Non-tremor motor dysfunction in Lewy body dementias is associated with AD biomarkers.

Motor features of Parkinson's disease (PD) are heterogeneous and well-studied; non-tremor features of postural instability and gait dysfunction (PIGD) have been linked to worse outcomes and Alzheimer's disease (AD) co-pathology. However, these features are understudied in Lewy body dementias (LBD). Here we perform retrospective analysis of a unique cohort of LBD (n = 30) with Unified Parkinson's Disease Rating Scale (UPDRS) data collected at baseline in proximity to cerebrospinal fluid collection to test the hypothesis that LBD patients with a positive AD biomarker profile (LBD + AD = 13) would have higher PIGD burden compared with LBD patients without AD biomarker positivity (LBD-AD = 17). We find novel evidence for selective impairment of PIGD burden in LBD + AD vs LBD-AD (OR = 1.95, 95%CI = 1.02-3.70, p = 0.04) and a direct association of increasing CSF tau/Aß1-42 ratio with increasing PIGD disability in the total cohort (ß = 0.23, SE = 0.08, p = 0.01). This unique biomarker stratification approach suggests AD co-pathology may contribute to PIGD motor signs in LBD.

Olfaction as an early marker of Parkinson's disease and Alzheimer's disease.

Olfactory impairment is a common and early sign of Parkinson's disease (PD) and Alzheimer's disease (AD), the two most prevalent neurodegenerative conditions in the elderly. This phenomenon corresponds to pathologic processes emerging in the olfactory system prior to the onset of typical clinical manifestations. Clinically available tests can establish hyposmia through odor identification assessment, discrimination, and odor detection threshold. There are significant efforts to develop preventative or disease-modifying therapies that slow down or halt the progression of PD and AD. Due to the convenience and low cost of its assessment, olfactory impairment could be used in these studies as a screening instrument. In the clinical setting, loss of smell may also help to differentiate PD and AD from alternative causes of Parkinsonism and cognitive impairment, respectively. Here, we discuss the pathophysiology of olfactory dysfunction in PD and AD and how it can be assessed in the clinical setting to aid in the early and differential diagnosis of these disorders.

Drug experience epigenetically primes Fosb gene inducibility in rat nucleus accumbens.

ΔFosB, a Fosb gene product, is induced in nucleus accumbens (NAc) and caudate-putamen (CPu) by repeated exposure to drugs of abuse such as cocaine. This induction contributes to aberrant patterns of gene expression and behavioral abnormalities seen with repeated drug exposure. Here, we assessed whether a remote history of cocaine exposure in rats might alter inducibility of the Fosb gene elicited by subsequent drug exposure. We show that prior chronic cocaine administration, followed by extended withdrawal, increases inducibility of Fosb in NAc, as evidenced by greater acute induction of ΔFosB mRNA and faster accumulation of ΔFosB protein after repeated cocaine reexposure. No such primed Fosb induction was observed in CPu; in fact, subsequent acute induction of ΔFosB mRNA was suppressed in CPu. These abnormal patterns of Fosb expression are associated with chromatin modifications at the Fosb gene promoter. Prior chronic cocaine administration induces a long-lasting increase in RNA polymerase II (Pol II) binding at the Fosb promoter in NAc only, suggesting that Pol II "stalling" primes Fosb for induction in this region upon reexposure to cocaine. A cocaine challenge then triggers the release of Pol II from the gene promoter, allowing for more rapid Fosb transcription. A cocaine challenge also decreases repressive histone modifications at the Fosb promoter in NAc, but increases such repressive marks and decreases activating marks in CPu. These results provide new insight into the chromatin dynamics at the Fosb promoter and reveal a novel mechanism for primed Fosb induction in NAc upon reexposure to cocaine.