Thread by @alicechenp

Cognitive heterogeneity in Parkinson’s disease: A mechanistic view cell.com/neuron/fulltex…

Our thoughts on #synuclein strains, #Alzheimer pathology, and individual genetic and biomarker characteristics in why individuals with #Parkinson disease manifest so differently. 1/n

We review how cognition looks in #Parkinsons (short answer: lots of different ways in different people). We review treatment options for cognitive impairment in PD (short answer: not many). We argue that mechanistic focus is needed for better treatment options to emerge. 2/n

Mechanistically, we focus on cell-to-cell spread of pathological #synuclein (aSyn). We think evidence for aSyn spreading and for strains (conformations) of aSyn w different biological behaviors and subsequent cognitive consequences in aSyn diseases is strong. 3/n

Coexisting #Alzheiners pathology (in ~40% of PD at autopsy) matters, too. Can we predict which PD pts might benefit from anti-amyloid tx?

But by far we think host characteristics are the most understudied factor in why some people have a little tremor while others dement. 4/n

We mean by “host factors” the genetic and exposure signatures (latter is hard to get at biologically but biomarkers help) of individuals that govern the pace and pattern of pathology spread. We’ve worked on common genetic variants (e.g. GPNMB, TMEM175, TMEM106B), and found, 5/n

That even GWAS hits w small effect sizes can impact v central processes in aSyn spread, for example. 6/n

Reviews are fun if they allow you to synthesize (my very) scattered thoughts w colleagues and students. Many thanks to D Weintraub and my wonderful #MDPhD student M Carceles Cordon for their partnership! We hope you enjoy reading as much as we enjoyed writing!