NeuroimagingPerfusion abnormalities in prodromal AD
Introduction
Patients with memory complaints are often arrayed along a continuum from normal function through varying degrees of impairment. A crucial question for both patients and clinicians evaluating them is to what extent these complaints are the harbinger of Alzheimer’s disease (AD). This issue is of particular importance as strategies for the prevention or delay of dementia are developed.
However, early detection of AD is complicated by the fact that the disease progresses in an insidious manner, generally starting with mild memory impairments that go unrecognized for years, until a more generalized cognitive decline prompts a diagnosis of dementia. Moreover, mild memory impairments are quite common in the elderly, and not everyone with subtle memory difficulties progresses to develop AD. Current diagnostic techniques have limited utility in predicting which individuals with mild memory impairments will progress over time.
Modern imaging techniques offer one potential method of early detection. In addition, by identifying the neuroimaging measurements useful in the discrimination of prodromal AD, one might learn more about which brain regions are the most affected in the earliest stage of AD.
This review will focus primarily on the area of functional neuroimaging with radiolabeled tracers, specifically Positron Emission Tomography (PET) and Single Photon Emission Tomography (SPECT). There is considerable experience with the application of both techniques to patients with established AD. More recently, these approaches have been expanded to the study of patients who are either in the prodromal phase of AD or to individuals who are at increased risk for developing AD due to family history or genetic profile. Though the findings of these studies are not in uniform agreement, taken together they suggest that a brain network or networks with multiple nodes is affected in the earliest stage of AD, and that functional imaging techniques, such as PET and SPECT, might facilitate early diagnosis. The nature of these findings will be discussed, and their implications for future work will be examined.
Section snippets
Perfusion abnormalities in established AD
Functional imaging techniques, such as PET or SPECT, have demonstrated specific regional abnormalities in brain perfusion in patients with established AD. The most consistent finding to emerge from these studies is that decreased perfusion or metabolism in temporoparietal cortex is common among mildly impaired patients with probable AD (e.g. [7], [8], [9], [10], [17]). Decreased metabolism has been found in other areas as well but is not the predominant pattern reported [23], [25], [32].
Perfusion alterations in prodromal AD
More recently, investigators have demonstrated PET and SPECT alterations in individuals prior to the time that they meet clinical criteria for AD. These studies implicate a set of brain regions that appear to be affected in prodromal AD.
One group of studies has examined individuals at risk for AD because of their genetic profile or family history. One of these studies has been conducted among individuals with a mutation for a dominant gene for AD. However, the majority have been conducted among
Brain networks implicated in prodromal AD
Perfusion alterations in the hippocampal complex in prodromal AD are consistent with a large body of knowledge indicating that this region is involved at the earliest stage of this disorder (e.g. [3], [11], [15]). Recent neuropathological studies indicate that the pathological hallmarks of AD (i.e. the neurofibrillary tangles and neuritic plaques) are first evident in the entorhinal cortex [11]. This finding is consistent with the fact that most patients with AD have a progressive memory
Future directions in the study of perfusion alterations in prodromal AD
Taken together, these data suggest that there are alterations in a distributed brain network or networks in prodromal AD, which are measurable with functional neuroimaging. It is not yet clear whether these measures of perfusion or metabolism can be used to identify individuals in the prodromal phase of AD for clinical intervention, because the accuracy with which such individuals can be identified with certainty is still limited. In addition, it is not yet known whether the findings described
Conclusion
Considerable research efforts have been focused on the development of an accurate, noninvasive laboratory test for the presence of AD pathology, which can be easily and widely applied. The potential for effective treatments for AD has further motivated a vigorous research effort to identify surrogate markers of early AD pathology. Neuroimaging methods have the potential to satisfy these requirements because they are acquired noninvasively, using techniques and equipment that are widely
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