Genetics of Vascular Dementia

Abstract

Genetic studies are transforming the way we diagnose, evaluate and treat patients. The era of genome-wide association studies promised to discover common risk variants in heterogeneous disorders where previous small-scale association studies had on the whole failed. However, as we enter the post-association era a degree of disappoint is felt regarding the lack of risk factors with large effect for a number of disorders including vascular disease. Vascular disorders are sporadic by nature, though a familial component has been observed. This review will focus on vascular dementia, the genetic risk factors for vascular disorders and highlight how new technologies may overcome the limitations of genome-wide association and nominate those genes that influence disease risk.

Figure 1

(a) postmortem MR imaging of a patient with VaD reveals cribriform status of the putamen (solid arrow) as well as extensive increased signal in frontal white matter (dotted arrow). (b) At autopsy the cribriform change is grossly visible as dilated vessels (arrow) in the putamen that are associated with decreased signal change seen on MRI. (Panel A courtesy of Dr. Clifford R. Jack, Jr; Panel B courtesy of Dr. Joseph E. Parisi)

Figure 2

(A) Dissection of an atherosclerotic vessel from a pathologically confirmed case of VaD reveals complicated atheromatous plaques, with a markedly expanded intima filled with grumose material. (b) In another patient rarefied white matter and obliterative small vessel disease are associated with subcortical white matter hyperintensities on neuroimaging. (c) An arteriosclerotic vessel in the basal ganglia shows an intima expanded by cholesterol containing, lipid material from lipohyalinosis. (d) Marked gliosis and a paucity of CA1 neurons are evident in hippocampal sclerosis. (Panel A courtesy of Dr. Joseph E. Parisi)

Figure 3. NOTCH Signaling

Mammals express four members of the Notch family of receptors (notch 1–4), and two families of ligands (delta-like 1,3,4 and jagged 1,2). Notch receptors and ligands are both single-pass transmembrane proteins that enable signaling between neighboring cells. Binding of the ligand triggers proteolytic cleavage of the Notch receptor, releasing the Notch intracellular domain (NICD) into the cytoplasm. The final step of proteolytic cleavage is mediated by the γ-secretase complex, of which presenilin (PSEN) acts as the catalytic subunit. The cleaved NICD translocates to the nucleus where it forms an active transcriptional complex with the DNA binding protein RBPJ (recombination signal binding protein for immunoglobulin J-kappa region), the co-activator mastermind-like (MAML) and other co-activators (CoA) (Adapted from High & Epstein JA, 2008; 33).

Figure 4. Granular osmiophilic material

Granular osmiophilic material (GOM) in cerebral autosomal dominant arteriopathy with subcortical infarctions and leukoencephalopathy (CADASIL). A low-power image of a small artery in CADASIL with reduplicated basal lamina, degeneration of smooth muscle cells, and extensive GOM in the outer media (original magnification × 9000; image courtesy of Dr. Wen-Lang Lin).