Episodic Memory in Alzheimer’s Disease
recognition memory task, Saykin and colleagues76 showed reduced prefrontal activation in patients with mild AD relative to age-matched controls. Within the patient group, interindividual variations in frontal activity were related to hippocampal volume. Patients with greater preservation of the hippocam- pus showed greater activity in bilateral prefrontal regions. This is consistent with the notion that medial temporal and frontal regions form an integrated circuitry subserving episodic memory, and that damage in one part of the circuitry may be reflected in altered activation of other regions. Corkin73 also found that frontal activation during retrieval was related to the success with which older adults, regardless of whether or not they had AD, recognized previously presented pictures. Position emission tomography (PET) stud- ies provide related data; for example, in one study, patients with mild AD showed reduced functional connectivity of frontal, hippocampal, and other regions during a face-recognition memory task.77
Evidence is emerging that functional neuroimaging is sensitive to the earliest stages of dementia before the clinical symptoms of AD or MCI are evident.78 Bookheimer and colleagues77 examined cognitively intact, middle- aged to older individuals who were at risk for AD by virtue of their genetic [apolipoprotein E (ApoE) ε4] status. Although not a valid clinical predictor at the individual level, there is a clear correlation between presence of the ε4 allele and likelihood of developing AD.80 Bookheimer and colleagues found increased intensity and spatial extent of activation in temporal, parietal, and Figure 7.3. Left hippocampal and parahippocampal regions where controls showed greater activation than patients with AD during encoding of visual information.
Controls also showed more activation than patients in right parahippocampal gyrus (not shown). Reprinted with permission from Rombouts SA, Barkhof F, Veltman DJ, et al. Functional MR imaging in Alzheimer’s disease during memory encoding.
ANJR Am J Neuroradiol. 2000;21(10):1867–1875. American Society of Neuroradiology.
(Neurologic coordinates).
prefrontal regions during episodic encoding and retrieval in individuals who were ε4 positive compared to those without the ε4 allele (Figure 7.4).
Baseline activation patterns predicted memory decline over the next two years. The fact that these individuals were recruiting broader areas of brain tissue to accomplish the episodic memory task suggests that changes in acti- vation may occur very early during the course of memory disorders such as AD. These changes may play a compensatory role and may represent an early marker for subsequent cognitive decline. Some of the same researchers reported no differences between ε4 positive and negative groups in fMRI brain activation patterns on an attention/working memory task.81 This was interpreted as evidence that compensatory brain activation in ε4 carriers is specific to the episodic memory system.
Daselaar and colleagues82 examined activation patterns associated with successful recognition of incidentally encoded words in healthy adult males.
Figure 7.4. Brain activation patterns associated with learning and recall in indi- viduals with increased genetic risk for AD (ApoE ε4 carriers) compared to ApoE ε3 carriers. Both groups showed increased activation in left inferior frontal cortex, right prefrontal cortex, transverse temporal gyri bilaterally, left posterior temporal, and inferior parietal regions during learning or recall compared to rest, as shown in the top two panels. However, the intensity and spatial extent of activation was greater in those with the ε4 allele (bottom panel). Reprinted with permission from Bookheimer SY, Strojwas MH, Cohen MS, et al. Patterns of brain activation in people at risk for Alzheimer’s disease. N Engl J Med. 2000;343(7):450–456. Copyright © 2000 Massachusetts Medical Society. All rights reserved.
Young adults with normal memory were compared with two older groups, one cognitively intact and the other with mildly impaired memory. During successful encoding, the younger group showed significantly more left anterior medial temporal lobe activation than the older adults with reduced memory, but did not significantly differ from the older adults with normal memory.
Grön and colleagues83 examined fMRI patterns of brain activity in older adults presenting for first-time medical evaluation of subjective memory complaints. After comprehensive assessment, twelve individuals were diagnosed with probable AD and twelve with major depression. These participants were compared to twelve healthy older adults without cogni- tive complaints. In general, those participants who were diagnosed with AD showed reduced hippocampal activation during episodic memory processing relative to either of the other groups. Increased bilateral prefrontal activity also was seen in the AD patients, consistent with possible attempted compensa- tory recruitment or de-differentiation.
In a preliminary study of seven patients with mild AD, Rombouts and colleagues recently investigated the effects of rivastigmine, a cholinesterase inhibitor, on brain activity patterns during episodic memory performance (and working memory, as described below).84 A single dose of the medica- tion led to a bilateral increase in activation in the fusiform gyrus during face encoding. This suggests that rivastigmine affects activity in regions associ- ated with cholingeric circuitry, and that fMRI may be useful in monitoring treatment effects in AD, MCI, and other disorders.
Together, these studies suggest that fMRI is sensitive to preclinical and very early clinical stages of AD and may be useful in early diagnosis, prog- nosis, and treatment monitoring. Functional MRI may be able to assist in determining whether a drug is effective and the mechanisms by which its effects occur.