Domain-Specific Improvement of Cognition on Memantine in Patients with Alzheimer’s Disease Treated with Rivastigmine

Abstract

Objective: Cholinergic therapy is used in mild-to-moderate Alzheimer’s disease (AD) and antiglutamatergic therapy in moderate-to-severe AD. Global scales, as commonly used in clinical trials, blur specifics of disease progression and drug effects. The objective was to assess combination therapy of rivastigmine plus memantine by specific neuropsychological tests in patients with mild-to-moderate AD. Methods: 12-week-short multicenter open-label pilot study. Ninety patients with mild-to-moderate AD already on stable medication with rivastigmine (3–6 mg b.i.d.) additionally received memantine for 12 weeks. Subscales of the Alzheimer’s Disease Assessment Scale (ADAS-cog), the Mini-Mental State Examination (MMSE) and additional neuropsychological tests (e.g. span tasks, semantic fluency) were assessed. Results: The scores in the ADAS-cog memory subscale, the MMSE score, and digit span and semantic fluency significantly improved on combination therapy. Conclusion: Memory improvement was correlated with ADAS-cog memory score at baseline and inversely with age at onset of treatment. The data suggest that improvement on combination therapy results from an improvement of attention/executive function with secondary memory improvement, which will need to be confirmed in a subsequent double-blind study on a larger number of patients.

Contribution of N-methyl-D-aspartate receptors to attention and episodic spatial memory during senescence

“…Memantine has been reported to increase attention and executive function in postmenopausal women (Wroolie et al, 2009), elderly humans with memory complaints (Ferris et al, 2007), and people with probable Alzheimer’s disease (Riepe et al, 2007; Nakamura et al, 2014). It has been suggested that the beneficial effects may be related to the ability of memantine to act on other receptor systems including serotonin, nicotine, and dopamine receptors (Rammes et al, 2001; Aracava et al, 2005; Seeman et al, 2008).…”

“…The 0.05 mg/kg dose which improved 5-CSRTT performance, impaired hippocampal-dependent episodic memory. Similarly, in most cases in which memantine was reported to improve attention and executive function, the drug either had little effect on memory or impaired learning and memory (Rammsayer, 2001; Ferris et al, 2007; Riepe et al, 2007; Wroolie et al, 2009; Nakamura et al, 2014). Previous work suggests that impaired hippocampal function or a decrease in hippocampal activation can result in recruitment of the PFC (Cabeza et al, 2004; Zelikowsky et al, 2013).…”

“…Interestingly, some studies have reported that activity-dependent NMDAR channel antagonists at low doses have little effect or impair memory and yet improve attention and executive function in humans (Rammsayer, 2001; Ferris et al, 2007; Riepe et al, 2007; Wroolie et al, 2009; Nakamura et al, 2014) and in animals (Higgins et al, 2005; Smith et al, 2011; Pehrson et al, 2013; Benn and Robinson, 2014). Given that attention is an important factor in multiple cognitive processes that decline with aging, including executive function and memory, an understanding the dose dependent effect of NMDAR blockade with regard to age-sensitive cognitive processes is a critical question with clinical significance.…”

Methylthioninium chloride reverses cognitive deficits induced by scopolamine: comparison with rivastigmine

“…Several combination therapies for AD have been evaluated in preclinical models to demonstrate that successful synergy of compounds can be achieved with lower doses and fewer adverse sideeffects. Such combination therapies have been conducted for memantine (a non-competitive NMDA-receptor antagonist) and donepezil (a marketed ChEI) (Tariot et al 2004); memantine and rivastigmine (Riepe et al 2007); donepezil and cilostazol (a cyclic AMP enhancer with antiapoptotic and anti-inflammatory action) ); donepezil and selegiline (a selective monoamine oxidase-B inhibitor) (Takahata et al 2005); rivastigmine and fluoxetine (a 5-hydroxytryptamine [HT]-enhancing agent) (Mowla et al 2007); ascorbic acid and oxiracetam (a nootropic drug) (de Angelis and Furlan 1995) and, most recently, donepezil and prucalopride (a 5-HT4 receptor antagonist) (Cachard-Chastel et al 2008). Principle outcomes met with enhanced success relative to the respective mono-therapy.…”

Changes in cerebral glucose metabolism in patients with posttraumatic cognitive impairment after memantine therapy: a preliminary study

“…However, memantine is under investigation as a potential treatment for other diseases as well, including traumatic and hypoxic brain injuries [23,24]. In AD, memantine monotherapy or combined with cholinesterase inhibitors improved attention, memory, and language functions [19,25]. Based on the current findings, increased cerebral glucose metabolism in the frontal lobe, including the dorsolateral prefrontal cortex, and in the parietal lobe, including the precuneus, the angular gyrus, and the inferior parietal lobule, may be associated with the previously reported cognitive enhancing effects of memantine.…”