François Mouton-Liger

Inverse association between CSF Aβ 42 levels and years of education in mild form of Alzheimer's disease: The cognitive reserve theory

In Alzheimers disease (AD), the cognitive reserve theory predicts that at any level of assessed clinical severity, the underlying brain pathology is more advanced in patients with more cognitive reserve. Recent evidences suggest that cerebrospinal fluid (CSF) biomarkers may reflect the brain pathology in AD. We investigated the relationship between education level and CSF concentrations of β-amyloid, total tau and phosphorylated tau (ptau-181) in a cohort of 70 subjects newly diagnosed with AD. We report that CSF concentration of β-amyloid was inversely associated with years of education, after adjustment for age, sex, and severity of the disease. We further demonstrate in stratified analysis that this relation was mainly present in mild form of the disease (CDR1), and was attenuated in more advanced forms of the disease. These results are consistent with the cognitive reserve theory, and suggest that cognitive reserve may be protective against amyloid related cognitive impairment at the onset of the clinical dementia.

Developmental molecular and functional cerebellar alterations induced by PCP4/PEP19 overexpression: Implications for Down syndrome

PCP4/PEP19 is a modulator of Ca(2+)-CaM signaling. In the brain, it is expressed in a very specific pattern in postmitotic neurons. In particular, Pcp4 is highly expressed in the Purkinje cell, the sole output neuron of the cerebellum. PCP4, located on human chromosome 21, is present in three copies in individuals with Down syndrome (DS). In a previous study using a transgenic mouse model (TgPCP4) to evaluate the consequences of 3 copies of this gene, we found that PCP4 overexpression induces precocious neuronal differentiation during mouse embryogenesis. Here, we report combined analyses of the cerebellum at postnatal stages (P14 and adult) in which we identified age-related molecular, electrophysiological, and behavioral alterations in the TgPCP4 mouse. While Pcp4 overexpression at P14 induces an earlier neuronal maturation, at adult stage it induces increase in cerebellar CaMK2alpha and in cerebellar LTD, as well as learning impairments. We therefore propose that PCP4 contributes significantly to the development of Down syndrome phenotypes through molecular and functional changes.

Dual Kinase Inhibition Affords Extended in vitro Neuroprotection in Amyloid-β Toxicity.

In Alzheimers disease (AD), the amyloid cascade hypothesis proposes that amyloid-beta (Aβ) neurotoxicity leads to neuroinflammation, synaptic loss, and neuronal degeneration. In AD patients, anti-amyloid immunotherapies did not succeed because they were possibly administered late in AD progression. Modulating new targets associated with Aβ toxicity, such as PKR (double-stranded RNA dependent kinase), and JNK (c-Jun N-terminal kinase) is a major goal for neuroprotection. These two pro-apoptotic kinases are activated in AD brains and involved in Aβ production, tau phosphorylation, neuroinflammation, and neuronal death. In HEK cells transfected with siRNA directed against PKR, and in PKR knockout (PKR-/-) mice neurons, we showed that PKR triggers JNK activation. Aβ-induced neuronal apoptosis, measured by cleaved PARP (Poly ADP-ribose polymerase) and cleaved caspase 3 levels, was reduced in PKR-/- neurons. Two selective JNK inhibitory peptides also produced a striking reduction of Aβ toxicity. Finally, the dual inhibition of PKR and JNK nearly abolished Aβ toxicity in primary cultured neurons. These results reveal that dual kinase inhibition can afford neuroprotection and this approach is worth being tested in in vivo AD and oxidative stress models.

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.

CLINICAL IMPACT OF CEREBROSPINAL FLUID BIOMARKERS IN MILD COGNITIVE IMPAIRMENT DIAGNOSIS

TDP had lower levels of sAPPb and higher levels of YKL-40 in CSF compared to controls (Fig. 1). The sAPPb/YKL-40 ratio was lower in both FTLD groups compared to controls. In the ROC analysis (Fig. 2), the sAPPb/YKL-40 ratio had an area under the curve of 0.91 (95%CI 0.86-0.96) to distinguish FTLD subjects from controls, but lower values to distinguish FTLD from AD (AUC 0.70; 95%CI 0.61-0.79) and to discriminate FTLDTau from FTLD-TDP (AUC 0.67; 95%CI 0.51-0.82). Conclusions:These findings suggest that the sAPPb/YKL-40 ratio could be of interest to distinguish patients with FTLD from those with similar clinical phenotypes. Although the ratio cannot be used to discriminate between the main pathologies underlying FTLD, it might be useful to interrogate the neuropathological substrate in some clinical scenarios and, eventually, to select potential candidates for clinical trials.

Involvement of a cerebral “metaflammasome” in experimental obesity

Background:Neuropathologic confirmation of Alzheimer’s disease (AD) is considered secure with a Braak Stage1⁄46 at autopsy, strongly supported by a Braak stage1⁄45, weakly supported by a Braak stage1⁄44, and unlikely at lesser stages. Some decedents with Braak stages of 5 or 6 at autopsy had been cognitively normal during life. Others with a Braak stage of 4 had been definitely demented. Is there an explanation for such variation in cognitive resilience or vulnerability to the brain lesions of AD? Comprehensive research protocol brain autopsies on 774 decedent participants in the HAASwho had been evaluated for cognitive impairment during life provide opportunity to address this question. Methods: The Cognitive Abilities and Screening Instrument (CASI) was administered at 2-3 year intervals between 1991-2012, during which more than 90% of the 3734 participants died. The last CASI score within 3 years of death was used as a measure of cognitive functioning in the final years of life. Brain autopsies were done on decedent participants when death was identified and legal consent obtained within 72 hours. Results: Definite cognitive impairment (CASI<60) had been present in 83% of 41 autopsied decedents with a Braak stage1⁄4 6, 50% of 98 with Braak stage 1⁄45, and 41% of 128 with Braak stage1⁄4 4. Fully normal cognitive impairment (CASI>1⁄482) had existed in none of of those with Braak stage 1⁄46, in 15% with Braak1⁄45, and 23% with Braak1⁄44. Among the 98 decedents with Braak stage1⁄45, definite cognitive impairment in the years prior to death was significantly associated with several coprevalent non-AD brain lesions and/or generalized brain atrophy, shorter interval between final examination and death, and marginally with counts of neocortical neuritic amyloid plaques. Several other factors (head size, education, occupational complexity, late life depression, heart disease, etc.) were not significantly associated with cognitive impairment in decedents with Braak stages of 4, 5, or 6. Conclusions:Among HAAS decedents with autopsy Braak scores of 4, 5, or 6 (considered independently), resilience or vulnerability to cognitive impairment or dementia in the final years of life was significantly associated with three neuropathologic factors: coprevalent non-AD brain lesions, generalized brain atrophy, and neocortical neuritic plaque counts.

Education level and CSF biomarkers in Alzheimer's disease: The cognitive reserve theory

O4-06-08 EDUCATION LEVEL AND CSF BIOMARKERS IN ALZHEIMER’S DISEASE: THE COGNITIVE RESERVE THEORY Julien Dumurgier, Claire Paquet, Sarah Benisty, Claire Kiffel, Claude Lidy, François Mouton-Liger, Hughues Chabriat, Jean-Louis Laplanche, Jacques Hugon, CMRR Paris Nord, Lariboisière Fernand Widal Hospital, Paris, France; Department of Geriatrics, Lariboisière Fernand Widal Hospital, Paris, France; Department of Histology and Biology of Aging, Lariboisière Fernand Widal Hospital, Paris, France; Department of Neurology, Lariboisière Fernand Widal Hospital, Paris, France; Department of Biochemistry, Lariboisière Fernand Widal Hospital, Paris, France. Contact e-mail: julien.dumurgier@upmc.fr