by Christos Evangelou, MSc, PhD – Medical Writer and Editor
In a recent study, researchers at Lund University (Lund, Sweden), Istituto delle Scienze Neurologiche di Bologna (Bologna, Italy), and Instituto de Salud Carlos III (Madrid, Spain) identified a distinctive MRI signature associated with α-synuclein pathology in the brain. This protein, known for its role in Parkinson’s disease and Lewy body dementia, appears to leave its mark on brain structure long before clinical symptoms emerge.1
The study’s findings point to the nucleus basalis of Meynert, a key region in the brain’s cholinergic system, as an early ‘hotspot’ of α-synuclein accumulation.1 According to the authors, this finding sheds light on the early impact t of α-synuclein-related on the brain.
“In this study, which included three large cohorts, α-synuclein-positivity determined by seed amplification assay was consistently associated with an atrophy pattern that was mostly restricted nucleus basalis of Meynert volume, even in asymptomatic stages,” said Nicola Spotorno, PhD, senior researcher at Lund University and one of the leading authors of the paper.
“Participants likely to harbor α-synuclein pathology, even in the absence of clinical symptoms, are also likely to have a reduced volume of a critical hub in the cholinergic system, also known as the nucleus basalis of Meynert. These results helped to elucidate the early impact of α-synuclein on the cholinergic system,” he added.
The report was published in JAMA Neurology.
The Elusive Effects of α-Synuclein on Brain Structure
α-Synuclein has been a protein of interest in neurodegenerative research, but its effects on brain structure in living individuals have remained largely unknown. Dr. Spotorno explained that the lack of reliable methods to detect α-synuclein pathology in living individuals has hampered our understanding of how α-synuclein affects brain structure, especially in the early stages of disease.
Leveraging recent advances in cerebrospinal fluid (CSF) biomarker technology, a multidisciplinary team of researchers aimed to characterize the structural brain changes associated with α-synuclein pathology across the disease spectrum, from clinically unimpaired to cognitively impaired individuals. By doing so, the researchers hoped to identify potential early markers of α-synuclein-related neurodegeneration and gain insights into how this pathology contributes to cognitive decline.
A Multi-Cohort Approach to Uncover α-Synuclein’s Footprint
The research team used data from three large independent cohorts: the Swedish BioFINDER-2 study (discovery cohort) consisting of 1,388 participants, the Swedish BioFINDER-1 study (replication cohort) comprising 752 participants, and the Alzheimer’s Disease Neuroimaging Initiative (ADNI; replication cohort) consisting of 821 participants.1
Participants in each cohort underwent cerebrospinal fluid analysis using seed amplification assays to detect α-synuclein pathology, structural MRI scans, cognitive testing, and CSF biomarker analysis for Alzheimer’s disease pathology (amyloid-β and phosphorylated tau).1
Commenting on their approach, Dr. Spotorno said:
“We combined three large cohorts with available seed amplification assay data into a single study. BioFINDER-1 and BioFINDER-2 have the advantage of MRI scans conducted at the same site and on the same machine. In contrast, ADNI includes data from numerous centers, presenting both challenges and opportunities.”
He explained that the challenge lies in potential center-specific differences in imaging procedures and hardware, which could impact the analyses.
“One of the biggest challenges in large studies like this is collecting and harmonizing sufficient data to ensure confidence in the results,” he said. “We were able to address this challenge thanks to the excellent international collaborations that made this study possible.”
The researchers employed voxel-based morphometry to conduct an unbiased, whole-brain analysis of structural changes associated with α-synuclein positivity.1 They then performed targeted region-of-interest analyses, focusing on areas known to be vulnerable to α-synuclein pathology or involved in the cholinergic system. The analyses were adjusted for Alzheimer’s disease biomarkers, allowing the team to isolate the effects of α-synuclein pathology from those of concurrent Alzheimer’s pathology.1
α-Synuclein Positivity Is Associated with Brain Atrophy
The study revealed consistent patterns across all three cohorts. α-Synuclein positivity was significantly associated with atrophy of the nucleus basalis of Meynert, a key structure in the brain’s cholinergic system.1 This association was present in both clinically unimpaired and cognitively impaired individuals, suggesting that atrophy of the nucleus basalis of Meynert occurs early in the disease process, even before clinical symptoms become apparent.
The relationship between α-synuclein positivity and atrophy of the nucleus basalis of Meynert remained significant even after adjusting for Alzheimer’s disease biomarkers, indicating a specific effect of α-synuclein pathology.1 According to the authors, the association between α-synuclein positivity and brain atrophy in clinically unimpaired individuals suggests that structural MRI measures of the nucleus basalis of Meynert could serve as an early marker of α-synuclein pathology.
In cognitively impaired individuals, atrophy of the nucleus basalis of Meynert partially mediated the association between α-synuclein positivity and impairments in attention and executive function.1
Interestingly, the study showed that the α-synuclein-associated atrophy pattern was relatively restricted, primarily affecting the nucleus basalis of Meynert, and to a lesser extent, other cholinergic regions. This contrasts with the more widespread atrophy patterns typically seen in advanced neurodegenerative diseases.1
Dr. Spotorno emphasized the significance of these findings:
“Our results contribute to the understanding of the initial stages of central nervous system degeneration related to the accumulation of α-synuclein. We hope they will also pave the way for further investigation into very early cholinergic dysfunction in Lewy body disorders.”
Future Work
Looking ahead, the researchers outlined several promising avenues for future research. Longitudinal studies are warranted to track the progression of brain atrophy and its relationship with α-synuclein accumulation and cognitive decline over time. Investigation of additional imaging modalities, such as diffusion tensor imaging or functional MRI, is needed to better characterize the downstream effects of α-synuclein pathology on brain connectivity and function.
Moreover, studies combining in vivo α-synuclein biomarkers with post-mortem neuropathological examinations are warranted to further validate and refine our understanding of the effects of α-synuclein on brain structure.
The study received financial support from the National Institute of Aging, European Research Council, Alzheimer’s Association, GHR Foundation, Swedish Research Council, ERA PerMed, Knut and Alice Wallenberg Foundation, Strategic Research Area MultiPark at Lund University, Swedish Alzheimer Foundation, EU Joint Programme Neurodegenerative Diseases, Wallenberg AI, Autonomous Systems and Software Program and Data-Driven Life Science Joint call for research projects, Swedish Brain Foundation, Parkinson Foundation of Sweden, Cure Alzheimer’s fund, Rönström Family Foundation, Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, Crafoord Foundation, Skåne University Hospital Foundation, Regionalt Forskningsstöd and Swedish federal government under the Avtal om Läkarutbildning och Forskning agreement on medical education and research, and Miguel Servet Fellowship of the Instituto de Salud Carlos III.
References
- Wisse LEM, Spotorno N, Rossi M, et al. MRI Signature of α-Synuclein Pathology in Asymptomatic Stages and a Memory Clinic Population. JAMA Neurol. Published online July 28, 2024. doi:10.1001/jamaneurol.2024.2713
