Plasma neurofilament light chain in memory clinic practice: Evidence from a real-life study.

OBJECTIVE: To explore the accuracy of plasma neurofilament light chain (NfL) as a biomarker for diagnosis and staging of cognitive impairment, in a large cohort with of previously diagnosed patients in clinical practice. METHODS: Retrospective, cross-sectional, monocentric study, from a tertiary memory clinic. Patients underwent cerebrospinal fluid core Alzheimer's disease (AD) biomarker evaluation using ELISA or Elecsys methods, and plasma NfL analysis using the single molecule array technology. The patients' biomarker data were examined for associations with: i/cognitive status ii/presence of neurodegenerative disease and iii/diagnostic groups. Associations between core CSF biomarkers and plasma NfL were determined. RESULTS: Participants (N = 558, mean age = 69.2 ± 8.8, 56.5% women) were diagnosed with AD (n = 274, considering dementia and MCI stages), frontotemporal dementia (FTD, n = 55), Lewy body disease (LBD, n = 40, considering MCI and dementia stages), other neurodegenerative diseases, n = 57 (e.g Supranuclear Palsy, Corticobasal syndrome), non-neurodegenerative cognitive impairment (NND, n = 79, e.g. vascular lesions, epilepsy or psychiatric disorders) or subjective cognitive impairment (SCI, n = 53). Mean plasma NfL (log, pg/mL) levels were higher in neurodegenerative than non-neurodegenerative disorders (1.35 ± 0.2 vs 1.16 ± 0.23, p < 0.001), higher in all diagnostic groups than in SCI (1.06 ± 0.23) p < 0.001), and associated with the stage of cognitive impairment (p < 0.001). The addition of plasma NfL to a clinical model (age, MMSE and APOE ε4 carriership) marginally improved the discrimination of degenerative from non-degenerative disorders in ROC analysis (AUC clinical model: 0.81, 95% CI = [0.77;0.85] AUC clinical model + plasma NfL: AUC = 0.83 95% CI = [0.78;0.87], delta Akaike information criterion = -11.7). DISCUSSION: Plasma NfL could help discrimination between degenerative and non-degenerative cognitive disorders, albeit not better than comprehensive clinical evaluation.

BPSD Patterns in Patients With Severe Neuropsychiatric Disturbances: Insight From the RECAGE Study.

OBJECTIVE: Behavioral and psychological symptoms of dementia (BPSD) profiles vary depending on etiology in patients with mild-to-moderate BPSD. It is not known if similar differences exist in patients with severe BPSD. METHODS: We analyzed data collected at baseline in 398 patients with severe BPSD (NPI ≥ 32) and defined diagnosis of dementia (Alzheimer's disease [AD] 297; frontotemporal dementia [FTD] 39; Lewy body disease/Parkinsonian dementia [LBD/PD] 31; and vascular dementia [VD] 31) included in the European multicenter cohort RECAGE. RESULTS: Mean total NPI was 52.11 (18.55). LBD/PD patients demonstrated more hallucinations, more anxiety and more delusions than patients with other dementia. FTD patients had less delusions and more disinhibition than patients with other neurodegenerative disorders. These profiles overlapped partially with those reported in the literature in patients with less severe symptoms. CONCLUSION: Patients with severe BPSD display different and specific profiles of neuropsychiatric symptoms depending on dementia etiology.

Long COVID: Does SARS-CoV-2 induce lingering brain lesions?

Hundreds of millions of COVID cases have been reported so far and long-term lingering clinical symptoms are frequent and are called long COVID. Neurological signs including cognitive complaints are often described in long Covid. In COVID patients, the Sars-Cov-2 virus can reach the brain and could be responsible for cerebral anomalies observed in long COVID. Long-term careful clinical follow-up of these patients is necessary to detect early signs of neurodegeneration.

Plasma amyloid beta predicts conversion to dementia in subjects with mild cognitive impairment: The BALTAZAR study.

INTRODUCTION: Blood-based biomarkers are the next challenge for Alzheimer's disease (AD) diagnosis and prognosis. METHODS: Mild cognitive impairment (MCI) participants (N = 485) of the BALTAZAR study, a large-scale longitudinal multicenter cohort, were followed-up for 3 years. A total of 165 of them converted to dementia (95% AD). Associations of conversion and plasma amyloid beta (Aß)1-42 , Aß1-40 , Aß1-42 /Aß1-40 ratio were analyzed with logistic and Cox models. RESULTS: Converters to dementia had lower level of plasma Aß1-42 (37.1 pg/mL [12.5] vs. 39.2 [11.1] , P value = .03) and lower Aß1-42 /Aß1-40 ratio than non-converters (0.148 [0.125] vs. 0.154 [0.076], P value = .02). MCI participants in the highest quartile of Aß1-42 /Aß1-40 ratio (>0.169) had a significant lower risk of conversion (hazard ratio adjusted for age, sex, education, apolipoprotein E ε4, hippocampus atrophy = 0.52 (95% confidence interval [0.31-0.86], P value = .01). DISCUSSION: In this large cohort of MCI subjects we identified a threshold for plasma Aß1-42 /Aß1-40 ratio that may detect patients with a low risk of conversion to dementia within 3 years.

Cerebrospinal Fluid Alpha-Synuclein Improves the Differentiation between Dementia with Lewy Bodies and Alzheimer's Disease in Clinical Practice.

Background: Alpha-synuclein, abnormally aggregated in Dementia with Lewy Bodies (DLB), could represent a potential biomarker to improve the differentiation between DLB and Alzheimer's disease (AD). Our main objective was to compare Cerebrospinal Fluid (CSF) alpha-synuclein levels between patients with DLB, AD and Neurological Control (NC) individuals. Methods: In a monocentric retrospective study, we assessed CSF alpha-synuclein concentration with a validated ELISA kit (ADx EUROIMMUN) in patients with DLB, AD and NC from a tertiary memory clinic. Between-group comparisons were performed, and Receiver Operating Characteristic analysis was used to identify the best CSF alpha-synuclein threshold. We examined the associations between CSF alpha-synuclein, other core AD CSF biomarkers and brain MRI characteristics. Results: We included 127 participants (mean age: 69.3 ± 8.1, Men: 41.7%). CSF alpha-synuclein levels were significantly lower in DLB than in AD (1.28 ± 0.52 ng/mL vs. 2.26 ± 0.91 ng/mL, respectively, p < 0.001) without differences due to the stage of cognitive impairment. The best alpha-synuclein threshold was characterized by an Area Under the Curve = 0.85, Sensitivity = 82.0% and Specificity = 76.0%. CSF alpha-synuclein was associated with CSF AT(N) biomarkers positivity (p < 0.01) but not with hippocampal atrophy or white matter lesions. Conclusion: CSF Alpha-synuclein evaluation could help to early differentiate patients with DLB and AD in association with existing biomarkers.

Brain Glucose Metabolism in Cerebral Amyloid Angiopathy: An FDG-PET Study.

BACKGROUND AND PURPOSE: The in vivo diagnosis of cerebral amyloid angiopathy (CAA) is currently based on the Boston criteria, which largely rely on hemorrhagic features on brain magnetic resonance imaging. Adding to these criteria 18F-fluoro-deoxy-D-glucose (FDG) positron emission tomography, a widely available imaging modality, might improve their accuracy. Here we tested the hypothesis that FDG uptake is reduced in posterior cortical areas, particularly the primary occipital cortex, which pathologically bear the brunt of vascular Aß deposition. METHODS: From a large memory clinic database, we retrospectively included all patients in whom both brain magnetic resonance imaging and FDG positron emission tomography had been obtained as part of routine clinical care and who fulfilled the Boston criteria for probable CAA. None had a history of symptomatic intracerebral hemorrhage. FDG data processing involved (1) spatial normalization to the Montreal Neurology Institute/International Consortium for Brain Mapping 152 space and (2) generation of standardized FDG uptake (relative standardized uptake value; relative to the pons). The relative standardized uptake value data obtained in 13 regions of interest sampling key cortical areas and the cerebellum were compared between the CAA and age-matched control groups using 2 separate healthy subject databases and image-processing pipelines. The presence of significant hypometabolism (2-tailed P<0.05) was assessed for the bilaterally averaged regions-of-interest relative standardized uptake values. RESULTS: Fourteen patients fulfilling the Boston criteria for probable CAA (≥2 exclusively lobar microbleeds) were identified. Significant hypometabolism (P range, 0.047 to <0.0001) consistently affected the posterior cortical areas, including the superior and inferior parietal, primary visual, lateral occipital, lateral temporal, precuneus, and posterior cingulate regions of interest. The anterior cortical areas were marginally or not significantly hypometabolic, and the cerebellum was spared. CONCLUSIONS: Supporting our hypothesis, significant glucose hypometabolism predominantly affected posterior cortical regions, including the visual cortex. These findings from a small sample may have diagnostic implications but require replication in larger prospective studies. In addition, whether they generalize to CAA-related symptomatic intracerebral hemorrhage warrants specific studies.

[18 F]FDG PET may differentiate cerebral amyloid angiopathy from Alzheimer's disease.

BACKGROUND: Cerebral amyloid angiopathy (CAA) is a frequent cause of both intracerebral hemorrhage (ICH) and cognitive impairment in the elderly. Diagnosis relies on the Boston criteria, which use magnetic resonance imaging markers including ≥2 exclusively lobar cerebral microbleeds (lCMBs). Although amyloid positron emission tomography (PET) may provide molecular diagnosis, its specificity relative to Alzheimer's disease (AD) is limited due to the prevalence of positive amyloid PET in cognitively normal elderly. Using early-phase 11 C-Pittsburgh compound B as surrogate for tissue perfusion, a significantly lower occipital/posterior cingulate (O/PC) tracer uptake ratio in probable CAA relative to AD was recently reported, consistent with histopathological lesion distribution. We tested whether this finding could be reproduced using [18 F]fluorodeoxyglucose (FDG)-PET, a widely available modality that correlates well with early-phase amyloid PET in both healthy subjects and AD. METHODS: From a large memory clinic database, we retrospectively included 14 patients with probable CAA (Boston criteria) and 21 patients with no lCMB fulfilling AD criteria including cerebrospinal fluid biomarkers. In all, [18 F]FDG-PET/computed tomography (CT) was available as part of routine care. No subject had a clinical history of ICH. Regional standardized [18 F]FDG uptake values normalized to the pons (standard uptake value ratio [SUVr]) were obtained, and the O/PC ratio was calculated. RESULTS: The SUVr O/PC ratio was significantly lower in CAA versus AD (1.02 ± 0.14 vs. 1.19 ± 0.18, respectively; p = 0.024). CONCLUSIONS: Despite the small sample, our findings are consistent with the previous early-phase amyloid PET study. Thus, [18 F]FDG-PET may help differentiate CAA from AD, particularly in cases of amyloid PET positivity. Larger prospective studies, including in CAA-related ICH, are however warranted.

Biomarker counseling, disclosure of diagnosis and follow-up in patients with mild cognitive impairment: A European Alzheimer's disease consortium survey.

OBJECTIVES: Mild cognitive impairment (MCI) is associated with an increased risk of further cognitive decline, partly depending on demographics and biomarker status. The aim of the present study was to survey the clinical practices of physicians in terms of biomarker counseling, management, and follow-up in European expert centers diagnosing patients with MCI. METHODS: An online email survey was distributed to physicians affiliated with European Alzheimer's disease Consortium centers (Northern Europe: 10 centers; Eastern and Central Europe: 9 centers; and Southern Europe: 15 centers) with questions on attitudes toward biomarkers and biomarker counseling in MCI and dementia. This included postbiomarker counseling and the process of diagnostic disclosure of MCI, as well as treatment and follow-up in MCI. RESULTS: The response rate for the survey was 80.9% (34 of 42 centers) across 20 countries. A large majority of physicians had access to biomarkers and found them useful. Pre- and postbiomarker counseling varied across centers, as did practices for referral to support groups and advice on preventive strategies. Less than half reported discussing driving and advance care planning with patients with MCI. CONCLUSIONS: The variability in clinical practices across centers calls for better biomarker counseling and better training to improve communication skills. Future initiatives should address the importance of communicating preventive strategies and advance planning.

The PKR/P38/RIPK1 Signaling Pathway as a Therapeutic Target in Alzheimer's Disease.

Neuropathological lesions in Alzheimer's disease (AD) include amyloid plaques formed by the accumulation of amyloid peptides, neurofibrillary tangles made of hyperphosphorylated tau protein, synaptic and neuronal degenerations, and neuroinflammation. The cause of AD is unknown, but according to the amyloid hypothesis, amyloid oligomers could lead to the activation of kinases such as eukaryotic translation initiation factor 2-alpha kinase 2 (PKR), p38, and receptor-interacting serine/threonine-protein kinase 1 (RIPK1), which all belong to the same stress-activated pathway. Many toxic kinase activations have been described in AD patients and in experimental models. A p38 mitogen-activated protein kinase inhibitor was recently tested in clinical trials but with unsuccessful results. The complex PKR/P38/RIPK1 (PKR/dual specificity mitogen-activated protein kinase kinase 6 (MKK6)/P38/MAP kinase-activated protein kinase 2 (MK2)/RIPK1) is highly activated in AD brains and in the brains of AD transgenic animals. To delineate the implication of this pathway in AD, we carried out a search on PubMed including PKR/MKK6/p38/MK2/RIPK1, Alzheimer, and therapeutics. The involvement of this signaling pathway in the genesis of AD lesions, including Aß accumulations and tau phosphorylation as well as cognitive decline, is demonstrated by the reports described in this review. A future combination strategy with kinase inhibitors should be envisaged to modulate the consequences for neurons and other brain cells linked to the abnormal activation of this pathway.

Age and the association between apolipoprotein E genotype and Alzheimer disease: A cerebrospinal fluid biomarker-based case-control study.

BACKGROUND: The ε4 allele of apolipoprotein E (APOE) gene and increasing age are two of the most important known risk factors for developing Alzheimer disease (AD). The diagnosis of AD based on clinical symptoms alone is known to have poor specificity; recently developed diagnostic criteria based on biomarkers that reflect underlying AD neuropathology allow better assessment of the strength of the associations of risk factors with AD. Accordingly, we examined the global and age-specific association between APOE genotype and AD by using the A/T/N classification, relying on the cerebrospinal fluid (CSF) levels of ß-amyloid peptide (A, ß-amyloid deposition), phosphorylated tau (T, pathologic tau), and total tau (N, neurodegeneration) to identify patients with AD. METHODS AND FINDINGS: This case-control study included 1,593 white AD cases (55.4% women; mean age 72.8 [range = 44-96] years) with abnormal values of CSF biomarkers from nine European memory clinics and the American Alzheimer's Disease Neuroimaging Initiative (ADNI) study. A total of 11,723 dementia-free controls (47.1% women; mean age 65.6 [range = 44-94] years) were drawn from two longitudinal cohort studies (Whitehall II and Three-City), in which incident cases of dementia over the follow-up were excluded from the control population. Odds ratio (OR) and population attributable fraction (PAF) for AD associated with APOE genotypes were determined, overall and by 5-year age categories. In total, 63.4% of patients with AD and 22.6% of population controls carried at least one APOE ε4 allele. Compared with non-ε4 carriers, heterozygous ε4 carriers had a 4.6 (95% confidence interval 4.1-5.2; p < 0.001) and ε4/ε4 homozygotes a 25.4 (20.4-31.2; p < 0.001) higher OR of AD in unadjusted analysis. This association was modified by age (p for interaction < 0.001). The PAF associated with carrying at least one ε4 allele was greatest in the 65-70 age group (69.7%) and weaker before 55 years (14.2%) and after 85 years (22.6%). The protective effect of APOE ε2 allele for AD was unaffected by age. Main study limitations are that analyses were based on white individuals and AD cases were drawn from memory centers, which may not be representative of the general population of patients with AD. CONCLUSIONS: In this study, we found that AD diagnosis based on biomarkers was associated with APOE ε4 carrier status, with a higher OR than previously reported from studies based on only clinical AD criteria. This association differs according to age, with the strongest effect at 65-70 years. These findings highlight the need for early interventions for dementia prevention to mitigate the effect of APOE ε4 at the population level.

Seasonal plasticity of cognition and related biological measures in adults with and without Alzheimer disease: Analysis of multiple cohorts.

BACKGROUND: There are few data concerning the association between season and cognition and its neurobiological correlates in older persons-effects with important translational and therapeutic implications for the diagnosis and treatment of Alzheimer disease (AD). We aimed to measure these effects. METHODS AND FINDINGS: We analyzed data from 3,353 participants from 3 observational community-based cohort studies of older persons (the Rush Memory and Aging Project [MAP], the Religious Orders Study [ROS], and the Minority Aging Research Study [MARS]) and 2 observational memory-clinic-based cohort studies (Centre de Neurologie Cognitive [CNC] study at Lariboisière Hospital and the Sunnybrook Dementia Study [SDS]). We performed neuropsychological testing and, in subsets of participants, evaluated cerebrospinal fluid AD biomarkers, standardized structured autopsy measures, and/or prefrontal cortex gene expression by RNA sequencing. We examined the association between season and these variables using nested multiple linear and logistic regression models. There was a robust association between season and cognition that was replicated in multiple cohorts (amplitude = 0.14 SD [a measure of the magnitude of seasonal variation relative to overall variability; 95% CI 0.07-0.23], p = 0.007, in the combined MAP, ROS, and MARS cohorts; amplitude = 0.50 SD [95% CI 0.07-0.66], p = 0.017, in the SDS cohort). Average composite global cognitive function was higher in the summer and fall compared to winter and spring, with the difference equivalent in cognitive effect to 4.8 years' difference in age (95% CI 2.1-8.4, p = 0.002). Further, the odds of meeting criteria for mild cognitive impairment or dementia were higher in the winter and spring (odds ratio 1.31 [95% CI 1.10-1.57], p = 0.003). These results were robust against multiple potential confounders including depressive symptoms, sleep, physical activity, and thyroid status and persisted in cases with AD pathology. Moreover, season had a marked effect on cerebrospinal fluid Aß 42 level (amplitude 0.30 SD [95% CI 0.10-0.64], p = 0.003), which peaked in the summer, and on the brain expression of 4 cognition-associated modules of co-expressed genes (m6: amplitude = 0.44 SD [95% CI 0.21-0.65], p = 0.0021; m13: amplitude = 0.46 SD [95% CI 0.27-0.76], p = 0.0009; m109: amplitude = 0.43 SD [95% CI 0.24-0.67], p = 0.0021; and m122: amplitude 0.46 SD [95% CI 0.20-0.71], p = 0.0012), which were in phase or anti-phase to the rhythms of cognition and which were in turn associated with binding sites for several seasonally rhythmic transcription factors including BCL11A, CTCF, EGR1, MEF2C, and THAP1. Limitations include the evaluation of each participant or sample once per annual cycle, reliance on self-report for measurement of environmental and behavioral factors, and potentially limited generalizability to individuals in equatorial regions or in the southern hemisphere. CONCLUSIONS: Season has a clinically significant association with cognition and its neurobiological correlates in older adults with and without AD pathology. There may be value in increasing dementia-related clinical resources in the winter and early spring, when symptoms are likely to be most pronounced. Moreover, the persistence of robust seasonal plasticity in cognition and its neurobiological correlates, even in the context of concomitant AD pathology, suggests that targeting environmental or behavioral drivers of seasonal cognitive plasticity, or the key transcription factors and genes identified in this study as potentially mediating these effects, may allow us to substantially improve cognition in adults with and without AD.

Plasma amyloid levels within the Alzheimer's process and correlations with central biomarkers.

INTRODUCTION: Diagnostic relevance of plasma amyloid ß (Aß) for Alzheimer's disease (AD) process yields conflicting results. The objective of the study was to assess plasma levels of Aß42 and Aß40 in amnestic mild cognitive impairment (MCI), nonamnestic MCI, and AD patients and to investigate relationships between peripheral and central biomarkers. METHODS: One thousand forty participants (417 amnestic MCI, 122 nonamnestic MCI, and 501 AD) from the Biomarker of AmyLoïd pepTide and AlZheimer's diseAse Risk multicenter prospective study with cognition, plasma, cerebrospinal fluid (CSF), and magnetic resonance imaging assessments were included. RESULTS: Plasma Aß1-42 and Aß1-40 were lower in AD (36.9 [11.7] and 263 [80] pg/mL) than in amnestic MCI (38.2 [11.9] and 269 [68] pg/mL) than in nonamnestic MCI (39.7 [10.5] and 272 [52] pg/mL), respectively (P = .01 for overall difference between groups for Aß1-42 and P = .04 for Aß1-40). Globally, plasma Aß1-42 correlated with age, Mini-Mental State Examination, and APOE Îµ4 allele. Plasma Aß1-42 correlated with all CSF biomarkers in MCI but only with CSF Aß42 in AD. DISCUSSION: Plasma Aß was associated with cognitive status and CSF biomarkers, suggesting the interest of plasma amyloid biomarkers for diagnosis purpose.

Effect of active Aß immunotherapy on neurons in human Alzheimer's disease.

Amyloid ß peptide (Aß) immunization of Alzheimer's disease (AD) patients has been reported to induce amyloid plaque removal, but with little impact on cognitive decline. We have explored the consequences of Aß immunotherapy on neurons in post mortem brain tissue. Eleven immunized (AN1792, Elan Pharmaceuticals) AD patients were compared to 28 non-immunized AD cases. Immunohistochemistry on sections of neocortex was performed for neuron-specific nuclear antigen (NeuN), neurofilament protein (NFP) and phosphorylated-(p)PKR (pro-apoptotic kinase detected in degenerating neurons). Quantification was performed for pPKR and status spongiosis (neuropil degeneration), NeuN-positive neurons/field, curvature of the neuronal processes and interneuronal distance. Data were corrected for age, gender, duration of dementia and APOE genotype and also assessed in relation to Aß42 and tau pathology and key features of AD. In non-immunized patients, the degree of neuritic curvature correlated with spongiosis and pPKR, and overall the neurodegenerative markers correlated better with tau pathology than Aß42 load. Following immunization, spongiosis increased, interneuronal distance increased, while the number of NeuN-positive neurons decreased, consistent with enhanced neuronal loss. However, neuritic curvature was reduced and pPKR was associated with Aß removal in immunized patients. In AD, associations of spongiosis status, curvature ratio and pPKR load with microglial markers Iba1, CD68 and CD32 suggest a role for microglia in neurodegeneration. After immunization, correlations were detected between the number of NeuN-positive neurons and pPKR with Iba1, CD68 and CD64, suggesting that microglia are involved in the neuronal loss. Our findings suggest that in established AD this form of active Aß immunization may predominantly accelerate loss of damaged degenerating neurons. This interpretation is consistent with in vivo imaging indicating an increased rate of cerebral atrophy in immunized AD patients.

Effect of amyloid-ß (Aß) immunization on hyperphosphorylated tau: a potential role for glycogen synthase kinase (GSK)-3ß.

AIMS: Active amyloid-ß (Aß) immunotherapy in Alzheimer's disease (AD) induces removal of Aß and phosphorylated tau (ptau). Glycogen synthase kinase (GSK)-3ß is a kinase, responsible for phosphorylation of tau, activation of which can be induced by phosphorylated double-stranded RNA-dependent protein kinase (pPKR). Using a post-mortem cohort of immunized AD cases, we investigated the effect of Aß immunization on GSK-3ß expression and pPKR. METHODS: We immunostained 11 immunized AD cases and 28 unimmunized AD cases for active, inactive and total GSK-3ß, and for pPKR. Quantification of protein load was performed in the hippocampal region including CA1, subiculum and entorhinal cortex. RESULTS: All three areas showed a significant decrease in the three forms of GSK-3ß (P < 0.05) and a nonsignificant trend towards lower pPKR load in the immunized AD cases compared with the unimmunized AD cases. CONCLUSION: The lower GSK-3ß expression generated by Aß immunotherapy shows evidence of a modification of the signalling pathway induced by GSK-3ß leading to the overall reduction of tau, supporting the contention that in humans, GSK-3ß unifies Aß and tau-related neuropathology.

Increased levels of cerebrospinal fluid JNK3 associated with amyloid pathology: links to cognitive decline.

BACKGROUND: Alzheimer disease is characterized by cognitive decline, senile plaques of ß-amyloid (Aß) peptides, neurofibrillary tangles composed of hyperphosphorylated τ proteins and neuronal loss. Aß and τ are useful markers in the cerebrospinal fluid (CSF). C-Jun N-terminal kinases (JNKs) are serine-threonine protein kinases activated by phosphorylation and involved in neuronal death. METHODS: In this study, Western blots, enzyme-linked immunosorbent assay and histological approaches were used to assess the concentrations of Aß, τ and JNK isoforms in postmortem brain tissue samples (10 Alzheimer disease and 10 control) and in CSF samples from 30 living patients with Alzheimer disease and 27 controls with neurologic disease excluding Alzheimer disease. Patients with Alzheimer disease were followed for 1-3 years and assessed using Mini-Mental State Examination scores. RESULTS: The biochemical and morphological results showed a significant increase of JNK3 and phosphorylated JNK levels in patients with Alzheimer disease, and JNK3 levels correlated with Aß42 levels. Confocal microscopy revealed that JNK3 was associated with Aß in senile plaques. The JNK3 levels in the CSF were significantly elevated in patients with Alzheimer disease and correlated statistically with the rate of cognitive decline in a mixed linear model. LIMITATIONS: The study involved different samples grouped into 3 small cohorts. Evaluation of JNK3 in CSF was possible only with immunoblot analysis. CONCLUSION: We found that JNK3 levels are increased in brain tissue and CSF from patients with Alzheimer disease. The finding that increased JNK3 levels in CSF could reflect the rate of cognitive decline is new and merits further investigation.

Screening for cognitive and affective dysfunction in patients suspected of mild cognitive impairment.

OBJECTIVE: Disturbances of affect expression and perception, as well as accuracy of predicting memory difficulties, have been reported in various brain dysfunctional groups. Screening tests of higher cerebral functions seldom sample these dimensions. The goal of this study was to determine if patients with mild cognitive impairment (MCI) of the amnestic type would demonstrate impairments in these domains, as well as show expected memory deficits. METHODS: Thirty-nine French-speaking patients with a clinical diagnosis of MCI were compared with 39 age- and education-matched normal functioning individuals on the French translation of the Barrow Neurological Institute Screen for Higher Cerebral Functions (BNIS). Patients and controls also made subjective ratings regarding their cognitive and affective functioning in everyday life. RESULTS: Patients with MCI performed significantly worse than controls on the BNIS subtests sampling memory, orientation, affect expression and perception, and accurate prediction of memory performance. They did not differ on other subtests of the BNIS, as predicted. Poor self-awareness (i.e., inaccurate prediction of the number of words one could recall after distraction) correlated with self-reported deficits in several areas of cognitive and affective functioning. CONCLUSION: This sample of MCI patients demonstrated disturbances not only in memory but also in self-awareness and affect expression and perception on the BNIS. These dimensions should be included in the neuropsychological assessment of patients suspected of MCI.

Impact of harmonization of collection tubes on Alzheimer's disease diagnosis.

OBJECTIVE: The objective of this study was to analyze differences in biomarker outcomes before and after harmonization of cerebrospinal fluid (CSF) collection tubes in Alzheimer's disease (AD) diagnosis. METHODS: We analyzed data from French memory centers that switched from different CSF collection tubes to a common one. A total of 1966 patients were included in the study. CSF concentrations of ß-amyloid 1-42 (Aß42), total tau, and phosphorylated tau (p-tau181) were measured in each center using the same commercial enzyme-linked immunoabsorbent assay (ELISA) kits. The diagnostic value of CSF biomarkers according to the type of tube used was then assessed using different cutoffs. RESULTS: The predictive value of Aß42 was highly affected by the type of collection tube used. The optimal cutoff value for p-tau181 appeared not to be affected by the type of collection tube whereas that of total tau was slightly changed. New optimal cutoff values were then computed. CONCLUSIONS: In a routine clinical environment, the selection of the collection tube and biomarker cutoff value makes a major difference in AD biological diagnosis. The use of a common collection tube among different centers will reduce the risk of misdiagnosis and incorrect patient stratification.

Oxidative stress increases BACE1 protein levels through activation of the PKR-eIF2α pathway.

Beta-site APP cleaving enzyme 1 (BACE1) is the rate limiting enzyme for accumulation of amyloid ß (Aß)-peptide in the brain in Alzheimer's disease (AD). Oxidative stress (OS) that leads to metabolic dysfunction and apoptosis of neurons in AD enhances BACE1 expression and activity. The activation of c-jun N-terminal kinase (JNK) pathway was proposed to explain the BACE1 mRNA increase under OS. However, little is known about the translational control of BACE1 in OS. Recently, a post-transcriptional increase of BACE1 level controlled by phosphorylation of eIF2α (eukaryotic translation initiation factor-2α) have been described after energy deprivation. PKR (double-stranded RNA dependant protein kinase) is a pro-apoptotic kinase that phosphorylates eIF2α and modulates JNK activation in various cellular stresses. We investigated the relations between PKR, eIF2α and BACE1 in AD brains in APP/PS1 knock-in mice and in hydrogen peroxide-induced OS in human neuroblastoma (SH-SY5Y) cell cultures. Immunoblotting results showed that activated PKR (pPKR) and activated eIF2α (peIF2α) and BACE1 levels are increased in AD cortices and BACE1 correlate with phosphorylated eIF2α levels. BACE1 protein levels are increased in response to OS in SH-SY5Y cells and specific inhibitions of PKR-eIF2α attenuate BACE1 protein levels in this model. Our findings provide a new translational regulation of BACE1, under the control of PKR in OS, where eIF2α phosphorylation regulates BACE1 protein expression.

Exacerbated CSF abnormalities in younger patients with Alzheimer's disease.

Increasing age is the most important risk factor for developing Alzheimer's disease (AD). The aim of this study was to investigate the relationships between age and cerebrospinal fluid (CSF) levels of ß-amyloid (Aß 1-42), total Tau and phosphorylated Tau (pTau-181), in AD and non-AD patients explored for cognitive disorders. 966 patients (AD, n=528; non-AD, n=438) were included between January 2008 and December 2010 (mean age, 69.5years; mean MMSE, 20.2) from three French memory centers. Multivariable linear regression models were used to study the relationship between CSF biomarker levels and age in AD and non-AD patients. The capacity of each CSF biomarker in discriminating patients was evaluated using the area under the receiver-operating characteristic (ROC) curves by quartile of distribution of age. In AD patients, older age was associated with higher CSF Aß 1-42 and lower Tau levels. Conversely, in non-AD patients, age was associated with lower CSF Aß 1-42, higher Tau, and higher pTau-181 levels. In sex-stratified analysis, these relationships were significant only in women. Using ROC curve analysis, CSF AD biomarkers were more discriminant in younger patients than in older ones. In this clinically-based study, younger patients with AD had exacerbated CSF anomalies compared to older patients with AD. CSF biomarkers were more discriminant in younger patients than in older ones for the diagnosis of AD, especially in women. These results support the idea of an overlap in AD neuropathological lesions in oldest subjects with or without AD.