Vascular dementia: New molecular therapies on the rise?

Studies show a causal relationship between different risk factors and microangiopathies, one of the main causes of vascular dementia. They also shed light on the effectiveness of therapeutic approaches.

Novel statistical studies bring innovative therapeutic approaches

Studies using Mendelian randomization have shown that there is a causal relationship between different risk factors and microangiopathies, one of the main causes of vascular dementia. New findings have also been made with regard to the effectiveness of different therapeutic approaches.

Vascular disease alone or as a co-pathology is responsible for 40% of dementia diseases. The risk factors do not differ from the classic vascular risk profile, many of them are related to individual lifestyles and can be modified, others are genetic and an important starting point for new therapies.

For the diagnosis and prognosis of central vascular pathologies, two surrogate markers in particular (measured value to assess the effectiveness of an intervention in clinical studies) have proven to be effective:

• Serum NfL (neurofilament light): increased after acute stroke or secondary event, detectable for months, serves as a predictor of clinical outcome and secondary neurodegenerative processes
• Diffusion Tensor Imaging (DTI): biomarker for follow-up, complex but highly sensitive, superior to all other markers

Review of known risk factors using Mendelian randomisation

Using Mendelian randomisation, new causal relationships between some known risk factors and the outcome of vascular disease have also been shown, as well as the efficacy of certain drugs. This statistical method can be used to investigate causal influences on certain diseases in non-experimental studies.

Microangiopathies are one of the main causes of vascular pathologies and genetic elevated blood pressure is one of the major risk factors for all forms of stroke. It has been shown that mean systolic blood pressure increases the risk, but not increased pulse pressure. The effect of different antihypertensive drugs on stroke risk - ACE inhibitors, beta-blockers and calcium channel blockers - was also studied. The latter were the only ones that had a proven reducing effect on vascular events.

Subtype of HDL protects against stroke

The effect of lipoproteins on the risk of stroke was also studied. Increased HDL-C levels showed a protective effect on vascular events, in this case small vessel disease (SVD) and the volume of white matter hyperintensity (WMH). A more detailed analysis of the subforms showed that M-HDL-C alone, but not L- and XL-HDL-C, is responsible for this risk reduction. This was followed by an investigation into the protective effect of HDL-increasing and LDL-lowering drugs. A protective effect of CETP (cholesteryl ester transfer protein) inhibitors was demonstrated.

Conclusion

• Mendelian randomisation allows the establishment of causal relationships between the exposure of a risk factor and the outcome, as well as the effectiveness of certain drugs.
• There is a causal relationship between increased mean arterial pressure, but not pulse pressure, and the risk of vascular events.
• Calcium channel blockers reduce this risk more effectively than beta blockers.
• M-HDL-C has a protective effect, as does the use of CETP inhibitors.

Source:
Prof. Dr. med. M. Dichgans, Institute for Stroke and Dementia Research (ISD) at the LMU Klinikum University Hospital in Munich, Germany. DGN 2020, 04.11.2020