Lenalidomide reduces microglial activation and behavioral deficits in a transgenic model of Parkinson’s disease

BACKGROUND: Parkinson’s disease (PD) is one of the most common causes of dementia and motor deficits in the elderly. PD is characterized by the abnormal accumulation of the synaptic protein alpha-synuclein (α-syn) and degeneration of dopaminergic neurons in substantia nigra, which leads to neurodegeneration and neuroinflammation. Currently, there are no disease modifying alternatives for PD; however, targeting neuroinflammation might be a viable option for reducing motor deficits and neurodegeneration. Lenalidomide is a thalidomide derivative designed for reduced toxicity and increased immunomodulatory properties. Lenalidomide has shown protective effects in an animal model of amyotrophic lateral sclerosis, and its mechanism of action involves modulation of cytokine production and inhibition of NF-κB signaling. METHODS: In order to assess the effect of lenalidomide in an animal model of PD, mThy1-α-syn transgenic mice were treated with lenalidomide or the parent molecule thalidomide at 100 mg/kg for 4 weeks. RESULTS: Lenalidomide reduced motor behavioral deficits and ameliorated dopaminergic fiber loss in the striatum. This protective action was accompanied by a reduction in microgliosis both in striatum and hippocampus. Central expression of pro-inflammatory cytokines was diminished in lenalidomide-treated transgenic animals, together with reduction in NF-κB activation. CONCLUSION: These results support the therapeutic potential of lenalidomide for reducing maladaptive neuroinflammation in PD and related neuropathologies. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12974-015-0320-x) contains supplementary material, which is available to authorized users

Substance use history in behavioral-variant frontotemporal dementia versus primary progressive aphasia

BACKGROUND: As older adults are prone to cognitive disorders, the interaction of the fields of substance use and misuse and cognitive neuroscience is an emerging area of research. Substance use has been reported in some subtypes of frontotemporal dementia (FTD), such as behavioral variant frontotemporal dementia (bvFTD). However, characterization of substance use in other subtypes of FTD, such as primary progressive aphasia (PPAPH), is unknown. OBJECTIVE: The objective of this baseline analysis was to explore whether any measures of substance use history differed significantly among bvFTD (n = 842) and PPAPH (n = 526) in a large national dataset. DESIGN/METHODS: The National Alzheimer’s Coordinating Center’s (NACC) Uniform Data Set (UDS) study is a national dataset that collects data on patients with various cognitive disorders and includes some questions on substance use. We used each substance use variable as the outcome and the FTD subtype as the predictor. RESULTS: Total years smoked cigarettes, age when last smoked cigarettes, and average # of packs/day smoked when participants smoked, and any recent, remote, or combined recent/remote history of alcohol abuse or drug abuse did not significantly differ between the bvFTD and PPAPH subtypes (all p-values > 0.001). A significantly greater percentage of participants smoked in the last 30 days in the bvFTD subtype (10.4%, n = 834) compared to the PPAPH subtype (3.3%, n = 517) (p < 0.001). DISCUSSION: Clinical providers in both the dementia and substance use fields are encouraged to screen for and monitor substance use in all FTD subtypes