Larger studies should characterize sleep and cognition in patients with NFPA (and other pituitary diseases) to confirm whether disruption of the former mediates impairment in the latter.

Patient-reported cognitive impairments and objective neuropsychological deficits in young sarcoma patients undergoing chemotherapy and its comparison to healthy controls: A tertiary health care study from India.

The study aims to investigate the patient-reported cognitive deficits and objective neuropsychological functions in younger adult (YA) sarcoma patients (16-40 years of age). Ninety patients and 30 age-matched healthy controls from a single tertiary healthcare hospital, were recruited into four groups: Pre-chemotherapy (Pre Cx), During chemotherapy (During Cx), Post-chemotherapy (Post Cx) and Controls. Neurocognitive functions were assessed subjectively using FACT-Cog v3 questionnaire; objectively using ACE-III and neuropsychological tests (NPT). FACT-Cog scores of During Cx (P = .041) and Post Cx (P = .008) groups were significantly lower than Pre Cx group. ACE-III scores of During Cx (P = .048) and Post Cx (P = .043) groups were lower as compared to Pre Cx group. In addition, reaction times and accuracies of the NPT (Flanker's, Sternberg's and Emotional Stroop tests) were worse (P < .05) in During Cx and Post Cx groups as compared to either Pre Cx or control groups. In the Post Cx group, the dose of chemotherapy showed significant negative correlation with the Sternberg reaction time (P = .040) as well as the scores of language (P = .047), and attention (P = .044) domains of ACE-III. Observations demonstrate that cancer/chemotherapy-related neurocognitive deficits fail to improve even after cessation of treatment, and high dosage of chemotherapy used, could be an underlying factor. This emphasizes the need for developing 'model of care' in these patients for monitoring the side effects, and possible titration in the therapeutic regimen for sarcoma in YA.

Functional network disorganization and cognitive decline following fractionated whole-brain radiation in mice.

Cognitive dysfunction following radiotherapy (RT) is one of the most common complications associated with RT delivered to the brain, but the precise mechanisms behind this dysfunction are not well understood, and to date, there are no preventative measures or effective treatments. To improve patient outcomes, a better understanding of the effects of radiation on the brain's functional systems is required. Functional magnetic resonance imaging (fMRI) has shown promise in this regard, however, compared to neural activity, hemodynamic measures of brain function are slow and indirect. Understanding how RT acutely and chronically affects functional brain organization requires more direct examination of temporally evolving neural dynamics as they relate to cerebral hemodynamics for bridging with human studies. In order to adequately study the underlying mechanisms of RT-induced cognitive dysfunction, the development of clinically mimetic RT protocols in animal models is needed. To address these challenges, we developed a fractionated whole-brain RT protocol (3Gy/day for 10 days) and applied longitudinal wide field optical imaging (WFOI) of neural and hemodynamic brain activity at 1, 2, and 3 months post RT. At each time point, mice were subject to repeated behavioral testing across a variety of sensorimotor and cognitive domains. Disruptions in cortical neuronal and hemodynamic activity observed 1 month post RT were significantly worsened by 3 months. While broad changes were observed in functional brain organization post RT, brain regions most impacted by RT occurred within those overlapping with the mouse default mode network and other association areas similar to prior reports in human subjects. Further, significant cognitive deficits were observed following tests of novel object investigation and responses to auditory and contextual cues after fear conditioning. Our results fill a much-needed gap in understanding the effects of whole-brain RT on systems level brain organization and how RT affects neuronal versus hemodynamic signaling in the cortex. Having established a clinically-relevant injury model, future studies can examine therapeutic interventions designed to reduce neuroinflammation-based injury following RT. Given the overlap of sequelae that occur following RT with and without chemotherapy, these tools can also be easily incorporated to examine chemotherapy-related cognitive impairment.

Middle aged CAMKII-Cre:Cbsfl/fl mice: a new model for studying perioperative neurocognitive disorders.

Postoperative complications, such as perioperative neurocognitive disorders (PND), have become a major issue affecting surgical outcomes. However, the mechanism of PND remains unclear, and stable animal models of middle-aged PND are lacking. S-adenosylmethionine (SAM), a cystathionine beta-synthase (CBS) allosteric activator, can reduce the level of plasma homocysteine and prevent the occurrence of PND. However, the time and resource-intensive process of constructing models of PND in elderly animals have limited progress in PND research and innovative therapy development. The present study aimed to construct a stable PND model in middle-aged CAMKII-Cre:Cbsfl/fl mice whose Cbs was specifically knocked out in CAMKII positive neurons. Behavioral tests showed that these middle-aged mice displayed cognitive deficits which were aggravated by exploratory laparotomy under isoflurane anesthesia. Compared with typical PND mice which were 18-month-old, these middle-aged mice showed similar cognitive deficits after undergoing exploratory laparotomy under isoflurane anesthesia. Though there was no significant difference in the number of neurons in either the hippocampus or the cortex, a significant increase in numbers of microglia and astrocytes in the hippocampus was observed. These indicate that middle-aged CAMKII-Cre:Cbsfl/fl mice can be used as a new PND model for mechanistic studies and therapy development for PND.

Active or passive? Investigating different types of cognitive fatigue.

Research in cognitive fatigue has identified the negative impact that cognitive exertion can have on subsequent task performance. An underexamined question is whether there are different types of fatigue, particularly: active fatigue, similar to cognitive fatigue, and passive fatigue, similar to boredom. This online study examined whether active and passive fatigue can be elicited and differentiated using computerized cognitive tasks. We compared subjective and behavioural outcomes to look for distinctions between fatigue types in response to different cognitive tasks. A sample of 122 participants (53% male; age 30.04 ± 3.50 years) rated their subjective state before and after one of three 8-min cognitive task conditions (TloadDback, Mackworth Clock, Documentary/Control). Next, participants also completed a second cognitive task (Flanker task). The task expected to be actively fatiguing (TloadDback) was rated the most difficult, effortful, and mentally and temporally demanding. The task expected to be passively fatiguing (Mackworth Clock) had the greatest increases in subjective fatigue, boredom, and sleepiness, and the greatest decrease in "want-to" motivation. There were no differences between conditions for Flanker performance. We showed that different fatigue types could be elicited using different computerized cognitive tasks. The passively fatiguing task had the most negative influence on subjective fatigue and motivation, suggesting a nonengaging or "boringly fatiguing" task induces a more detrimental type of fatigue. A key next step is to examine longer cognitive tasks to determine whether effects from different fatigue types become more prominent with time-on-task. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Coconut oil ameliorates behavioral and biochemical alterations induced by D-GAL/AlCl3 in rats.

Alzheimer's disease (AD) is a chronic, progressive neurodegenerative condition marked by cognitive impairment. Although coconut oil has been shown to be potentially beneficial in reducing AD-related cognitive deficits, information on its mechanism of action is limited. Thus, we investigated the effects of coconut oil on spatial cognitive ability and non-cognitive functions in a rat model of AD induced by G-galactose (D-GAL) and aluminum chloride (AlCl3), and examined the changes in synaptic transmission, cholinergic activity, neurotrophic factors and oxidative stress in this process. The AD model was established by administering D-GAL and AlCl3 for 90 days, while also supplementing with coconut oil during this time. Cognitive and non-cognitive abilities of the rats were evaluated at the end of the 90-day supplementation period. In addition, biochemical markers related to the pathogenesis of the AD were measures in the hippocampus tissue. Exposure to D-GAL/AlCl3 resulted in a reduction in locomotor activity, an elevation in anxiety-like behavior, and an impairment of spatial learning and memory (P < 0.05). The aforementioned behavioral disturbances were observed to coincide with increased oxidative stress and cholinergic impairment, as well as reduced synaptic transmission and levels of neurotrophins in the hippocampus (P < 0.05). Interestingly, treatment with coconut oil attenuated all the neuropathological changes mentioned above (P < 0.05). These findings suggest that coconut oil shows protective effects against cognitive and non-cognitive impairment, AD pathology markers, oxidative stress, synaptic transmission, and cholinergic function in a D-GAL/AlCl3-induced AD rat model.

Protecting the Brain While Healing Hearts: The Protective Role of Cognitive Reserve in Cardiac Surgery.

OBJECTIVE: One of the most significant complications following coronary artery bypass grafting (CABG) is postoperative cognitive decline (POCD). CABG patients frequently experience considerable postoperative cognitive dysfunction (POCD), including decline in attention, orientation, memory, judgment, and social functioning. DESIGN: These negative effects may potentially be resolved by a protective factor, cognitive reserve (CR) that has been considered to function as a buffer against the consequences of neuropathology. SETTING: We explored the frequency of POCD and CR in coronary artery disease patients undergoing CABG. We hypothesized that high levels of CR would protect against POCD after cardiac surgery. PARTICIPANTS: We assessed 101 patients before surgery, and 4 months after cardiopulmonary bypass surgery with the use of extracorporeal circulation. MEASUREMENTS: Measures of cognitive functions, CR, anxiety, and depression were included in the assessment. RESULTS: Each patient was placed in the high (n = 50) or low CR (n = 51) group, based on median split. Chi-square tests effect showed that patients with low CR were more likely to a great extend to demonstrate postsurgical cognitive decline in attention, memory, visuospatial perception and executive functions than patients with high CR upon postsurgery neuropsychological assessment. CONCLUSIONS: Our results suggest that CR can forecast neuropsychological outcomes of cardiac surgery, recognizing the patients with low CR and help them to participate to interventions programs that could slow cognitive aging or reduce the risk of dementia and enhance their overall postsurgical functional outcome.

Inhibiting CSF1R alleviates cerebrovascular white matter disease and cognitive impairment.

White matter abnormalities, related to poor cerebral perfusion, are a core feature of small vessel cerebrovascular disease, and critical determinants of vascular cognitive impairment and dementia. Despite this importance there is a lack of treatment options. Proliferation of microglia producing an expanded, reactive population and associated neuroinflammatory alterations have been implicated in the onset and progression of cerebrovascular white matter disease, in patients and in animal models, suggesting that targeting microglial proliferation may exert protection. Colony-stimulating factor-1 receptor (CSF1R) is a key regulator of microglial proliferation. We found that the expression of CSF1R/Csf1r and other markers indicative of increased microglial abundance are significantly elevated in damaged white matter in human cerebrovascular disease and in a clinically relevant mouse model of chronic cerebral hypoperfusion and vascular cognitive impairment. Using the mouse model, we investigated long-term pharmacological CSF1R inhibition, via GW2580, and demonstrated that the expansion of microglial numbers in chronic hypoperfused white matter is prevented. Transcriptomic analysis of hypoperfused white matter tissue showed enrichment of microglial and inflammatory gene sets, including phagocytic genes that were the predominant expression modules modified by CSF1R inhibition. Further, CSF1R inhibition attenuated hypoperfusion-induced white matter pathology and rescued spatial learning impairments and to a lesser extent cognitive flexibility. Overall, this work suggests that inhibition of CSF1R and microglial proliferation mediates protection against chronic cerebrovascular white matter pathology and cognitive deficits. Our study nominates CSF1R as a target for the treatment of vascular cognitive disorders with broader implications for treatment of other chronic white matter diseases.

A rat model established by simulating genetic-environmental interactions recapitulates human Alzheimer's disease pathology.

BACKGROUND: In humans, Alzheimer's disease (AD) is typically sporadic in nature, and its pathology is usually influenced by extensive factors. The study established a rat model based on the genetic-environmental interaction. METHODS: A rat model was established by transduction of an adeno-associated virus combined with acrolein treatment. Rats were assigned to the normal control (NC), acrolein group, AAV (-) group, AAV-APP group, and AAV-APP/acrolein group. The success of model construction was verified in multiple ways, including by assessing cognitive function, examining microstructural changes in the brain in vivo, and performing immunohistochemistry. The contribution of genetic (APP mutation) and environmental (acrolein) factors to AD-like phenotypes in the model was explored by factorial analysis. RESULTS: 1) The AAV-APP/acrolein group showed a decline in cognitive function, as indicated by a reduced gray matter volume in key cognition-related brain areas, lower FA values in the hippocampus and internal olfactory cortex, and Aß deposition in the cortex and hippocampus. 2) The AAV-APP group also showed a decline in cognitive function, although the group exhibited atypical brain atrophy in the gray matter and insignificant Aß deposition. 3) The acrolein group did not show any significant changes in Aß levels, gray matter volume, or cognitive function. 4) The genetic factor (APP mutation) explained 39.74% of the AD-like phenotypes in the model factors, and the environmental factor (acrolein exposure) explained 33.3%. CONCLUSIONS: The genetic-environmental interaction rat model exhibited a phenotype that resembled the features of human AD and will be useful for research on AD.

J147 affects cognition and anxiety after surgery in Zucker rats.

Vulnerable patients are at risk for neuroinflammation-mediated post-operative complications, including depression (POD) and cognitive dysfunction (POCD). Zucker rats, expressing multiple risk factors for post-operative complications in humans, may provide a clinically relevant model to study pathophysiology and explore potential interventions. J147, a newly developed anti-dementia drug, was shown to prevent POCD in young healthy rats, and improved early post-surgical recovery in Zucker rats. Aim of the present study was to investigate POCD and the therapeutic potential of J147 in male Zucker rats. Risk factors in the Zucker rat strain were evaluated by comparison with lean littermates. Zucker rats were subjected to major abdominal surgery. Acute J147 treatment was provided by a single iv injection (10 mg/kg) at the start of surgery, while chronic J147 treatment was provided in the food (aimed at 30 mg/kg/day), starting one week before surgery and up to end of protocol. Effects on behavior were assessed, and plasma, urine and brain tissue were collected and processed for immunohistochemistry and molecular analyses. Indeed, Zucker rats displayed increased risk factors for POCD, including obesity, high plasma triglycerides, low grade systemic inflammation, impaired spatial learning and decreased neurogenesis. Surgery in Zucker rats reduced exploration and increased anxiety in the Open Field test, impaired short-term spatial memory, induced a shift in circadian rhythm and increased plasma neutrophil gelatinase-associated lipocalin (NGAL), microglia activity in the CA1 and blood brain barrier leakage. Chronic, but not acute J147 treatment reduced anxiety in the Open Field test and protected against the spatial memory decline. Moreover, chronic J147 increased glucose sensitivity. Acute J147 treatment improved long-term spatial memory and reversed the circadian rhythm shift. No anti-inflammatory effects were seen for J147. Although Zucker rats displayed risk factors, surgery did not induce extensive POCD. However, increased anxiety may indicate POD. Treatment with J147 showed positive effects on behavioral and metabolic parameters, but did not affect (neuro)inflammation. The mixed effect of acute and chronic treatment may suggest a combination for optimal treatment.