Groundbreaking Hokkaido University Study Unveils Region-Specific Brain Lipidomics Biomarkers in AD, HD, and PD

A team of researchers from Hokkaido University in Sapporo, Japan, has published a pioneering study mapping detailed changes in brain lipids across three major neurodegenerative diseases: Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD). This comprehensive lipidomics analysis highlights disease-specific and region-specific alterations, offering new hope for early diagnosis through blood or CSF-accessible biomarkers.

Lipidomics, the large-scale study of lipids within cells, tissues, or organisms, reveals how these fatty molecules—essential for cell membranes, signaling, and energy storage—dysregulate in neurodegeneration. The study, led by Jayashankar Jayaprakash and colleagues from the Faculty of Health Sciences and Graduate School of Global Food Resources, used untargeted liquid chromatography-mass spectrometry (LC/MS) on postmortem brain tissues from four regions: frontal, temporal, parietal, and occipital lobes.

Rising Burden of Neurodegenerative Diseases in Japan

Japan faces one of the world's fastest-aging populations, driving a surge in neurodegenerative diseases. Alzheimer's disease affects over 4.6 million people aged 65+, projected to rise with life expectancy exceeding 84 years. Parkinson's impacts about 200,000, while HD, rarer at 5-10 per 100,000, carries devastating genetic implications. These conditions strain healthcare, emphasizing the need for non-invasive biomarkers beyond amyloid PET scans or tau CSF tests.

Hokkaido University's work aligns with national priorities like AMED's neuroscience funding and JSPS grants, positioning Japanese universities as leaders in omics-driven research.

Detailed Methodology: From Brain Tissue to Lipid Profiles

Researchers analyzed 96 brain samples (24 each from healthy volunteers (HV), AD, PD, HD patients), balanced by sex (12 males/12 females per group). Tissues from the Human Brain and Spinal Fluid Resource Center underwent Folch extraction, followed by HPLC/LTQ-Orbitrap-MS in positive/negative modes. MS-DIAL identified 243 lipid species across classes like sphingomyelins (SM), phosphatidylserines (PS), phosphatidylinositols (PI), and cholesteryl esters (CE).

Orthogonal partial least squares-discriminant analysis (OPLS-DA) separated groups (e.g., 43% variance for PD vs HV), volcano plots flagged significant changes (p<0.05), and ROC curves validated biomarkers (AUC up to 1.0).

Alzheimer's Disease: Sphingomyelin Surge and Oxidized PS Elevation

In AD brains, sphingomyelins like SM(d18:1/16:0), SM(d18:1/18:1), and oxidized PS[PS(16:1/24:0;O1)] rose significantly, especially in occipital (p<0.0001) and parietal lobes. Lysophosphatidylcholines (LPC 18:2, LPC 17:2) dropped, suggesting phospholipase A2 hyperactivity and membrane breakdown.

• SM(d18:1/16:0): Upregulated across regions, linked to amyloid-beta aggregation.
• PS(16:1/24:0;O1): AUC=0.6736 for AD diagnosis, higher in females.
• LPC 17:2: Downregulated, indicating reduced anti-inflammatory signaling.

These shifts point to oxidative stress (GPX4 deficiency) and neuroinflammation, hallmarks of AD pathology.

Huntington's Disease: Ether-PS and Cholesterol Dysregulation

HD showed pronounced elevations in ether-PS[PS(O-17:0/22:6)], ω-6 CE(18:2, 20:4), and fatty acids (FA 18:0, 20:4;2OH), with PI(18:1/18:1) and LPI(18:0) depletion across parietal/occipital (p<0.0001). Changes were most severe in posterior regions, reflecting striatal vulnerability spillover.

• PS(O-17:0/22:6): AUC=1.000, ideal HD biomarker.
• CE 18:2: Elevated ω-6 esters, tied to ACAT1 upregulation.
• PI 18:0/20:3: Decreased, disrupting phosphoinositide signaling.

This profile suggests mitochondrial dysfunction and mutant huntingtin-induced lipid remodeling.

Photo by Rick Wallace on Unsplash

Parkinson's Disease: Shared Pathways with HD

PD mirrored HD with PS(O-17:0/22:6), CE, CL(78:10) increases, and HexCer(d18:0/25:0), Cer(d18:1/18:1), PI(20:4/17:1;O1) decreases, prominent in occipital/parietal. PG(18:0/18:1;O1) rose uniquely.

• PS(O-17:0/22:6): AUC=0.9167.
• PI(18:1/18:1): AUC=0.9236.
• HexCer d18:0/25:0: Down, lysosomal storage hint.

Overlaps imply common synuclein/tau-independent mechanisms like ferroptosis.

Region-Specific Vulnerabilities: Parietal and Occipital Hotspots

Parietal and occipital cortices showed maximal dysregulation across diseases, with frontal/temporal milder. E.g., PS(16:1/24:0;O1) peaked in AD occipital; PS(O-17:0/22:6) in HD/PD parietal. This maps pathology progression from association areas.

KEGG analysis linked changes to FA biosynthesis, glycerophospholipid metabolism, sphingolipid pathways.

Validated Lipid Biomarkers with High Diagnostic Potential

Three lipids emerged as candidates:

• PS(16:1/24:0;O1): AD-specific oxidized marker.
• PS(O-17:0/22:6): HD/PD ether-PS distinguisher.
• PI(18:1/18:1): Universal depletor, synaptic role.

Mechanistic Insights: Oxidative Stress, Inflammation, and Metabolism

Increased OxPS signals ROS overload; ether-PS/PI drops suggest ferroptosis and PI3K/Akt disruption. SM buildup in AD ties to APP processing; CE in HD/PD to cholesterol trafficking defects. Sex differences (female AD OxPS bias) highlight hormonal influences.

These findings contextualize lipidome heterogeneity via KEGG pathways.

Future Directions and Validation Needs

While promising, larger cohorts, early-stage tissues, and confounders (diet, PMI) need addressing. Longitudinal plasma validation and mechanistic knockouts could translate to therapies. Japan's iPS cell trials for PD/AD complement this.PubMed abstract.

Photo by Asmut Dante on Unsplash

Hokkaido University's Neuroscience Excellence

Hokkaido leads in lipidomics, with prior AD blood tests and glycomics. Amid JSPS/AMED funding, it attracts global talent for ND research. Explore research jobs or postdoc positions in Japanese universities.

Career Opportunities in Neuro-Lipidomics Research

This study underscores demand for lipidomics experts. Japan invests ¥10 trillion in endowments, boosting neuroscience. Check Rate My Professor for mentors, career advice, or higher ed jobs at institutions like Hokkaido. University jobs in neuroscience abound.