Pauline Lapalus

Cerebrospinal Fluid PKR Level Predicts Cognitive Decline in Alzheimer’s Disease

The cerebrospinal fluid (CSF) levels of the proapoptotic kinase R (PKR) and its phosphorylated PKR (pPKR) are increased in Alzheimer’s disease (AD), but whether CSF PKR concentrations are associated with cognitive decline in AD patients remain unknown. In this study, 41 consecutive patients with AD and 11 patients with amnestic mild cognitive impairment (aMCI) from our Memory Clinic were included. A lumbar puncture was performed during the following month of the clinical diagnosis and Mini-Mental State Examination (MMSE) evaluations were repeated every 6 months during a mean follow-up of 2 years. In AD patients, linear mixed models adjusted for age and sex were used to assess the cross-sectional and longitudinal associations between MMSE scores and baseline CSF levels of Aβ peptide (Aβ 1-42), Tau, phosphorylated Tau (p-Tau 181), PKR and pPKR. The mean (SD) MMSE at baseline was 20.5 (6.1) and MMSE scores declined over the follow-up (-0.12 point/month, standard error [SE] = 0.03). A lower MMSE at baseline was associated with lower levels of CSF Aβ 1–42 and p-Tau 181/Tau ratio. pPKR level was associated with longitudinal MMSE changes over the follow-up, higher pPKR levels being related with an exacerbated cognitive deterioration. Other CSF biomarkers were not associated with MMSE changes over time. In aMCI patients, mean CSF biomarker levels were not different in patients who converted to AD from those who did not convert.These results suggest that at the time of AD diagnosis, a higher level of CSF pPKR can predict a faster rate of cognitive decline.

Increased Cerebrospinal Fluid Levels of Double-Stranded RNA-Dependant Protein Kinase in Alzheimer's Disease

BACKGROUND The pathological hallmarks of Alzheimers disease (AD) include accumulation of amyloid-β (Aß) peptide forming extracellular senile plaques, neurofibrillary tangles made of hyperphosphorylated tau protein with neuronal loss. Aβ peptide (1-42), total tau (T-tau), and phosphorylated tau at threonine 181 (p181tau) levels in the cerebrospinal fluid (CSF) are now validated biomarkers. The proapoptotic kinase R (PKR), is activated by Aβ accumulates in degenerating neurons in AD brains and controls protein synthesis and indirectly tau phosphorylation. METHODS In a prospective cohort study, the CSF of 91 patients were studied (AD: 45; amnestic mild cognitive impairment: 11; neurological disease control subjects [NDC]: 35). The levels of total PKR (T-PKR), phosphorylated PKR (pPKR), Aß 1-42, T-tau, and p181tau were assessed by immunoblotting or enzyme-linked immunosorbent assay methods. Receivers operating characteristic curves were used to examine the discriminatory power of T-PKR, pPKR, and pPKR/T-PKR ratio between AD and NDC patients. RESULTS Total PKR and pPKR concentrations were elevated in AD and amnestic mild cognitive impairment subjects. We have determined a pPKR value (optical density units) that could discriminate AD patients from control subjects with a sensitivity of 91.1% and a specificity of 94.3%. Among AD patients, T-PKR and pPKR levels correlate with CSF p181tau levels. Some AD patients with normal CSF Aß, T-tau, or p181tau levels had abnormal T-PKR and pPKR levels. CONCLUSIONS The evaluation of CSF T-PKR and pPKR can discriminate between AD patients and NDC and could help to improve the biochemical diagnosis of AD.

Involvement of PKR in Alzheimer?s Disease

Alzheimer’s disease (AD) is characterized by memory troubles followed by aphasia apraxia and agnosia associated with behavioral disturbances. Neuropathological lesions include senile plaques formed by Aβ peptide, neurofibrillary tangles made of hyperphosphorylated tau and neuronal loss. The cause of AD is unknown but Aβ peptide could be responsible for neuronal degeneration. PKR is a stress and pro-apoptotic kinase that controls protein translation via the phosphorylation of the eukariotic initiation factor 2α (eIF2α). Activated PKR accumulates in affected neurons in AD brains and the phosphorylation of PKR can be induced by Aβ peptide. We have found increased levels of PKR in the cerebrospinal fluid of AD patients and PKR level is a good predictor of the cognitive decline. In addition PKR can modulate the levels of BACE1, an APP cleaving enzyme, and can influence tau phosphorylation. Altogether, PKR represents a potential new biomarker and a valid new therapeutic target for neuroprotection in AD.

CSF Aβ1-42 Levels and Glucose Metabolism in Alzheimer's Disease>

Glucose dysmetabolism has been consistently associated with an increased risk of cognitive disorders, and brain insulin resistance could play a role in Alzheimers disease (AD) pathogenesis. Recent evidence suggests that cerebrospinal fluid (CSF) biomarkers may reflect the brain pathology in AD. We have investigated the relationship between CSF concentrations of amyloid-β peptide 1-42 (Aβ₁₋₄₂), total tau, and phosphorylated tau (ptau-181) and plasma and CSF glucose levels in a cohort of 94 newly diagnosed non-diabetics AD patients. We report that CSF Aβ₁₋₄₂ level was inversely associated with CSF to plasma glucose ratio (Spearmans coefficient = -0.27, p = 0.008). This relationship remained after adjustment for age, gender, body mass index, hypertension, and MMSE score (β [SE] of linear regression = -0.93 [0.37], p = 0.01). In stratified analysis, this relationship was observed only in patients who did not carry the apolipoprotein E4 allele. No significant relationship was found between glucose levels and total tau or phosphorylated tau 181. These results support the idea that a link between glucose dysmetabolism and the amyloid pathway may exist in the pathogenesis of AD.

CSF PKR can predict cognitive decline in Alzheimer’s disease

Next using a random forest based backward elimination method, we identified and compared the sets of CSF protein analytes found in each cohort. Pathway analysis was performed on the commonly selected analytes. Results: Fatty acid binding protein, pancreatic polypeptide and vascular endothelial growth factor, in complement with Ab 42 and t-tau, were consistently identified to be associated with AD diagnosis in all three independent cohorts. Age and gender effects were found to be insignificantly associated with the selected analyses. Canonical pathways related to coagulation system, atherosclerosis signaling and IL-17 signaling were selected by Ingenuity PathwayAnalyses (p<0.001).Conclusions:The quality control steps we standardized contribute to the discovery of three protein analytes in addition to Ab 42 and tau, with high reproducibility across three independent cohorts, whichmay serve as important drug targets. Significant pathways identified may provide insights to AD pathology, and hence point out underlying AD mechanisms.

Long-term amnesia following electroconvulsive therapy

and SC RDT scores were comparable. Control RDT score was higher (better performance) than aMCI,mMCI andDementia scores. aMCI scorewasworse than mMCI score in RDT. RDT score in dementia group was lesser than any other. (Table)Conclusions: In our study only RDT scorewere able to discriminate between aMCI and other groups. Additions, to classic ADAS-cog, of semantic encoding and delayed free and cued recall of the word list could be useful in aMCI detection.