Frontiers in Clinical Drug Research - Alzheimer Disorders

The increase in EEG alpha3/alpha2 frequency power ratio has been associated with AD-converters subjects with mild cognitive impairment (MCI) as well as a reduction in the regional cerebral blood flow (rCBF).

In this study, the association between alpha3/alpha2 frequency power ratio with rCBF changes in subjects with MCI was evaluated.

The alpha3/alpha2 frequency power ratio was computed in 27 subjects with MCI. Two groups were obtained according to the median values of alpha3/alpha2, at a cut-off value of 1.17. In the groups so obtained, the correlation between brain perfusion and EEG markers was detected.

In the MCI group with the alpha3/alpha2 frequency power ratio above 1.17 as compared to the group with alpha3/alpha2 frequency power ratio below 1.17 there were: 1) a constant trend to lower rCBF values; 2) smaller hippocampal volumes; and 3) higher theta frequency power.

The higher EEG alpha3/alpha2 frequency power ratio individuates two different groups of MCI subjects. A complex interplay between alpha and theta rhythms activity MCI patients is suggested in patients with prodromal Alzheimer`s disease.

Alzheimer`s Disease (AD) is a disease carrying a huge negative effect upon both patients and their families, and also on society in terms of health services. New symptomatic and disease modifying therapies will be described in the following pages, many of these therapeutic approaches being directed towards modifying the amyloid cascade, and others aiming tau pathology, inflammation, oxidative stress and neurogenesis. Because AD is a multi-factorial neurodegenerative disease, combined treatment to target multiple pathological mechanisms, currently under investigation, will be discussed.

Nowadays research focuses on the possibility of developing prevention studies. Research results acknowledge the positive effects of adopting a healthy lifestyle, better control of cardiovascular risk factors, supplementation with vitamins, antioxidants, maintaining physical and mental activity, active involvement in social and professional activities can help reduce the occurrence of Alzheimer`s disease. Multiple therapy, targeting multiple disease aspects may have the greatest therapeutic potential. Developing new therapeutic strategies either to prevent or slow down the disease onset and progression will obviously have a profound effect on the lives of millions of people.

Behavioural and psychological symptoms of dementia (BPSD) are common in people with Alzheimer`s Disease. They include agitation, aggression, psychosis, depression and sleep disturbance, and can cause great distress for the individual and their caregivers. Management of BPSD is particularly challenging due to the lack of effective pharmacological treatments, and current clinical guidance is complex. This chapter outlines the causes and impacts of BPSD in people with AD. In particular it explores the evidence supporting the use of both pharmacological and nonpharmacological treatments and the role they play in the prevention and treatment of BPSD.

Alzheimer`s disease (AD) is the most common age-related neurodegenerative disease and the most common cause of dementia. One of the characteristic hallmarks of AD brains upon post-mortem examination is the presence of amyloid plaques containing aggregates of the neurotoxic amyloid-β peptide Aβ. This peptide is produced from the amyloid precursor protein (APP) by proteolytic cleavage, firstly by BACE1 (β-site amyloid precursor protein cleaving enzyme 1 or β-secretase) and subsequently by γ-secretase. After Phase III, clinical trials of a α γ-secretase inhibitor were abandoned due to adverse secondary effects, the focus has shifted to BACE1 as a key drug target in AD. Numerous BACE inhibitors have been produced, many of which have been shown in animal models to reduce the levels of Aβ in the brain. Intensive research effort for more than a decade has seen certain BACE1 inhibitors advance through human trials. Despite this progress, however, concerns that using BACE1 inhibition to reduce Aβ could cause unwanted side effects (termed “mechanism-based toxicity”) that have arisen as the list of BACE1 substrates continues to grow. In addition to APP, recent proteomics studies have identified novel BACE1 substrates, many of which have known roles in the developing and mature brain. This chapter aims to review the BACE inhibition strategy and describe the development of BACE inhibitors for AD therapy, highlighting both the promise and the potential pitfalls of this approach. The potential consequences of inhibiting BACE1 processing of these other BACE1 substrates along with APP will be discussed.

In this chapter, we discuss the development of therapies for frontotemporal dementia caused by progranulin mutations. Although this is a relatively rare and very specific form of neurodegeneration, the upstream disease cause, being haploinsufficiency of the growth factor progranulin, offers straightforward opportunities for therapy development. Substitution of the progranulin deficiency is likely to counteract the detrimental effects of progranulin haploinsufficiency in patients with frontotemporal dementia and may prevent the manifestation of the disease in presymptomatic mutation carriers. As progranulin has neurotrophic and antiinflammatory properties, therapeutic interventions aimed at augmenting progranulin levels may also become useful in other forms of neurodegeneration.