19 Low white matter grade and ventricular grade on MRI are powerful determinants of long-term survival among older individuals.20

Recent functional neuroimaging studies indicated reduced cortical activation in the default-mode network for mild cognitive impairment patients, compared with age-matched healthy elderly persons, mainly in the retrosplenial Inhibitors,research,lifescience,medical region/posterior cingulate cortex, left hippocampus, and bilateral inferior and middle frontal areas, while increased activation for patients was observed in the medial prefrontal and bilateral middle temporal/ angular cortex, probably as a compensatory mechanism.21 Resting state networks have been found to be hierarchically organized.22 Age-related atrophy is observed Inhibitors,research,lifescience,medical in the hippocampal region.23 This region is of particular interest given its contribution to memory function, working memory decline being a common complaint in healthy aging24 and one of the earliest signs of AD. Impaired hippocampal synaptic function is an early detectable pathologic alteration, well before amyloid plaque accumulation and cell death.25 Positive relationships

emerged consistently between the Inhibitors,research,lifescience,medical hippocampal formation, global Sepantronium Bromide mouse cognition, and memory, and between frontal measures and executive function.26 The hippocampal formation and the Papez circuit are targeted differentially by diseases of late life.27 Volumetric MRI of temporal and parietal brain Inhibitors,research,lifescience,medical structures distinguishes AD patients from healthy subjects, volumetry of the

left and right hippocampus providing the highest diagnostic accuracy in separating these groups.28 Recent advances in imaging techniques (diffusion tensor imaging [DTI] and magnetization transfer imaging [MTI]) indicate that age-related small-vessel disease is a diffuse process affecting the whole brain and that WMLs are probably only the tip of the iceberg,19,29-31 while decreased gray matter diffusivity might be a potential new biomarker for early AD.32 Aβ-associated cortical thinning has been observed in clinically normal Inhibitors,research,lifescience,medical elderly subjects.33 Age-related neuronal dysfunction involves a host of subtle changes SPTLC1 such as reduction in the complexity of dendritic arborization and length, decrease in spine numbers and related synaptic densities, changes involving receptors, neurotransmitters, cytology, electric transmission, vascular or Alzheimer-related changes, and myelin dystrophy. Together, these multiple alterations in the brain may lead to age-related cognitive dysfunction.1,2 However, every lesion in the nervous system triggers an endogenous neuroprotective reaction, combining neuroplasticity and neurogenesis, which are initiated and regulated by neurotrophic factors in a multimodal way.34 Extrusion of misfolded and aggregated (toxic) proteins may be a protective strategy of aging neurons.