Pattern of brain destruction in Parkinson's and Alzheimer's diseases

Abstract

Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common age-related degenerative disorders of the human brain. Both diseases involve multiple neuronal systems and are the consequences of cytoskeletal abnormalities which gradually develop in only a small number of neuronal types. In AD, susceptible neurons produce neurofibrillary tangles (NFTs) and neuropil threads (NTs), while in PD, they develop Lewy bodies (LBs) and Lewy neurites (LNs). The specific lesional pattern of both illnesses accrues slowly over time and remains remarkably consistent across cases. In AD, six developmental stages can be distinguished on account of the predictable manner in which the neurofibrillary changes spread across the cerebral cortex. The pathologic process commences in the transentorhinal region (clinically silent stages I and II), then proceeds into adjoining cortical and subcortical components of the limbic system (stages III and IV - incipient AD), and eventually extends into association areas of the neocortex (stages V and VI - fully developed AD). During the course of PD, important components of the limbic system undergo specific lesions as well. The predilection sites include the entorhinal region, the CA2-sector of the hippocampal formation, the limbic nuclei of the thalamus, anterior cingulate areas, agranular insular cortex (layer VI), and - within the amygdala - the accessory cortical nucleus, the ventromedial divisions both of the basal and accessory basal nuclei, and the central nucleus. The amygdala not only generates important projections to the prefrontal association areas but also exerts influence upon all non-thalamic nuclei which in a non-specific manner project upon the cerebral cortex and upon the nuclei regulating endocrine and autonomic functions. All these amygdala-dependent structures themselves exhibit severe PD-specific lesions. In general, the extranigral destructions are in themselves not sufficient to produce overt intellectual deterioration. Similarly, AD-related pathology up to stage III may be asymptomatic as well. Fully developed PD with concurring incipient AD, however, is likely to cause impaired cognition. Presently available data support the view that the occurrence of additional lesions in the form of AD stage III (or more) destruction is the most common cause of intellectual decline in PD.

Gender and Iron Genes May Modify Associations Between Brain Iron and Memory in Healthy Aging

“…The Hip region has been shown to have elevated iron levels in AD (Deibel et al, 1996;Good et al, 1992;Smith et al, 1997;Thompson et al, 1988) (Bartzokis et al, unpublished data), and is affected early and severely in age-related proteinopathies such as AD and DLB (Braak et al, 1996;Kotzbauer et al, 2001) that cause the vast majority (over 70%) of dementia (Barker et al, 2002;Fratiglioni et al, 2000;Lobo et al, 2000). The observation that increased hippocampal iron is associated with poorer memory function even in healthy older individuals supports the suggestion that the 'normal' trajectory of age-related increases in brain ferritin iron may represent an underlying risk factor for age-related degenerative brain diseases ) (reviewed in Bartzokis, 2009).…”

“…We hypothesized that even in healthy individuals, agerelated increases in ferritin iron levels in the Hip, which is damaged early and severely in dementia-causing diseases such as AD and DLB (Braak et al, 1996;Kotzbauer et al, 2001), will negatively impact memory function (Bartzokis et al, 2007a;Bartzokis et al, 2007c;Bartzokis et al, 2004). Based on data that men may develop neurodegenerative diseases at younger ages (Barker et al, 2002;Friedman, 1994;Miech et al, 2002;Pantelatos and Fornadi, 1993;Raber et al, 2004) (reviewed in Bartzokis et al, 2004), we also hypothesized that healthy older men may be at increased risk for such iron-associated declines in memory function compared to women (Bartzokis et al, 2007c;Bartzokis et al, 2004).…”

The APOE ɛ4 allele modulates brain white matter integrity in healthy adults

“…29 Very few studies have investigated the potential effects of the APOE genotype on white matter (WM) structure. This is surprising considering that the major role of apoE in the brain is the transport of lipid components which contribute to building up the myelin sheath.…”

The effect of hormone therapy on olfactory sensitivity is dependent on apolipoprotein E genotype

“…Neuropathologically, AD is characterized by the presence of amyloid plaques, neurofibrillary tangles and cell atrophy in susceptible brain regions. These cytoskeletal abnormalities develop initially in brain regions of the medial temporal lobe that are involved in processing olfactory information such as the entorhinal and transentorhinal cortex (Braak et al, 1996). The brain degeneration proceeds from these initial areas to other temporal lobe structures and eventually reaches association areas (Braak et al, 1996).…”

“…These cytoskeletal abnormalities develop initially in brain regions of the medial temporal lobe that are involved in processing olfactory information such as the entorhinal and transentorhinal cortex (Braak et al, 1996). The brain degeneration proceeds from these initial areas to other temporal lobe structures and eventually reaches association areas (Braak et al, 1996). This pattern of brain degeneration suggests that AD patients may show impairments in olfactorymediated tasks in the early stages of the disease.…”