premutation service providers over age 50 may develop fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disorder characterized by intention tremor, cerebellar gait ataxia, neuropathy, and cognitive deficits in executive function, attention, memory space, and visual-spatial control (Brega mRNA toxic gain-of-function is the pathogenic molecular mechanism of neurodegeneration in FXTAS (Hagerman, 2013; Jacquemont premutation. characterize verbal memory space. Data from 41 individuals who completed the 1-12 months memantine trial (21 on memantine) and also completed longitudinal ERP studies were analyzed. Results showed Rabbit Polyclonal to TSPO treatment-associated benefits on both cued-recall memory space and N400 repetition effect amplitude. Importantly, dBET57 improvement in cued recall was positively correlated with amplitude increase of dBET57 the N400 repetition effect. The placebo group, in contrast, displayed a significant reduction of the N400 repetition effect after 1 year. These results suggest that memantine treatment may have beneficial effects on verbal memory space in FXTAS. Additional studies of memantine, maybe in combination with additional restorative providers, appear warranted, as symptomatic treatments and neuroprotective treatments are both needed for this recently acknowledged neurodegenerative disorder. Intro The fragile X mental retardation 1 (premutation-associated disorders have a significant impact on society. premutation service providers over age 50 may develop fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disorder characterized by intention tremor, cerebellar gait ataxia, neuropathy, and cognitive deficits in executive function, attention, memory space, and visual-spatial processing (Brega mRNA toxic gain-of-function is the pathogenic molecular mechanism of neurodegeneration in FXTAS (Hagerman, 2013; Jacquemont premutation. Specifically, the premutation was linked to glutamatergic receptor dependent long-term potentiation (LTP) reduction and long-term depressive disorder (LTD) increase (Hunsaker premutation mouse model. Furthermore, Liu (2012) reported significantly increased response to glutamate in human induced pluripotent stem cell-derived neurons harboring the premutation growth. To date, no specific treatment has been proven effective for FXTAS. Memantine, an uncompetitive antagonist of mRNA level and N400 amplitude. In depth recording studies of human hippocampus, the NMDA receptor antagonist ketamine has been shown to severely disrupt N400 amplitude (Grunwald premutation carriers with FXTAS. The present study used a word repetition paradigm to elicit and modulate the N400 and P600 ERP components (Olichney CGG repeat lengths were quantified in all subjects using previously described procedures (Tassone CGG repeat length. No group differences at baseline were found in verbal memory (as evaluated by the CVLT and subsequent memory tests for the target words), or executive function (measured by the BDS and COWAT) either. Table 1 Baseline Non-ERP Steps: Mean (SD) premutation mouse model. Our ERP results support the view that treatment with the uncompetitive NMDA receptor antagonist memantine improves glutamatergic signaling (Lipton, 2006) in FXTAS patients. This uncompetitive antagonist can block excessive activation of the NMDA receptors while leaving normal physiological activity relatively intact. It also is thought to increase the signal-to-noise ratio in glutamatergic signaling (eg, Danysz and Parsons, 2003). This is a likely mechanism by which these individuals’ incidental learning and associative memory processes (ie, cued-recall) were improved/facilitated. The memantine-associated behavioral improvements in the subsequent cued-recall memory for the experimental stimuli suggest treatment benefits not only on implicit memory, but also may impact declarative/explicit memory. Although most of our prior ERP studies using this word repetition paradigm have not found significant correlations between the N400 repetition effect and memory, some of these were underpowered to find moderate correlations, and/or had restricted ranges of memory scores. Several other investigators have hypothesized and/or found relationships between the N400 and aspects of declarative memory (see Kutas and Federmeier, 2011 for a systematic review). For example, Helmstaedter (1997) reported that this N400 was related to verbal dBET57 learning (rather than retention) abilities on the basis of subdural recordings over lateral temporal cortex of well-characterized epileptic patients. Consistent with the familiarity/recollection model of recognition memory (Yonelinas mRNA associated glutamatergic signaling abnormalities, but no apparent benefits on executive dysfunction. Limitations of the present study include: (1) limited power to detect small effect sizes due to a modest sample size; (2) possible type I error due to lack of adjustment for multiple statistical comparisons. Therefore, the modest treatment effects we found on cued-recall memory and the N400 repetition effect are in need of independent replication. Further research trials of memantine and combinational therapies with other therapeutic agents for this neurodegenerative disorder appear warranted, especially considering the lack of any confirmed therapy to date. Cao (2012) suggested allopregnanolone, a positive modulator of GABAA receptors, as a candidate therapeutic agent to ameliorate the abnormal mGluR1/5 signaling in premutation neurons. Also, in a model of premutation, Qurashi (2012) found that phospholipase A2 (PLA2) inhibitors can ameliorate the premutation CGG repeat-mediated neuronal toxicity. Future clinical trials testing the additive and/or synergic effects and safety of the.