Elsevier

Biological Psychiatry

Volume 71, Issue 9, 1 May 2012, Pages 829-835
Biological Psychiatry

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

https://doi.org/10.1016/j.biopsych.2011.11.031Get rights and content

Background

The pathological hallmarks of Alzheimer's 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.

Section snippets

Patients

Between January 2010 and January 2011, 119 consecutive patients from our outpatient Memory Clinic who had a CSF analysis to explore cognitive impairment were included. We excluded, because of the small number, five subjects with lobar frontotemporal dementia or Lewy Body diseases and six patients with stroke or those who scored greater than 4 at the Hachinski Ischemic Scale and those with cardiovascular disease with consequences visible on brain magnetic resonance imaging (multiple large vessel

Results

Among the 108 included patients, 6 AD, 10 NDC, and 1 aMCI patients were excluded for technical reasons related to CSF assessment (8 for insufficient quantity of CSF; 9 for insufficient CSF protein concentration). These excluded patients were not different from included patients for age and sex ratio (Figure S1 in Supplement 1). A total of 91 patients were eventually enrolled in this study (AD, n = 45; aMCI, n = 11; NDC, n = 35). Neurological disease control patients were referred for cognitive

Discussion

Our results have revealed that pPKR and the ratio pPKR/T-PKR are increased in the CSF of AD patients compared with NDC. The sensitivity and the specificity of pPKR are 91.1% and 94.3%, respectively. In some AD patients whose CSF biomarker levels (Aß, T-tau, and p181tau) were not in the abnormal range, pPKR levels were abnormally high. These analyses were also abnormal in several MCI patients, but the small number of patients does not allow drawing, so far, any appropriate conclusions. A

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    Authors FM-L, CP, and JD contributed equally to this work.

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