Aquilani Roberto, Cotta Ramusino Matteo, Maestri Roberto, Iadarola Paolo, Boselli Mirella, Perini Giulia, Boschi Federica, Dossena Maurizia, Bellini Anna, Buonocore Daniela, Doria Enrico, Costa Alfredo, Verri Manuela
Department of Biology and Biotechnology, "Lazzaro Spallanzani," University of Pavia, Pavia, Italy.
Unit of Behavioral Neurology and Center for Cognitive Disorders and Dementia, IRCCS C. Mondino Foundation, Pavia, Italy.
Front Aging Neurosci. 2023 Aug 16;15:1237469. doi: 10.3389/fnagi.2023.1237469. eCollection 2023.
Dementias and mild cognitive impairment (MCI) are associated with variously combined changes in the neurotransmitter system and signaling, from neurotransmitter synthesis to synaptic binding. The study tested the hypothesis that different dementia subtypes and MCI may share similar reductions of brain availability in amino acid precursors (AAPs) of neurotransmitter synthesis and concomitant similar impairment in energy production and increase of oxidative stress, i.e., two important metabolic alterations that impact neurotransmission.
Sixty-five demented patients (Alzheimer's disease, AD, = 44; frontotemporal disease, FTD, = 13; vascular disease, VaD, = 8), 10 subjects with MCI and 15 control subjects (CTRL) were recruited for this study. Cerebrospinal fluid (CSF) and plasma levels of AAPs, energy substrates (lactate, pyruvate), and an oxidative stress marker (malondialdehyde, MDA) were measured in all participants.
Demented patients and subjects with MCI were similar for age, anthropometric parameters, biohumoral variables, insulin resistance (HOMA index model), and CSF neuropathology markers. Compared to age-matched CTRL, both demented patients and MCI subjects showed low CSF AAP tyrosine (precursor of dopamine and catecholamines), tryptophan (precursor of serotonin), methionine (precursor of acetylcholine) limited to AD and FTD, and phenylalanine (an essential amino acid largely used for protein synthesis) ( = 0.03 to <0.0001). No significant differences were found among dementia subtypes or between each dementia subtype and MCI subjects. In addition, demented patients and MCI subjects, compared to CTRL, had similar increases in CSF and plasma levels of pyruvate (CSF: = 0.023 to <0.0001; plasma: < 0.002 to <0.0001) and MDA (CSF: < 0.035 to 0.002; plasma: < 0.0001). Only in AD patients was the CSF level of lactate higher than in CTRL ( = 0.003). Lactate/pyruvate ratios were lower in all experimental groups than in CTRL.
AD, FTD, and VaD dementia patients and MCI subjects may share similar deficits in AAPs, partly in energy substrates, and similar increases in oxidative stress. These metabolic alterations may be due to AAP overconsumption following high brain protein turnover (leading to phenylalanine reductions), altered mitochondrial structure and function, and an excess of free radical production. All these metabolic alterations may have a negative impact on synaptic plasticity and activity.
痴呆症和轻度认知障碍（MCI）与神经递质系统和信号传导从神经递质合成到突触结合的各种综合变化有关。本研究检验了以下假设：不同的痴呆症亚型和MCI可能在神经递质合成的氨基酸前体（AAPs）的脑内可用性降低方面具有相似之处，同时在能量产生受损和氧化应激增加方面也具有相似之处，即这两种重要的代谢改变会影响神经传递。
本研究招募了65名痴呆患者（阿尔茨海默病，AD，n = 44；额颞叶疾病，FTD，n = 13；血管性疾病，VaD，n = 8）、10名MCI受试者和15名对照受试者（CTRL）。测量了所有参与者脑脊液（CSF）和血浆中的AAPs、能量底物（乳酸、丙酮酸）以及氧化应激标志物（丙二醛，MDA）水平。
痴呆患者和MCI受试者在年龄、人体测量参数、生物体液变量、胰岛素抵抗（HOMA指数模型）和CSF神经病理学标志物方面相似。与年龄匹配的CTRL相比，痴呆患者和MCI受试者的CSF中AAP酪氨酸（多巴胺和儿茶胺的前体）、色氨酸（血清素的前体）、蛋氨酸（乙酰胆碱的前体，仅限于AD和FTD）以及苯丙氨酸（一种主要用于蛋白质合成的必需氨基酸）水平均较低（P = 0.03至<0.0001）。痴呆症亚型之间或各痴呆症亚型与MCI受试者之间未发现显著差异。此外，与CTRL相比，痴呆患者和MCI受试者的CSF和血浆中丙酮酸（CSF：P = 0.023至<0.0001；血浆：P < 0.002至<0.0001）和MDA（CSF：P < 0.035至0.002；血浆：P < 0.0001）水平均有相似程度的升高。仅AD患者的CSF乳酸水平高于CTRL（P = 0.003）。所有实验组的乳酸/丙酮酸比值均低于CTRL。
AD、FTD和VaD痴呆患者以及MCI受试者可能在AAPs方面存在相似的缺陷，部分在能量底物方面，并且在氧化应激方面有相似的增加。这些代谢改变可能是由于高脑蛋白周转率导致AAP过度消耗（导致苯丙氨酸减少）、线粒体结构和功能改变以及自由基产生过多。所有这些代谢改变可能对突触可塑性和活性产生负面影响。
