Cognitive Neuroscience Approaches to Therapy

Therapeutic interventions in adults with probable Alzheimer’s disease (AD) have been hampered by difficulty identifying sensitive endpoints that can monitor changes in natural history or responses to therapeutic interventions. Most therapies have been targeted at remediating episodic memory, a component of AD that is relatively unyielding to intervention given the underlying pathology. Other aspects of cognition such as naming are very frequently impaired in AD, but interventions for these disorders have not been addressed. The overall purpose of this proposal is to design and implement two markers of disease progression and therapeutic response, and to initiate a feasibility therapeutic trial for a very common non-memory problem in AD. Specific Aim 1 will use cognitive measures to chart the longitudinal course of naming difficulty, a problem affecting the vast majority of AD patients. We propose to develop a naming battery that can act as a surrogate marker for disease progression and response to therapeutic intervention in AD. We hypothesize that naming difficulty in AD is multifactorial in nature, including impairments in word meaning and word retrieval. Longitudinal studies will demonstrate the prognostic value of these naming components in predicting overall disease progression in AD. Specific Aim 2 will relate specific patterns of naming difficulty in AD to selective defects in the neural network underlying naming. We propose to identify cerebral regions sensitive to the evolution of AD where functional brain activity can be used as a marker for disease progression and therapeutic response. We hypothesize that activation neuroimaging with functional MRI (fMRI) during specific cognitive challenges will relate discrete aspects of naming difficulty to distinct patterns of compromised cerebral recruitment in AD. For example, control subjects will recruit supramodal association cortical regions of the left hemisphere during challenges for the meaning component of a word, and AD patients with semantic memory difficulty will have limited recruitment of these brain regions. Novel brain regions will be identified that are not activated in controls but are recruited by AD patients during their attempts to name. Longitudinal studies will demonstrate stable patterns of reduced brain activity in AD patients with naming difficulty. Specific Aim 3 will assess the feasibility of a therapy for naming while we test the sensitivity of our markers of disease progression. We will compare a pharmacologic intervention using methylphenidate or 4QH-amino-acridinamine (THA) with a cognitive therapy. We hypothesize that therapeutic interventions for naming deficits are feasible in AD. Cognitive therapy together with methylphenidate will prove more successful than monotherapy in retarding the progression of the naming deficit in AD.