A Study of Insulin-like Growth Factors and Other Neurotrophic Factors in the Cerebrospinal Fluid From Patients With Dementia

Introduction Dementia The estimated prevalence of dementia in Denmark is 85.000 (2011) and the global prevalence is close to 36 million (2010). Furthermore the number is predicted to double in the next 20 years, primarily due to the demographic ageing. The costs of dementia accounts for 1% of the world's GDP - a perspective that will challenge the current healthcare systems and national economies (1,2,3).

Dementia includes a number of progressive degenerative brain diseases. Dementia is characterized by progressive deterioration in cognition, function and behavior that is sufficiently severe to compromise social and occupational functioning. Dementia is characterized by loss of episodic memory, difficulty in naming and word finding, apraxia, executive dysfunction and changes in personality and mood. The most common cause of dementia is Alzheimer's disease (4, 5, 6).

The pathogenesis of Alzheimer dementia remains elusive. For many years the pathophysiological hallmark of Alzheimers dementia has been the toxicity caused by the accumulation of the proteins amyloid-beta in plaques and phosphorylated tau associated with neurofibrillary tangles. However, this theory is based on the genetic "early-onset familial Alzheimers", which is a less frequent inherited type. Currently, the hypotheses on the pathogenesis of Alzheimer actually disagree with that of the amyloid-beta theory. Thus, there is a need to increase our understanding of the mechanisms leading to the most common forms of Alzheimer's disease. A better understanding of the disease may enable an earlier diagnosis and importantly, a causal treatment of Alzheimer as opposed to the merely symptomatic options available to day (4, 7, 8, 9).

IGF-system One of the main areas of recent research in dementia is the role of neurotrophic support, a research area which embraces insulin and the insulin-like growth factor system. Insulin and the IGF system are important in normal somatic growth, development, tissue repair and regeneration throughout life. Earlier studies have indicated that impairments in cerebral glucose utilization and energy metabolism represent very early abnormalities that precede or accompany the initial stages of cognitive impairment. However, type 2 diabetes, which is often characterized by insulin resistance, has not been established as a cause of Alzheimer although there is a correlation between insulin resistance and cognitive dysfunction.

The cellular signaling pathways of IGF-I and IGF-II overlap to a great extent with the pathways used by insulin, and all three proteins bind to the same receptors though with different affinities. Several studies have shown that the ratio between the concentrations of IGF-I in cerebrospinal fluid (CSF) and plasma (the CSF/plasma ratio) is reduced in Alzheimer patients. Interestingly, IGF-I seems to promote amyloid-beta clearance.