The Characteristic Clinical Course of Retrogenic Dementias

Although the characteristic clinical course of AD, as outlined most clearly with the FAST staging procedure, is very different from many other dementing conditions, it is also interesting and of diagnostic relevance that many dementias of diverse etiology occasionally, or more frequently, follow the characteristic FAST sequential progression of AD more or less precisely. The advances in understanding of the etiopathogenic mechanisms of AD provide an explanation for the observed clinical similarities between these ostensibly etiopathogenically diverse, but frequently clinically similar, dementia processes.

As described earlier in this review, in AD an etiopathogenic process termed retrogenesis accounts for the pattern of functional losses and of clinical symptomatology. The pathologic basis of this retrogenic process is that the most thinly (recently) myelinated brain regions are the most vulnerable, and the most thickly myelinated brain regions are affected last in the evolution of dementing disorder. The myelin is a major constituent of the so-called "white matter'' of the brain. Therefore, any dementing disorder which progressively and diffusely affects the white matter of the brain is likely to produce a retrogenic-type dementia, similar to AD in its clinical progression.

Many conditions associated with dementia are known to produce white matter pathology as a prominent, or even pre-eminent, pathologic change. To the extent to which this white matter pathology is generalized and diffuse, these dementias are likely to mimic the clinical presentation of AD. For example, vitamin B12 deficiency is known to be associated with dementia as well as signs of demyelination, especially in the spinal cord, but also in the brain [98]. More general white matter lesions have also been found to be associated with vitamin B12 deficiency [99,100]. Treatment of the B12 deficiency has been associated with resolution of both myelin and white matter changes as well as resolution of neurologic and cognitive disturbances [98-100].

White matter pathology, in contrast to primary neuronal pathology, has also been implicated in the etiopathogenesis of other potentially dementing conditions, for example, anoxia. Basic studies in rats have shown that occlusion of the common carotid artery combined with hypoxemia "causes white matter necrosis in the ipsilateral cerebral hemisphere originating and spreading from myelinogenic foci'' [101,102],

Subsequent studies have supported these observations [103], Azzarelli et a! have studied this phenomenon in detail in neonates [102], They concluded that, at the moment of insult, damaged brain areas are ones which have the greatest susceptibility to oxygen deprivation. Consequently, at any given developmental age, tissues having higher metabolic rates for glucose should be particularly sensitive to oxygen deprivation. Furthermore, they note that myelinization is related to increased neuronal oxidative activity in oligodendroglia. Hence, brain areas most involved in myelination are the most sensitive to hypoxic damage.

Others have noted that the highly specialized architecture of myelinated axons renders them vulnerable to injury [104]. During anoxia, myelin, in contrast to glial cell bodies and proximal processes, accumulates ionic calcium [105]. The result may be relative vulnerability of oligodendroglia and related myelin to free radical damage, glutamate toxicity and anoxia per se [106-110].

It is also possible that "myelin may play a role... in protection of the axon and in maintenance of the integrity of the oligodendroglia/myelin/axonal relationship'' [71]. Therefore, the most recently and, as a result, thinly myelinated brain regions may be selectively vulnerable to anoxic and related insults. Anoxia and hypoxia, in turn, have been implicated in diverse brain and dementia-related pathologies, from hyponatremia [111] to cerebrovascular dementia and stroke.

Depression is a condition which has long been known to be associated with a potentially or frequently reversible dementia [112-114]. A series of recent studies have related late life depression to increased white matter hyperintensities in neuroimaging brain studies [115-121]. The cognitive impairment sometimes noted in late life depression can be difficult to distinguish from AD [112-114,122]. The reasons for these similarities appear to be explainable on the basis of the retrogenesis model. Specifically, the brain regions most vulnerable to the white matter insults would be the same as in AD, and hence the presentations of these conditions in the context of progressive dementia would be similar.

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