Vila-Castelar Clara, Ly Jenny J, Kaplan Lillian, Van Dyk Kathleen, Berger Jeffrey T, Macina Lucy O, Stewart Jennifer L, Foldi Nancy S
Department of Psychology, Queens College and The Graduate Center, City University of New York, New York, NY, USA.
Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Arch Clin Neuropsychol. 2019 May 1;34(3):277-289. doi: 10.1093/arclin/acy032.
Donepezil is widely used to treat Alzheimer's disease (AD), but detecting early response remains challenging for clinicians. Acetylcholine is known to directly modulate attention, particularly under high cognitive conditions, but no studies to date test whether measures of attention under high load can detect early effects of donepezil. We hypothesized that load-dependent attention tasks are sensitive to short-term treatment effects of donepezil, while global and other domain-specific cognitive measures are not.
This longitudinal, randomized, double-blind, placebo-controlled pilot trial (ClinicalTrials.gov Identifier: NCT03073876) evaluated 23 participants newly diagnosed with AD initiating de novo donepezil treatment (5 mg). After baseline assessment, participants were randomized into Drug (n = 12) or Placebo (n = 11) groups, and retested after approximately 6 weeks. Cognitive assessment included: (a) attention tasks (Foreperiod Effect, Attentional Blink, and Covert Orienting tasks) measuring processing speed, top-down accuracy, orienting, intra-individual variability, and fatigue; (b) global measures (Alzheimer's Disease Assessment Scale-Cognitive Subscale, Mini-Mental Status Examination, Dementia Rating Scale); and (c) domain-specific measures (memory, language, visuospatial, and executive function).
The Drug but not the Placebo group showed benefits of treatment at high-load measures by preserving top-down accuracy, improving intra-individual variability, and averting fatigue. In contrast, other global or cognitive domain-specific measures could not detect treatment effects over the same treatment interval.
The pilot-study suggests that attention measures targeting accuracy, variability, and fatigue under high-load conditions could be sensitive to short-term cholinergic treatment. Given the central role of acetylcholine in attentional function, load-dependent attentional measures may be valuable cognitive markers of early treatment response.
多奈哌齐被广泛用于治疗阿尔茨海默病（AD），但对临床医生而言，检测早期反应仍具有挑战性。已知乙酰胆碱可直接调节注意力，尤其是在高认知负荷条件下，但迄今为止尚无研究测试高负荷下的注意力测量能否检测多奈哌齐的早期疗效。我们假设负荷依赖性注意力任务对多奈哌齐的短期治疗效果敏感，而整体及其他特定领域的认知测量则不然。
这项纵向、随机、双盲、安慰剂对照的试点试验（ClinicalTrials.gov标识符：NCT03073876）评估了23名新诊断为AD且开始从头使用多奈哌齐治疗（5毫克）的参与者。在基线评估后，参与者被随机分为药物组（n = 12）或安慰剂组（n = 11），并在约6周后重新进行测试。认知评估包括：（a）注意力任务（前间隔效应、注意瞬脱和隐蔽定向任务），测量处理速度、自上而下的准确性、定向、个体内变异性和疲劳；（b）整体测量（阿尔茨海默病评估量表 - 认知分量表、简易精神状态检查表、痴呆评定量表）；以及（c）特定领域测量（记忆、语言、视觉空间和执行功能）。
药物组而非安慰剂组在高负荷测量中显示出治疗益处，即保持自上而下的准确性、改善个体内变异性并避免疲劳。相比之下，其他整体或特定认知领域的测量在相同治疗间隔内无法检测到治疗效果。
该试点研究表明，针对高负荷条件下的准确性、变异性和疲劳的注意力测量可能对短期胆碱能治疗敏感。鉴于乙酰胆碱在注意力功能中的核心作用，负荷依赖性注意力测量可能是早期治疗反应的有价值的认知标志物。
