Nordberg Agneta, Kadir Ahmadul, Andreasen Niels, Almkvist Ove, Wall Anders, Långström Bengt, Zetterberg Henrik
Karolinska Institutet, Dept NVS, Center for Alzheimer Research, Translational Alzheimer Neurobiology, Huddinge, Sweden.
Department of Geriatric Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
J Alzheimers Dis. 2015;47(3):691-704. doi: 10.3233/JAD-132474.
New therapeutic strategies in Alzheimer's disease (AD) are focused on targeting amyloid-β (Aβ) to modify the underlying cause of the disease rather than just the symptoms. The aim of this study was to investigate the long-term effects of treatment with the anti-Aβ compound phenserine on (i) cerebrospinal fluid (CSF) biomarkers for Aβ and tau pathology and (ii) brain metabolism as assessed by the regional cerebral metabolic rate for glucose (rCMRglc), using positron emission tomography. Twenty patients with mild AD were included in the study and after 12 months treatment with phenserine, CSF Aβ40 and α- and β-secretase-cleaved soluble amyloid-β protein precursor (sAβPP) levels had significantly increased and rCMRglc had stabilized. Levels of CSF Aβ40 and sAβPP correlated positively with rCMRglc and cognition while CSF Aβ42 levels, the Aβ42/40 ratio, P-tau, and T-tau correlated negatively with rCMRglc and cognition. In summary, long-term phenserine treatment resulted in increased levels of CSF Aβ40, sAβPPα, and sAβPPβ, which positively correlated with improvements in rCMRglc and cognition. The study illustrates the value of using biomarkers in the CSF and brain for evaluation of drug effects.
阿尔茨海默病（AD）的新治疗策略侧重于靶向淀粉样蛋白-β（Aβ）以改变疾病的潜在病因，而非仅仅缓解症状。本研究的目的是使用正电子发射断层扫描，研究抗Aβ化合物苯丝氨酸治疗对（i）Aβ和tau病理学的脑脊液（CSF）生物标志物以及（ii）通过局部脑葡萄糖代谢率（rCMRglc）评估的脑代谢的长期影响。20例轻度AD患者纳入本研究，经苯丝氨酸治疗12个月后，CSF Aβ40以及α和β分泌酶切割的可溶性淀粉样蛋白-β蛋白前体（sAβPP）水平显著升高，rCMRglc趋于稳定。CSF Aβ40和sAβPP水平与rCMRglc及认知呈正相关，而CSF Aβ42水平、Aβ42/40比值、磷酸化tau蛋白（P-tau）和总tau蛋白（T-tau）与rCMRglc及认知呈负相关。总之，长期苯丝氨酸治疗导致CSF Aβ40、sAβPPα和sAβPPβ水平升高，这些指标与rCMRglc及认知的改善呈正相关。该研究说明了使用CSF和脑内生物标志物评估药物疗效的价值。
