Towards a pathway definition of Parkinson’s disease: a complex disorder with links to cancer, diabetes and inflammation

We have previously established a first whole genome transcriptomic profile of sporadic Parkinson’s disease (PD). After extensive brain tissue-based validation combined with cycles of iterative data analysis and by focusing on the most comparable cases of the cohort, we have refined our analysis and established a list of 892 highly dysregulated priority genes that are considered to form the core of the diseased Parkinsonian metabolic network. The substantia nigra pathways, now under scrutiny, contain more than 100 genes whose association with PD is known from the literature. Of those, more than 40 genes belong to the highly significantly dysregulated group identified in our dataset. Apart from the complete list of 892 priority genes, we present pathways revealing PD ‘hub’ as well as ‘peripheral’ network genes. The latter include Lewy body components or interact with known PD genes. Biological associations of PD with cancer, diabetes and inflammation are discussed and interactions of the priority genes with several drugs are provided. Our study illustrates the value of rigorous clinico-pathological correlation when analysing high-throughput data to make optimal use of the histopathological phenome, or morphonome which currently serves as the key diagnostic reference for most human diseases. The need for systematic human tissue banking, following the highest possible professional and ethical standard to enable sustainability, becomes evident

Small Vessel Disease and Subcortical Vascular Dementia

Atherothromboembolism and intracranial small vessel disease are considered to be the main causes of cerebrovascular injury, which may lead to cognitive impairment and vascular dementia (VaD). VaD appears to be the second most common type of dementia with prevalence estimates of 10-15%. Cortical or multi-infarct dementia and subcortical vascular dementia (SVD) are suggested to be the two main forms of VaD. The main clinical features of SVD comprise decreased motor performance, early impairment of attention and executive function with slowing of information processing. SVD results from lacunar infarcts or multiple microinfarcts in the basal ganglia, thalamus, brainstem and white matter and are associated with more than 50% of the VaD cases. White matter changes including regions of incomplete infarction are usually widespread in VaD but their contribution to impairment of subcortical regions is unclear. While most of VaD occurs sporadically only a small proportion of cases bear clear familial traits. CADASIL is likely the most common form of hereditary VaD, which arises from subcortical arteriopathy. SVD needs unambiguous definition to impact on preventative and treatment strategies, and critical for selective recruitment to clinical trials

Cerebral Amyloid Angiopathy: A Systematic Review

Cerebral amyloid angiopathy (CAA) is a disorder characterized by amyloid deposition in the walls of leptomeningeal and cortical arteries, arterioles, and less often capillaries and veins of the central nervous system. CAA occurs mostly as a sporadic condition in the elderly, its incidence associating with advancing age. All sporadic CAA cases are due to deposition of amyloid-β, originating from proteolytic cleavage of the Amyloid Precursor Protein. Hereditary forms of CAA are generally familial (and therefore rare in the general population), more severe and earlier in onset. CAA-related lobar intracerebral hemorrhage is the most well-studied clinical condition associated with brain amyloid deposition. Despite ever increasing understanding of CAA pathogenesis and availability of reliable clinical and diagnostic tools, preventive and therapeutic options remain very limited. Further research efforts are required in order to identify biological targets for novel CAA treatment strategies. We present a systematic review of existing evidence regarding the epidemiology, genetics, pathogenesis, diagnosis and clinical management of CAA