Institute of Neuroscience and Medicine, Brain & Behaviour (INM-7), Research Centre Jülich, Jülich, Germany.
Institute of Systems Neuroscience, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
Elife. 2024 Jan 15;13:e86085. doi: 10.7554/eLife.86085.
Aside to clinical changes, behavioral variant frontotemporal dementia (bvFTD) is characterized by progressive structural and functional alterations in frontal and temporal regions. We examined if there is a selective vulnerability of specific neurotransmitter systems in bvFTD by evaluating the link between disease-related functional alterations and the spatial distribution of specific neurotransmitter systems and their underlying gene expression levels.
Maps of fractional amplitude of low-frequency fluctuations (fALFF) were derived as a measure of local activity from resting-state functional magnetic resonance imaging for 52 bvFTD patients (mean age = 61.5 ± 10.0 years; 14 females) and 22 healthy controls (HC) (mean age = 63.6 ± 11.9 years; 13 females). We tested if alterations of fALFF in patients co-localize with the non-pathological distribution of specific neurotransmitter systems and their coding mRNA gene expression. Furthermore, we evaluated if the strength of co-localization is associated with the observed clinical symptoms.
Patients displayed significantly reduced fALFF in frontotemporal and frontoparietal regions. These alterations co-localized with the distribution of serotonin (5-HT1b and 5-HT2a) and γ-aminobutyric acid type A (GABAa) receptors, the norepinephrine transporter (NET), and their encoding mRNA gene expression. The strength of co-localization with NET was associated with cognitive symptoms and disease severity of bvFTD.
Local brain functional activity reductions in bvFTD followed the distribution of specific neurotransmitter systems indicating a selective vulnerability. These findings provide novel insight into the disease mechanisms underlying functional alterations. Our data-driven method opens the road to generate new hypotheses for pharmacological interventions in neurodegenerative diseases even beyond bvFTD.
This study has been supported by the German Consortium for Frontotemporal Lobar Degeneration, funded by the German Federal Ministry of Education and Research (BMBF; grant no. FKZ01GI1007A).
除了临床变化外，行为变异额颞叶痴呆（bvFTD）的特征还包括额颞叶区域的进行性结构和功能改变。我们通过评估疾病相关功能改变与特定神经递质系统的空间分布及其潜在基因表达水平之间的联系，来研究在 bvFTD 中是否存在特定神经递质系统的选择性易损性。
我们从 52 名 bvFTD 患者（平均年龄=61.5±10.0 岁；14 名女性）和 22 名健康对照者（HC）（平均年龄=63.6±11.9 岁；13 名女性）的静息态功能磁共振成像中获得了局部活动的分数低频波动（fALFF）图。我们测试了患者的 fALFF 改变是否与特定神经递质系统的非病理性分布及其编码 mRNA 基因表达共定位。此外，我们评估了共定位的强度是否与观察到的临床症状有关。
患者的额颞和额顶叶区域的 fALFF 明显降低。这些改变与 5-羟色胺（5-HT1b 和 5-HT2a）和γ-氨基丁酸 A 型（GABAa）受体、去甲肾上腺素转运体（NET）及其编码 mRNA 基因表达的分布共定位。与 NET 共定位的强度与 bvFTD 的认知症状和疾病严重程度相关。
在 bvFTD 中，局部脑功能活动的减少遵循特定神经递质系统的分布，表明存在选择性易损性。这些发现为功能改变的疾病机制提供了新的见解。我们的数据驱动方法为神经退行性疾病的药物干预开辟了新的途径，甚至超越了 bvFTD。
本研究得到德国额颞叶变性联合研究组的支持，该研究组由德国联邦教育与研究部（BMBF；资助号：FKZ01GI1007A）资助。
