Association of serum cystatin C with white matter abnormalities in patients with amnestic mild cognitive impairment.

AIM: White matter hyperintensities (WMH) on MRI have been reported to be a risk factor for the conversion from mild cognitive impairment (MCI) to Alzheimer's disease, although the reason remains unclear. In the present study, we hence investigated the associations between WMH volumes and cognitive function, blood levels of various molecules, and the presence of lifestyle-associated diseases in patients with amnestic MCI. METHODS: The initial data of 38 patients with amnestic MCI and 10 normal control individuals were analyzed. The volumes of periventricular hyperintensities (PVH) and deep WMH (DWMH) were measured on T2 fluid-attenuated inversion recovery using the imaging software, 3D Slicer; and the association between PVH/DWMH volumes and cognitive function, blood levels of molecules (such as cystatin C [CysC], 25-hydroxyvitamin D and homocysteine) and the presence of lifestyle-associated diseases (such as hypertension, hyperlipidemia and diabetes mellitus) were analyzed. RESULTS: In the MCI group, the PVH volume : intracranial volume ratio significantly correlated with Trail Making Test-A/B scores and CysC level by Pearson's analysis, and the PVH volume : intracranial volume ratio significantly correlated with only CysC levels, whereas the DWMH volume : intracranial volume ratio did not correlate with any items at all by linear multiple regression analysis. CONCLUSIONS: PVH volume was closely associated with frontal lobe dysfunction, particularly with attention and executive dysfunction. Serum CysC level was associated with PVH volume, which suggests that CysC might be a useful marker for determining treatment strategies for white matter abnormalities in amnestic MCI. Geriatr Gerontol Int 2019; 19: 1036-1040.

Conjugated Linoleic Acid Administration Induces Amnesia in Male Sprague Dawley Rats and Exacerbates Recovery from Functional Deficits Induced by a Controlled Cortical Impact Injury.

Long-chain polyunsaturated fatty acids like conjugated linoleic acids (CLA) are required for normal neural development and cognitive function and have been ascribed various beneficial functions. Recently, oral CLA also has been shown to increase testosterone (T) biosynthesis, which is known to diminish traumatic brain injury (TBI)-induced neuropathology and reduce deficits induced by stroke in adult rats. To test the impact of CLA on cognitive recovery following a TBI, 5-6 month old male Sprague Dawley rats received a focal injury (craniectomy + controlled cortical impact (CCI; n = 17)) or Sham injury (craniectomy alone; n = 12) and were injected with 25 mg/kg body weight of Clarinol® G-80 (80% CLA in safflower oil; n = 16) or saline (n = 13) every 48 h for 4 weeks. Sham surgery decreased baseline plasma progesterone (P4) by 64.2% (from 9.5 ± 3.4 ng/mL to 3.4 ± 0.5 ng/mL; p = 0.068), T by 74.6% (from 5.9 ± 1.2 ng/mL to 1.5 ± 0.3 ng/mL; p < 0.05), 11-deoxycorticosterone (11-DOC) by 37.5% (from 289.3 ± 42.0 ng/mL to 180.7 ± 3.3 ng/mL), and corticosterone by 50.8% (from 195.1 ± 22.4 ng/mL to 95.9 ± 2.2 ng/mL), by post-surgery day 1. CCI injury induced similar declines in P4, T, 11-DOC and corticosterone (58.9%, 74.6%, 39.4% and 24.6%, respectively) by post-surgery day 1. These results suggest that both Sham surgery and CCI injury induce hypogonadism and hypoadrenalism in adult male rats. CLA treatment did not reverse hypogonadism in Sham (P4: 2.5 ± 1.0 ng/mL; T: 0.9 ± 0.2 ng/mL) or CCI-injured (P4: 2.2 ± 0.9 ng/mL; T: 1.0 ± 0.2 ng/mL, p > 0.05) animals by post-injury day 29, but rapidly reversed by post-injury day 1 the hypoadrenalism in Sham (11-DOC: 372.6 ± 36.6 ng/mL; corticosterone: 202.6 ± 15.6 ng/mL) and CCI-injured (11-DOC: 384.2 ± 101.3 ng/mL; corticosterone: 234.6 ± 43.8 ng/mL) animals. In Sham surgery animals, CLA did not alter body weight, but did markedly increase latency to find the hidden Morris Water Maze platform (40.3 ± 13.0 s) compared to saline treated Sham animals (8.8 ± 1.7 s). In CCI injured animals, CLA did not alter CCI-induced body weight loss, CCI-induced cystic infarct size, or deficits in rotarod performance. However, like Sham animals, CLA injections exacerbated the latency of CCI-injured rats to find the hidden MWM platform (66.8 ± 10.6 s) compared to CCI-injured rats treated with saline (30.7 ± 5.5 s, p < 0.05). These results indicate that chronic treatment of CLA at a dose of 25 mg/kg body weight in adult male rats over 1-month 1) does not reverse craniectomy- and craniectomy + CCI-induced hypogonadism, but does reverse craniectomy- and craniectomy + CCI-induced hypoadrenalism, 2) is detrimental to medium- and long-term spatial learning and memory in craniectomized uninjured rats, 3) limits cognitive recovery following a moderate-severe CCI injury, and 4) does not alter body weight.

Peripheral inflammatory markers in amnestic mild cognitive impairment.

OBJECTIVE: To prospectively monitor plasma inflammatory marker concentrations in peripheral blood, over 12 months, in subjects with amnestic mild cognitive impairment (MCI), and to determine the relationship between peripheral inflammatory markers and cognitive decline. METHODS: Seventy patients with amnestic MCI were recruited from two sites providing specialist memory assessment services in Manchester. The baseline assessment included physical examination, neuro-psychological testing and venous blood samples for C-reactive protein (CRP) and interleukin 6 (IL-6) concentrations. Sixty two participants were followed up after 12 months and the assessments were repeated. RESULTS: Data analysis revealed a significant rise in CRP, but not IL-6 concentrations over 12 months, which was not confounded by demographic variables. The neuro-psychological test scores had no association with CRP or IL-6 concentrations at baseline or 12 months follow-up. CONCLUSION: This study adopted the unique approach of prospectively investigating peripheral inflammatory markers in a cohort with amnestic MCI. A significant rise in CRP concentrations over 12 months, but lack of significant association with cognition, provide no evidence for a relationship between systemic inflammation and cognitive decline in amnestic MCI.

Decreased serum levels of the angiogenic factors VEGF and TGF-ß1 in Alzheimer's disease and amnestic mild cognitive impairment.

Growing evidence suggests that angiogenesis might represent a new pathogenic mechanism involved in the progression of Alzheimer's disease (AD). Vascular endothelial growth factor (VEGF) and transforming growth factor-ß1 (TGF-ß1) are two cytokines having a pivotal role in angiogenesis. In the present study, serum VEGF and TGF-ß1 levels were measured with ELISA in 31 AD patients, 28 amnestic mild cognitive impairment (aMCI) patients and 29 controls. VEGF concentration in serum of AD patients was significantly lower than that in aMCI patients and controls (p<0.05). Serum VEGF levels in aMCI patients were also significantly decreased compared to controls (p<0.05). Serum TGF-ß1 levels in AD patients were significantly lower than those in controls (p<0.05). There was a negative correlation between serum VEGF/TGF-ß1 levels and the Clinical Dementia Rating (CDR) scores (p<0.05) and a positive correlation between serum VEGF levels and TGF-ß1 levels (p<0.05). These observations suggest that angiogenesis might be involved in the onset process of AD and the decrease of angiogenic factors might be related to the severity of cognitive impairment.

Plasma neopterin level as a marker of peripheral immune activation in amnestic mild cognitive impairment and Alzheimer's disease.

OBJECTIVE: Alterations of the immune system play important roles in Alzheimer's disease (AD). The primary purpose of this study was to compare the plasma levels of neopterin, a marker of cellular immune activity, in amnestic mild cognitive impairment (aMCI), early (mild to moderate) AD, and cognitively normal controls. In addition, the correlation of plasma neopterin with interferon-gamma (IFN-γ) and interleukin-6 (IL-6) was also examined. METHODS: Plasma samples from patients with mild-to-moderate AD (N = 34), aMCI (N = 27), and cognitively normal controls (N = 30) were obtained from the Johns Hopkins Alzheimer's Disease Research Center. Plasma neopterin, IFN-γ, and IL-6 levels were measured using commercially available ELISAs. Multiple linear regression was performed to study differences in the baseline neopterin levels between normal, aMCI, and AD patients. Pearson correlation coefficients were estimated for neopterin and IFN-γ and IL-6 levels. All analyses were conducted using SAS (SAS Institute, Inc., Cary, NC) and GraphPad Prism version 5.00 for Window (GraphPad Software, San Diego, CA, USA). RESULTS: AD subjects had significantly higher neopterin values compared with aMCI (ß = 0.202, p = 0.004) and normal (ß = 0.263, p = 0.0004) subjects. There was no statistically significant difference between normal and aMCI subjects. Significant associations between neopterin and IFN-γ (r = 0.41, p < 0.0001) and IL-6 (r = 0.35, p = 0.0006) levels were found. CONCLUSIONS: Our study demonstrates that peripheral immune response may be stronger in later stages of AD pathophysiology, when dementia has developed.

Model predicting survival/exitus after traumatic brain injury: biomarker S100B 24h.

BACKGROUND: The enigma of Traumatic Brain Injury (TBI), reflected in recent scientific literature, is its uncertain consequences, variability of the final prognosis with apparently similar TBI, necessity for peripheral biomarkers, and more specific predictive models. OBJECTIVES: To study the relationship between serum S100B and survival in TBI patients in various serious situations; the S100B level in patients without traumatic pathology or associated tumour, subjected to stressful situations such as neurological intensive care unit (NICU) stay; the possible overestimation caused by extracerebral liberation in TBI patients and associated polytraumatism; the predictive cutoffs to determine the most sensitive and specific chronology; and achieve a predictive prognostic model. METHODS: Patients admitted to the NICU within 6 hours after TBI were selected. We measured: a) clinical: exitus yes/no; age and gender, traumatic mechanism, polytraumatism yes/no, GCS score, unconsciousness duration, amnesia duration, neurological focality, and surgical interventions; b) radiological: CT scan for radiological lesions; c) biochemical: serum SB100B at 6, 24, 48 and 72 hours after TBI and drug abuse detected in the urine; d) GOS on hospital discharge. RESULTS: N: 149 TBI patients, independent of polytraumatism, mean serum S100B at 6, 24, 48, and 72 hours: 2.1, 1.3, 1.2, and 0.6 microg/L, respectively; N: 124 without associated polytraumatism, S100B at 6, 24, 48, and 72 hours: 2.0, 1.4, 1.3, and 0.6 microg/L; N: 50 control I S100B 24 hours: 0.17 microg/L (0.04 - 0.56) and 25 healthy subjects S100B 0.057 microg/L (0.02-0.094). CONCLUSIONS: Significantly higher S100B levels are observed on exitus, with excellent TBI prognosis and evolution performance. Hospital stay in the NICU produces significant increases in S100B compared to healthy subjects, without invalidating it as a biomarker. Polytraumatism associated to TBI does not significantly alter S100B levels. S100B at 24 hours > or = 0.90 microg/L appears to predict unfavourable TBI evolution with a NPV: 94.2% and PPV: 54.9%. We propose a predictive model when we associate S100B at 24 hours with amnesia duration over 30 minutes with a NPV of 85.5% and a PPV of 83.3%.

Activated platelets in transient global amnesia and TIA.

To assess whether platelets are activated in transient global amnesia (TGA) and TIA, blood samples were analyzed by fluorescence-activated cytoscan using antibodies specific for platelet fibrinogen receptor (PAC1) and P-selectin (CD62P). Samples from TIA contained high levels of CD62P compared with age-matched control subjects, whereas those from TGA did not. The authors suggest that activated platelets are involved in brain ischemia, whereas ischemia appears not to be associated with most TGA.

Relationship between testosterone, sex hormone binding globulin and plasma amyloid beta peptide 40 in older men with subjective memory loss or dementia.

In a group of 28 older men with either subjective memory loss or dementia, serum total testosterone and sex hormone binding globulin (SHBG) correlated inversely with plasma levels of amyloid beta peptide 40 (Abeta40, r=-0.5, P=0.01 and r=-0.4, P=0.04, respectively). Calculated free testosterone was also inversely correlated (r=-0.4, P=0.03), and all three relationships remained statistically significant after allowing for age. A similar but non-significant trend was seen with dehydroepiandrosterone sulphate (DHEAS), and neither luteinising hormone (LH) nor estradiol correlated with Abeta40. These data demonstrate that lower androgen levels are associated with increased plasma Abeta40 in older men with memory loss or dementia, suggesting that subclinical androgen deficiency enhances the expression of Alzheimer's disease-related peptides in vivo. An inverse correlation exists between SHBG and Abeta40, warranting further investigation.