Clinical Significance of the Plasma Biomarker Panels in Amyloid-Negative and Tau PET-Positive Amnestic Patients: Comparisons with Alzheimer's Disease and Unimpaired Cognitive Controls.

The purpose of this study was to investigate whether plasma biomarkers can help to diagnose, differentiate from Alzheimer disease (AD), and stage cognitive performance in patients with positron emission tomography (PET)-confirmed primary age-related tauopathy, termed tau-first cognitive proteinopathy (TCP) in this study. In this multi-center study, we enrolled 285 subjects with young-onset AD (YOAD; n = 55), late-onset AD (LOAD; n = 96), TCP (n = 44), and cognitively unimpaired controls (CTL; n = 90) and analyzed plasma Aß42/Aß40, pTau181, neurofilament light (NFL), and total-tau using single-molecule assays. Amyloid and tau centiloids reflected pathological burden, and hippocampal volume reflected structural integrity. Receiver operating characteristic curves and areas under the curves (AUCs) were used to determine the diagnostic accuracy of plasma biomarkers compared to hippocampal volume and amyloid and tau centiloids. The Mini-Mental State Examination score (MMSE) served as the major cognitive outcome. Logistic stepwise regression was used to assess the overall diagnostic accuracy, combining fluid and structural biomarkers and a stepwise linear regression model for the significant variables for MMSE. For TCP, tau centiloid reached the highest AUC for diagnosis (0.79), while pTau181 could differentiate TCP from YOAD (accuracy 0.775) and LOAD (accuracy 0.806). NFL reflected the clinical dementia rating in TCP, while pTau181 (rho = 0.3487, p = 0.03) and Aß42/Aß40 (rho = -0.36, p = 0.02) were significantly correlated with tau centiloid. Hippocampal volume (unstandardized ß = 4.99, p = 0.01) outperformed all of the fluid biomarkers in predicting MMSE scores in the TCP group. Our results support the superiority of tau PET to diagnose TCP, pTau181 to differentiate TCP from YOAD or LOAD, and NFL for functional staging.

Novel Panel of Long Noncoding RNAs as Diagnostic Biomarkers for Amnestic Mild Cognitive Impairment in Peripheral Blood.

Background: Long noncoding RNAs (lncRNAs) regulate the pathogenesis of Alzheimer's disease (AD). Objective: To identify lncRNAs in the peripheral blood as potential diagnostic biomarkers for amnestic mild cognitive impairment. Methods: In the discovery group, a microarray was used to screen for significant differences in lncRNA expression between patients with mild cognitive impairment (MCI) caused by AD and normal controls (NCs) (n = 10; MCI, 5; NC, 5). Furthermore, two analytic groups were assessed (analytic group 1: n = 10; amnestic MCI (aMCI), 5; NC, 5; analytic group 2: n = 30; AD, 10; aMCI, 10; NC, 10) and finalized in the validation group (n = 150; AD, 50; aMCI, 50; NC, 50). In the analytic and validation groups, real-time quantitative reverse-transcription polymerase chain reaction was used to identify differentially expressed lncRNAs between the aMCI and NC groups. Results: We identified 67 upregulated and 220 downregulated lncRNAs among the expression profiles. The panel with lncRNAs T324988, NR_024049, ENST00000567919, and ENST00000549762 displayed the highest discrimination ability between patients with aMCI and NCs. The area under the receiver operating characteristic curve of this combined model was 0.941, with a sensitivity of 92.00% and specificity of 84.00%. Conclusions: This study reports on a panel of four lncRNAs as promising biomarkers to diagnose aMCIs.

Serum beta-secretase 1 (BACE1) activity increases in patients with mild cognitive impairment.

Beta-secretase 1 (BACE1) is considered as the key enzyme in amyloid-ß formation. Previous works suggest that high BACE1 activity may be present in brain, cerebrospinal fluid and serum of patients with late-onset Alzheimer's disease (LOAD) as well as mild cognitive impairment (MCI). Therefore, we evaluated whether serum BACE1 activity increases in MCI patients and is associated with the progression from MCI to dementia. BACE1 activity was measured in the serum of 259 MCI patients (162 amnestic-aMCI, 97 non-amnestic-naMCI) and 204 healthy Controls. After a median follow-up of 32 months (range: 10-153), 116 MCI progressed to dementia (87 aMCI and 29 naMCI). Serum BACE1 activity was higher in MCI compared with Controls (p < 0.001), and in aMCI with brain atrophy compared with naMCI without brain atrophy (p = 0.04). No difference in BACE1 activity emerged between converter and non-converter MCI, and this was true for both aMCI and naMCI. However, among aMCI with better cognitive performance (n. 163, MMSE score ≥24/30) those converting to dementia had higher BACE1 activity compared to stable ones (p = 0.05). This was not associated with an increased risk to develop dementia (hazard ratio: 1.65; 95% confidence interval: 0.67-4.01). In conclusion, serum BACE1 activity significantly increased in MCI patients (both amnestic and non-amnestic) compared with Controls. Moreover, higher serum BACE1 activity was observed only among aMCI with a better cognitive performance who progressed to dementia, suggesting that a dysregulation of this enzyme might be an early event primarily associated with neurodegeneration.

Alpha 1-antichymotrypsin may be a biomarker for the progression of amnestic mild cognitive impairment.

Alpha 1-antichymotrypsin (ACT), an acute-phase protein, has been reported to be increased in the brain and blood of Alzheimer's disease (AD) patients. However, few previous studies have focused on amnestic mild cognitive impairment (aMCI) patients. The aim of our study was to investigate the changing trend in ACT concentrations during the progression of aMCI. Hence, we measured the cerebrospinal fluid (CSF) and serum levels of ACT in aMCI subjects and normal controls (NC) at 2-year follow-up assessments using ELISA and Western blot. Forty-four NCs, 28 stable aMCI (sMCI) patients, and 20 progressive aMCI (pMCI) patients finished the follow-up assessments, and their data were used for analysis. We found that CSF and serum ACT levels of both sMCI and pMCI patients increased over time, while those of NCs remained stable; CSF and serum ACT levels were significantly higher in both sMCI and pMCI patients than in NCs, except for baseline serum ACT. In pMCI patients prior to developing AD, CSF and serum ACT levels were already significantly higher than those in sMCI patients. The ROC curve results demonstrated that combining CSF and serum ACT levels can distinguish aMCI patients from NCs with high specificity and sensitivity. Our data suggest that ACT may be a biomarker for diagnosing aMCI.

Altered complexity of resting-state BOLD activity in Alzheimer's disease-related neurodegeneration: a multiscale entropy analysis.

Brain complexity, which reflects the ability of the brain to adapt to a changing environment, has been found to be significantly changed with age. However, there is less evidence on the alterations of brain complexity in neurodegenerative disorders such as Alzheimer's disease (AD). Here we investigated the altered complexity of resting-state blood oxygen level-dependent signals in AD-related neurodegeneration using multiscale entropy (MSE) analysis. All participants were recruited from the Alzheimer's Disease Neuroimaging Initiative, including healthy controls (HC, n=62), amnestic mild cognitive impairment (aMCI, n =81) patients, and Alzheimer's disease (AD, n=25) patients. Our results showed time scale-dependent MSE differences across the three groups. In scale=1, significantly changed MSE patterns (HC>aMCI>AD) were found in four brain regions, including the hippocampus, middle frontal gyrus, intraparietal lobe, and superior frontal gyrus. In scale=4, reversed MSE patterns (HC

Combining Select Blood-Based Biomarkers with Neuropsychological Assessment to Detect Mild Cognitive Impairment among Mexican Americans.

BACKGROUND: Recent work has supported use of blood-based biomarkers in detection of amnestic mild cognitive impairment (MCI). Inclusion of neuropsychological measures has shown promise in enhancing utility of biomarkers to detect disease. OBJECTIVE: The present study sought to develop cognitive-biomarker profiles for detection of MCI. METHODS: Data were analyzed on 463 participants (normal control n = 378; MCI n = 85) from HABLE. Random forest analyses determined proteomic profile of MCI. Separate linear regression analyses determined variance accounted for by select biomarkers per neuropsychological measure. When neuropsychological measure with the least shared variance was identified, it was then combined with select biomarkers to create a biomarker-cognitive profile. RESULTS: The biomarker-cognitive profile was 90% accurate in detecting MCI. Among amnestic MCI cases, the detection accuracy of the biomarker-cognitive profile was 92% and increased to 94% with demographic variables. CONCLUSION: The biomarker-cognitive profile for MCI was highly accurate in its detection with use of only five biomarkers.

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.

Plasma Aß42 and Total Tau Predict Cognitive Decline in Amnestic Mild Cognitive Impairment.

Levels of amyloid-ß (Aß) and tau peptides in brain have been associated with Alzheimer disease (AD). The current study investigated the abilities of plasma Aß42 and total-tau (t-tau) levels in predicting cognitive decline in subjects with amnestic mild cognitive impairment (MCI). Plasma Aß42 and t-tau levels were quantified in 22 participants with amnestic MCI through immunomagnetic reduction (IMR) assay at baseline. The cognitive performance of participants was measured through neuropsychological tests at baseline and annual follow-up (average follow-up period of 1.5 years). The predictive value of plasma Aß42 and t-tau for cognitive status was evaluated. We found that higher levels of Aß42 and t-tau are associated with lower episodic verbal memory performance at baseline and cognitive decline over the course of follow-up. While Aß42 or t-tau alone had moderate-to-high discriminatory value in the identification of future cognitive decline, the product of Aß42 and t-tau offered greater differential value. These preliminary results might suggest that high levels of plasma Aß42 and t-tau in amnestic MCI are associated with later cognitive decline. A further replication with a larger sample over a longer time period to validate and determine their long-term predictive value is warranted.

Alcohol-Induced Amnesia and Personalized Drinking Feedback: Blackouts Predict Intervention Response.

Alcohol-induced amnesia ("blackout") is a reliable predictor of alcohol-related harm. Given its association with other negative consequences, experience of alcohol-induced amnesia may serve as a teachable moment, after which individuals are more likely to respond to intervention. To test this hypothesis, alcohol-induced amnesia was evaluated as a moderator of brief intervention effect on (a) alcohol-related consequences and (b) the proposed intervention mediators, protective behavioral strategies and peak blood alcohol concentration (BAC). Baseline alcohol risk measured using the Alcohol Use Disorders Identification Test (AUDIT) was also evaluated as a moderator to rule out the possibility that amnesia is simply an indicator of more general alcohol risk. College students (N = 198) reporting alcohol use in a typical week completed assessments at baseline and 1-month follow-up as part of a larger intervention trial. Participants were randomized to assessment only (AO; n = 58) or personalized feedback intervention (PFI; n = 140). Hierarchical regression was used to examine direct and indirect intervention effects. A significant group-by-amnesia interaction revealed that only PFI participants who had experienced alcohol-induced amnesia in the past month reported decreases in alcohol consequences at 1-month follow-up. The PFI reduced alcohol-related consequences indirectly through changes in peak BAC, but only among those who had experienced amnesia at baseline. In contrast, baseline alcohol risk (AUDIT) did not moderate intervention effects, and use of protective behavioral strategies did not statistically mediate intervention effects. Findings suggest that loss of memory for drinking events is a unique determinant of young adult response to brief alcohol intervention. Normative feedback interventions may be particularly effective for individuals who have experienced alcohol-induced amnesia in the past 30 days.

Plasma Aß42 as a Biomarker of Prodromal Alzheimer's Disease Progression in Patients with Amnestic Mild Cognitive Impairment: Evidence from the PharmaCog/E-ADNI Study.

It is an open issue whether blood biomarkers serve to diagnose Alzheimer's disease (AD) or monitor its progression over time from prodromal stages. Here, we addressed this question starting from data of the European FP7 IMI-PharmaCog/E-ADNI longitudinal study in amnesic mild cognitive impairment (aMCI) patients including biological, clinical, neuropsychological (e.g., ADAS-Cog13), neuroimaging, and electroencephalographic measures. PharmaCog/E-ADNI patients were classified as "positive" (i.e., "prodromal AD" n = 76) or "negative" (n = 52) based on a diagnostic cut-off of Aß42/P-tau in cerebrospinal fluid as well as APOE ε 4 genotype. Blood was sampled at baseline and at two follow-ups (12 and 18 months), when plasma amyloid peptide 42 and 40 (Aß42, Aß40) and apolipoprotein J (clusterin, CLU) were assessed. Linear Mixed Models found no significant differences in plasma molecules between the "positive" (i.e., prodromal AD) and "negative" groups at baseline. In contrast, plasma Aß42 showed a greater reduction over time in the prodromal AD than the "negative" aMCI group (p = 0.048), while CLU and Aß40 increased, but similarly in the two groups. Furthermore, plasma Aß42 correlated with the ADAS-Cog13 score both in aMCI patients as a whole and the prodromal AD group alone. Finally, CLU correlated with the ADAS-Cog13 only in the whole aMCI group, and no association with ADAS-Cog13 was found for Aß40. In conclusion, plasma Aß42 showed disease progression-related features in aMCI patients with prodromal AD.

Serum ischaemia-modified albumin might be a potential biomarker for oxidative stress in amnestic mild cognitive impairment.

BACKGROUND: Amnestic mild cognitive impairment (aMCI) is considered to be a prodromal stage of Alzheimer's disease. The clinical role of ischaemia-modified albumin (IMA) and the association between IMA and oxidative stress in aMCI have not been investigated. The aim of the study was to explore this relationship and to generate new ideas for controlling Alzheimer's disease. METHODS: This community-based case-control study included 113 patients with aMCI and 832 cognitively normal controls. Serum levels of albumin and IMA, diacron-reactive oxygen metabolite, and biological anti-oxidant potential, were measured. The IMA/albumin ratio and the biological anti-oxidant potential/diacron-reactive oxygen metabolite ratio were calculated. RESULTS: In univariate analysis, the serum IMA level and the IMA/albumin ratio were higher in the aMCI patients than in the controls (P < 0.001, P < 0.001, respectively). In multivariate analysis, a serum IMA level ≥476.4 ng/mL and an IMA/albumin ratio ≥9.4 were separately associated with the development of aMCI (odds ratio = 3.56, 95% confidence interval: 2.33-5.46; odds ratio = 3.43, 95% confidence interval: 2.25-5.27, respectively). There was a linear correlation between serum IMA level and several oxidative stress markers (biological anti-oxidant potential/diacron-reactive oxygen metabolite ratio: r = -0.585, P < 0.001; diacron-reactive oxygen metabolite: r = 0.549, P < 0.001; biological anti-oxidant potential: r = -0.293, P < 0.001). CONCLUSION: Serum IMA might be a potential biomarker for oxidative stress in aMCI.

[Therapeutic monitoring and prediction of the efficacy of neurotrophic treatment in patients with amnestic type of mild cognitive impairment]. / Terapevticheskii monitoring i prognoz éffektivnosti neirotroficheskoi terapii u patsientov s sindromom miagkogo kognitivnogo snizheniia amnesticheskogo tipa.

AIM: To perform therapeutic monitoring and prediction of the neurotrophic therapy efficacy in patients with amnestic type of mild cognitive impairment (aMCI) in a model of course cerebrolysin therapy. MATERIAL AND METHODS: The study involved a group of 19 elderly patients who met the diagnostic criteria of aMCI. All patients received a course of neurotrophic therapy consisting of 20 intravenous infusions of cerebrolysin (30 ml of cerebrolysin in 100 ml of isotonic sodium chloride solution). To assess the therapy efficacy, psychometric scales (CGI, MMSE, MoCA-test, МDRS, FAB, Clock Drawing Test, BNT, Word Recall test, delayed reproduction of 10 words, naming digits in a direct and reverse order) were used at 0, 4, 10 and 26 weeks of the study. Antibodies to p75 neurotrophin receptor (NTR) were measured by ELISA in blood serum of 19 patients before cerebrolysin therapy and after 10 and 26 weeks of treatment. RESULTS AND CONCLUSION: The study showed that аMCI patients had an increased level of antibodies against P75NTR that was significantly decreased after 5.5 month of cerebrolysin treatment. Therefore, it can be a potential biomarker of long-term therapeutic effect of cerebrolysin treatment in aMCI patients. The modified fragment 155-164 of P75 NTR determined in the serum of patients can be an effective indicator for monitoring and predicting the efficacy of long-term neurotrophic therapy.

Elevated Plasma Aß42 in Cognitively Impaired Individuals Taking ACE Inhibitor Antihypertensives.

BACKGROUND/RATIONALE: Accumulating evidence suggests that the use of angiotensin-converting enzyme inhibitor (ACE-I) medication protects against cognitive decline in the elderly patients. We investigated whether ACE-I use was associated with higher plasma levels of amyloid-ß (Aß), possibly indicating improved Aß clearance from brain to blood. METHODS: We measured and compared plasma concentrations of Aß42, Aß40, and creatinine in cognitively impaired individuals with amnestic mild cognitive impairment, probable Alzheimer's disease (AD) dementia, and mixed probable AD/vascular dementia. RESULTS: Plasma Aß42 levels and Aß42/Aß40 ratios of participants taking ACE-Is (n = 11) significantly exceeded ( t = 3.1, df = 19, P = .006; U = 24, P = .029, respectively) those not taking ACE-Is (n = 10). CONCLUSIONS: This study is the first to show an association between ACE-I use and increased plasma Aß42 level and Aß42/Aß40 ratio in cognitively impaired individuals. Future investigations should assess whether a possible ACE-I-induced increase in plasma Aß42 indicates improved Aß42 clearance from brain that contributes to protection from cognitive decline.

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.

Plasma micro-RNA biomarkers for diagnosis and prognosis after traumatic brain injury: A pilot study.

Prediction of post-concussive syndrome after apparent mild traumatic brain injury (TBI) and subsequent cognitive recovery remains challenging, with substantial limitations of current methods of cognitive testing. This pilot study aimed to determine if levels of micro ribonucleic acids (RNAs) circulating in plasma are altered following TBI, and if changes to levels of such biomarkers over time could assist in determination of prognosis after TBI. Patients were enrolled after TBI on presentation to the Emergency Department and allocated to three groups: A - TBI (physical trauma to the head), witnessed loss of consciousness, amnesia, GCS=15, a normal CT Brain and a recorded first pass after post-traumatic amnesia (PTA) scale; B TBI, witnessed LOC, amnesia, GCS=15, a normal CT brain and a PTA scale test fail and: C - TBI and initial GCS <13 on arrival to the ED. Venous blood was collected at three time points (arrival, day 5 and day 30). Isolation of cell-free total RNA was then assayed using a custom miRNA PCR array. Two micro-RNAs, mir142-3p and mir423-3p demonstrated potential clinical utility differentiating patients after mild head injury into those at greater risk of developing amnesia and therefore, post-concussive syndromes. In addition, these miRNA demonstrated a decrease in expression over time, possibly indicative of brain healing after the injury. Further evaluation of these identified miRNA markers with larger patient cohorts, correlation with clinical symptoms and analysis over longer time periods are essential next steps in developing objective markers of severity of TBI.

Increased apoptosis in the platelets of patients with Alzheimer's disease and amnestic mild cognitive impairment.

OBJECTIVES: Alzheimer's disease (AD), the most common cause of dementia, is a progressive, incurable neurodegenerative disorder. Platelet is a suitable source of human peripheral tissue to study pathological mechanisms occurring in the brain. The present study aims to investigate (1) whether abnormal apoptotic events besides involved in AD within the central neurologic system, could also occur at peripheral platelet level; (2) whether apoptosis at peripheral platelet level starts at the early stage of AD. PATIENTS AND METHODS: Amnestic mild cognitive impairment (MCI), AD, and age-matched healthy individuals were recruited, and each group had 50 person. In the present study, we investigate whether alterations of caspase family and Bcl2 family could be found in the platelets in Alzheimer's disease (AD) and amnestic mild cognitive impairment (MCI) patients. The platelet levels of caspase protein and Bcl2 family were analyzed by western blot. RESULTS: The results show that the platelet levels of caspase-3, caspase-9, Bad, and Bax significantly increased in AD and amnestic MCI. The increased apoptosis proteins levels in amnestic MCI were found between AD and normal controls. The anti-apoptosis protein Bcl2 increased in amnestic MCI, while decreased in AD. CONCLUSION: We suggest that increased apoptosis exist in the platelet and might mirror apoptosis within the brain. Abnormal apoptosis may appear in the early of AD, and the ratio between pro- and anti-apoptotic protein levels partially determines the susceptibility of platelet to a death signal. In conclusion, platelet may be a good model to study apoptotic pathways of AD.

Amyloid-Independent Amnestic Mild Cognitive Impairment and Serum Apolipoprotein A1 Levels.

OBJECTIVES: The present study investigated the characteristics of amnestic mild cognitive impairment (aMCI) in subjects with low brain amyloid-beta (Aß) burden. Furthermore, the relationships between amyloid-independent cognitive decline and serum lipid profiles, particularly apolipoprotein A1 (APOA1), were evaluated. DESIGN: Cross-sectional and longitudinal follow-up study. SETTING: University hospital dementia clinic. PARTICIPANTS: 28 aMCI and 35 cognitive normal (CN) elderly. MEASUREMENTS: The study measures included baseline assessments of the subjects' clinical characteristics, lipid profiles, and magnetic resonance imaging and (11)C-labelled Pittsburgh Compound B (PiB) positron emission tomography scans. Based on PiB retention at baseline, the aMCI subjects were divided into low Aß (aMCI-) and high Aß (aMCI+) subgroups. All aMCI subjects were followed up over a 1-year period. RESULTS: The aMCI- group had a longer duration of illness than did the aMCI+ group. None of the aMCI- subjects were diagnosed with Alzheimer disease (AD) dementia during the 1-year follow-up period, whereas 26.7% of aMCI+ subjects developed AD dementia. The aMCI- group also exhibited lower serum APOA1 levels compared with both the aMCI+ and CN groups. Additionally, lower serum APOA1 levels were associated with cognitive decline and brain atrophy independent of Aß deposition and vascular burden. CONCLUSIONS: Patients with aMCI- likely exhibit different clinical and pathophysiological characteristics than patients with aMCI+. Additionally, APOA1 may be an important contributor underlying amyloid-independent neurodegeneration.

Plasma SUMO1 Protein is Elevated in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common type of dementia in the elderly. The accumulation of amyloid-ß peptides and tau proteins is the major pathogenic event of AD. There is accumulating evidence that both tau and amyloid-ß linked to the small ubiquitin-like modifier (SUMO), which is increased in the brain of AD model mouse. The present study focused on the determination of SUMO1 protein level in AD blood plasma by the ELISA methods. We compared plasma from 80 dementia patients (average age 75.3 y), 89 persons with amnestic mild cognitive impairment (MCI) (average age 73.71 y),and 133 cognitively normal controls (average age 71.97 y). The plasma level of SUMO1 was significantly increased in dementia patients, as compared to control groups. The levels of SUMO1 correlated to decreased Mini-Mental State Examination (r =-0.123, p = 0.029). These results suggest that elevated plasma SUMO1 levels may be associated with AD.

Serum Total Cholinesterase Activity on Admission Is Associated with Disease Severity and Outcome in Patients with Traumatic Brain Injury.

BACKGROUND: Traumatic brain injury (TBI) is one of the leading causes of neurological disability. In this retrospective study, serum total cholinesterase (ChE) activities were analyzed in 188 patients for diagnostic as well as predictive values for mortality. METHODS AND FINDINGS: Within 72 hours after injury, serum ChE activities including both acetylcholinesterase and butyrylcholinesterase were measured. Disease severity was evaluated with Acute Physiology and Chronic Health Evaluation (APACHE) II score, Glasgow Coma Score, length of coma, post-traumatic amnesia and injury feature. Neurocognitive and functional scores were assessed using clinical records. Of 188 patients, 146 (77.7%) survived and 42 (22.3%) died within 90 days. Lower ChE activities were noted in the non-survivors vs. survivors (5.94±2.19 vs. 7.04±2.16 kU/L, p=0.023), in septic vs. non-infected patients (5.93±1.89 vs. 7.31±2.45 kU/L, p=0.0005) and in patients with extremely severe injury vs. mild injury (6.3±1.98 vs. 7.57±2.48 kU/L, p=0.049). The trajectories of serum ChE levels were also different between non-survivors and survivors, septic and non-infected patients, mild and severely injured patients, respectively. Admission ChE activities were closely correlated with blood cell counts, neurocognitive and functional scores both on admission and at discharge. Receiver operating characteristic analysis showed that the area under the curve for ChE was inferior to that for either APACHE II or white blood cell (WBC) count. However, at the optimal cutoff value of 5 kU/L, the sensitivity of ChE for correct prediction of 90-day mortality was 65.5% and the specificity was 86.4%. Kaplan-Meier analysis showed that lower ChE activity (<5 kU/L) was more closely correlated with poor survival than higher ChE activity (>5 kU/L) (p=0.04). After adjusting for other variables, ChE was identified as a borderline independent predictor for mortality as analyzed by Binary logistic regression (P=0.078). CONCLUSIONS: Lowered ChE activity measured on admission appears to be associated with disease severity and outcome for TBI patients.

The feasibility of utilizing plasma MiRNA107 and BACE1 messenger RNA gene expression for clinical diagnosis of amnestic mild cognitive impairment.

OBJECTIVE: To investigate the relationship between microRNA107 (miRNA107) and BACE1 messenger RNA (mRNA) gene expressions in plasma and their diagnostic capability to distinguish subjects with amnestic mild cognitive impairment from healthy controls. METHOD: We recruited 97 patients with Alzheimer's disease according to diagnostic criteria of DSM-IV and National Institute of Neurologic and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association, 116 subjects with amnestic mild cognitive impairment, and 81 healthy controls from January 2012 to December 2012. The real-time PCR was used to quantify miRNA107 and BACE1 mRNA. The power of classification accuracies between patients with amnestic mild cognitive impairment and healthy controls was performed using linear discriminate analysis single or combining both the expression miRNA107 and BACE1 mRNA. RESULTS: For patients with Alzheimer's disease, the miRNA107 expressions in plasma and cerebral spinal fluid were correlated (Pearson correlation = 0.665, P = .034). There were statistically significant correlations between plasma miRNA107 and BACE1 mRNA gene expression in Alzheimer's disease, amnestic mild cognitive impairment, and healthy control groups (r value = -0.316 [P = .002], -0.615 [P < .001], and -0.367 [P = .001], respectively). The overall classification accuracy of miRNA107 to discriminate between patients with amnestic mild cognitive impairment and healthy controls was 91.9%, with sensitivity of 98.3% and specificity of 82.7%. CONCLUSIONS: The miRNA107 expression in plasma has a high capability to discriminate between patients with amnestic mild cognitive impairment and healthy controls. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01819545.