**2.8.5 Diagnostic criteria**

396 Neuroscience – Dealing with Frontiers

The hippocampal CA1 (1st cornus ammonis or Ammon's horn) region experiences the greatest loss of neurons in AD of approximately 70%. The CA1 is anatomically and functional connected to the entorhinal cortex where the earliest development of NFTs and neuronal loss in AD is thought to occur. The locus coeruleus (noradrenalin production), nucleus basalis of Meynert and the Raphe nuclei can also experience losses of greater than 50% as does the majority of the temporal lobe (Kril and Halliday, 2001). The loss of neurons in the nucleus basalis of Meynert is similar to the number of ghost tangles but in the hippocampus (Kril *et al.,* 2002) and entorhinal cortex (Gomez-Isla *et al.,* 1996) neuron loss actually exceeds the number of ghost tangle suggesting other neurodegenerative mechanisms are at work. The spread of pathology and associated neuronal loss in AD dictates the symptomology. The reader will note the early involvement of the hippocampus, a key region in both memory generation and consolidation. Interestingly the eventual spread of AD pathology mirrors the anatomical boundaries of the default network – the "brain system active when individuals are not focused on their external environment" (Buckner *et al.,* 2008). The default network is involves with the process of internal mentation or self-relevant mental simulation. This peculiarly human activity could explain the regional selectivity of neuronal loss in AD while deficits in the network are certainly consistent with the loss of self-awareness in moderate to severe stages of the disease (Buckner *et al.,* 2008).

AD is also characterised by a chronic inflammatory process that is commonly called reactive gliosis. Markers of inflammation such as MHC II expression are higher in demented patients than those in nondemented individuals with AD pathology and may be better correlated with synaptic dysfunction than either plaques or NFTs (Lue *et al.,* 1996). Essentially when we refer to reactive gliosis we mean reactive microgliosis, a hyperplastic and hypertrophic response of the resident macrophages in the brain. There is also astrocyte pathology but this remains less well defined in AD (Beach and McGeer, 1988). The increased expression of the cytosketal protein glial fibrillary acidic protein (GFAP) that characterised 'reactive' astrocytes has been described in AD brains although this was not correlated with either plaques or NFTs (Simpson *et al.*). Microglia are originally derived from the haemopoietic system and migrate to the brain during the early embryological period. Reactive microglia in AD are closely associated with plaques and studies with immunomodulatory therapies suggest that they are relatively effective, at least early in the disease process, at phagocytosing A plaques (Perlmutter *et al.,* 1990; Edison *et al.,* 2008). However neuroinflammation appears to exacerbate AD pathogenesis (Krause and Muller, 2010) and anti-inflammatory medication use is associated with a reduced risk of AD (Vlad *et al.,* 2008). This apparent paradox might be explained by microglia initially serving a protective role but eventually becoming overstimulated and producing excessive reactive oxygen species that lead to neurotoxicity (Innamorato *et al.,* 2009). Nevertheless anti-inflammatory medications do not reduce the progression of AD pathology (Halliday *et al.*, 2000). As microglia are now known to have physiological functions in the brain such the maintenance of synaptic plasticity and it has been suggested that they may be more 'victim' than 'villain'

**2.8.3 Neuronal loss** 

**2.8.4 Chronic inflammation** 

in AD (Graeber and Streit, 2010).

The current pathological criteria are based on the quantity of both plaques and NFTs (Hyman and Trojanowski, 1997) and incorporate a staging scheme for the neuropathological progression of NFTs ('Braak staging scheme') (Braak and Braak, 1991). The likelihood of AD is high if there are frequent neocortical plaques and NFTs consistent with Braak stage V/VI; is intermediate if plaques are moderate with Braak stage III/VI and low if neocortical plaques are sparse with Braak stage is I/II.
