Medical Bulletin 06/ August/ 2024

In a recent review published in the journal Experimental & Molecular Medicine, researchers reviewed available literature on the role and mechanisms by which cholesterol imbalances in the brain contribute to neurodegenerative disorders such as Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD).

They analysed more than 80 publications on key mechanisms such as synaptic dysfunctions, amyloid beta (Aβ) protein oligomers, protein clustering, changes in membrane structure, and α-synuclein aggregation. Their findings indicate that changes in cholesterol synthesis and metabolism are common across most neurodegenerative diseases studied. While cholesterol-lowering drugs can somewhat reduce the risk of these diseases, further research is needed to create targeted pharmacological treatments for these conditions.

Cholesterol is a waxy, fat-like compound present in the cell membranes of all human cells. It is crucial for neuronal signalling and synaptic connections, particularly in the brain. Interestingly, the brain holds 20-25% of the body's total cholesterol reserves, making it the organ with the highest concentration of cholesterol in the human body.

The present study collates and reviews more than 80 publications on cholesterol to elucidate four key molecular mechanisms underpinning the associations between cholesterol imbalances and subsequent adverse neurodegenerative outcomes. These mechanisms include: 1. Synaptic dysfunction, 2. Amyloid beta aggregation, 3. Protein clustering, membrane structure alterations, and 4. α-synuclein aggregation.

The most essential neural protein family involved in the transport and normal metabolism of cholesterol is the apolipoprotein E (ApoE) family. ApoE4 has further been identified as a crucial risk factor in last-onset AD. Unfortunately, the molecular contributions of the ApoE family are poorly understood and require further investigation.

The mechanisms by which cholesterol affects various neurodegenerative diseases depend on the specific context. However, this study emphasises that imbalances in cholesterol levels, particularly in the brain, can elevate the risk of these diseases and proposes potential management strategies.

References: Shin, K.C., Ali Moussa, H.Y. & Park, Y. Cholesterol imbalance and neurotransmission defects in neurodegeneration. Exp Mol Med (2024), DOI – 10.1038/s12276-024-01273-4, https://www.nature.com/articles/s12276-024-01273-4

In a recent study published in the journal Nature Medicine, researchers in the United Kingdom (UK) estimated the onset age, number of years spent, and life loss in diabetes-related multiple long-term conditions (MLTCs) among 46 million adults. The study revealed that diabetes hastened the development of severe multiple long-term conditions (MLTCs) by 15-20 years and significantly shortened life expectancy. The impact varied across different age groups: in older adults, hypertension, cancer, depression, and coronary heart disease were the primary contributors, while in younger adults, mental health conditions and asthma played a more significant role.

Type 2 diabetes significantly contributes to various forms of morbidity due to insulin resistance, chronic hyperglycemia, and related dysfunctions. It is strongly associated with both microvascular and macrovascular complications, including cardiovascular, eye, foot, and kidney diseases.

A total of 46,748,714 adults aged 20 and older were included in the study. Further, data on socio-demographics, geography, and clinical diagnoses for 35 long-term conditions. Among all the included participants, 7.8% were diagnosed with diabetes. Adults with diabetes showed a higher prevalence of multiple long-term conditions compared to those without diabetes. At 50 years of age, about one-third of the adults with diabetes had at least three multiple long-term conditions, a prevalence not reached in the general population until age 65–70 years.

In conclusion, this study underscores the significant burden of diabetes-related multiple long-term conditions from both individual and community perspectives. The results advocate for better allocation of healthcare resources and informed commissioning decisions, highlighting the importance of developing innovative prevention and treatment strategies for multiple long-term conditions.

References: The burden of diabetes-associated multiple long-term conditions on years of life spent and lost. Gregg, E.W. et al., Nature Medicine (2024), DOI: 10.1038/s41591-024-03123-2, https://www.nature.com/articles/s41591-024-03123-2

In a recent study published in the journal Nature Medicine, researchers examine clinical glioblastoma and benign intracranial samples to determine the presence and function of immune cells in the brain.

The brain is considered an 'immune-privileged' organ with minimal immunological activity. However, recent research has revealed the presence of both innate and adaptive immune cells in areas such as the choroid plexus, meninges, and dural sinuses. The presence of immune cells at the interface between the central nervous system (CNS) and the rest of the body enables information to be conveyed from the brain via interstitial, cerebrospinal, and lymphatic fluids.

The disruption of the neuro-immune barrier may be implicated in malignant diseases, such as glioblastoma; however, immune checkpoint inhibitors have been associated with limited efficacy in treating glioblastomas. Systemic immunosuppression and intrinsic, adaptive, and acquired immunotherapy resistance may prevent these immunotherapies from successfully reaching brain tumours.

Clinical samples are collected from patients with grade four isocitrate dehydrogenase (IDH)-wildtype glioblastoma who had not undergone chemotherapy or radiation. Post-surgical CT scans were performed within 24 hours of sample collection, while MRI scans were done within 72 hours. To visualise and quantify CXCR4-expressing cells in the cranial bone and tumour tissues, clinical CXC chemokine receptor 4 (CXCR4) radiolabeling was integrated with PET-CT imaging data.

A total of 19 glioblastoma patient samples were analyzed and compared with samples obtained from five patients with non-malignant intracerebral disease. Active lymphoid tissue populations were identified in cranial bone marrow at the initial diagnosis of glioblastoma tumours. The combination of CXCR4 radiolabeling with PET-CT imaging was found to be highly effective for investigating immune cell dynamics within brain tissues.

The study sheds light on the behavior of T-cell populations, especially cytotoxic and memory T-cells, within the brain and their role in cancerous environments. Further research is essential to fully understand the immune landscape of glioblastomas and to create more targeted and effective treatments. Additionally, employing CCCR4 radiolabeling in PET-CT imaging presents a new method for tracking and visualizing immune cell dynamics in glioblastoma patients throughout their treatment.

References: Dobersalske, C., Rauschenbach, L., Hua, Y. et al. (2024). Cranioencephalic functional lymphoid units in glioblastoma. Nature Medicine. doi:10.1038/s41591-024-03152-x

In a recent study published in the journal Psycho-oncology Mental health screenings must be incorporated in routine prostate cancer diagnoses. The call follows new research that shows men need more support both during and immediately after a diagnosis of prostate cancer.

It’s an important finding, not only highlighting the percentage of prostate cancer patients who seek mental health support, but notably, those who do not. Every year, more than 24,000 men are diagnosed with prostate cancer, with up to 40% of patients considered at risk of mental distress.

Prostate cancer can significantly impact mental wellbeing, creating uncertainty and morbidity. This study described patterns of psychotropic medication and mental health service use, as a proxy measure for mental health problems, 5 years before and 5 years after prostate cancer diagnosis.

Population-based registry data was used and a total of 13,693 participants were evaluated. The researchers estimated the proportion and rates of psychotropic medication and mental health service use before and after diagnosis.

The results showed that fifteen percent of men commenced psychotropic medications and 6.4% sought out mental health services for the first time after diagnosis. Psychotropic medication use rose from 34.5% 5 years before to 40.3% 5 years after diagnosis, including an increase in use of antidepressants (from 20.7% to 26.0%) and anxiolytics (from 11.3% to 12.8%). Mental health service use increased from 10.2% to 12.1%, with the increase mostly being general practice mental health visits. Multivariable analysis indicated a significant rise in medication and service utilization. immediately before and in the first 2 years following prostate cancer diagnosis.

Hence, it was observed that there is a clear increase in psychotropic medication use and mental health service use around the time of prostate cancer diagnosis. Mental health outcomes of men with prostate cancer may be improved with early mental health screening, particularly during the diagnosis process, to enable early intervention.

References: Australian Institute of Health and Welfare. Cancer data in Australia. Accessed August 31, 2023. https://www.aihw.gov.au/reports/cancer/cancer-data-in-australia/contents/overview-of-cancer-in-australia-2023