Memory failure has different mechanisms in subcortical stroke and Alzheimer's disease.

It is well recognized that patients with Alzheimer’s disease (AD) suffer from early and profound memory failure and that this is probably related to severe pathological involvement of the medial temporal lobe structures involved in episodic memory function. This mechanism of memory failure is supported in part by data from neuroimaging showing atrophy of medial temporal structures in AD,1,2 which is related to memory function.3-6 In addition to AD, however, patients with memory loss may suffer from cerebrovascular disease. These patients are sometimes diagnosed as having ischemic vascular dementia (IVD). Although the precise nature and frequency of cerebrovascular disease as a cause of dementia are contentious,7-9 there is little doubt that it frequently coexists with AD at the time of postmortem examination10,11 and may occur as the sole cause of dementia.12,13 The contributions of cere-brovascular pathological characteristics to cognitive loss are particularly uncertain when the pathological characteristics are manifested only in subcortical structures. Severe persistent failure of long-term memory, as is common in IVD and AD, is classically related to lim-bic or diencephalic lesions. IVD patients frequently have no apparent strokes in these regions but are nonetheless amnestic.10,14-16 Studies suggest that the application of current diagnostic criteria for IVD17,18 generally excludes patients with AD alone and results in groups of patients with disease consisting of pure IVD and mixed AD/IVD. Thus, AD clearly contributes to the memory loss in many cases but may not be the only cause of memory loss in this population. There are currently several competing models of how subcortical vascular pathological changes might lead to dementia, all of which emphasize diffuse cortical dysfunction as a general basis for cognitive loss.7,19-21 The strategic lesion model proposes that even a single stroke may cause dementia by destroying critical subcortical nuclei, with consequent widespread cortical dysfunction,22 although cumulative effect models propose that an aggregation of strokes may subtract a critical volume of brain parenchyma or may synergistically disrupt functional circuits.23 The exact mechanism of memory loss in subcortical IVD is unclear, however. One explanation for memory loss in IVD patients with primarily subcortical cerebrovascular disease (“subcortical IVD”) invokes impairment of functional systems involving the frontal lobes. Recent studies, especially those that have comprised reasonably homoge-Association neous groups of vascular dementia patients, have generally found a consistent pattern of cognitive impairment in IVD that has been labeled “subcortical-frontal” and differs from the characteristic pattern of cognitive impairments in AD. Several studies have compared clinically diagnosed groups of patients with these two dementias and have found evidence of greater impairment of executive function24 and verbal fluency25,26 in IVD patients. Studies examining memory function in IVD patients have found overall better function than in comparably demented AD patients but have also found that retrieval, an aspect of memory performance with a large executive function component, is more impaired in IVD patients.26 Although the functional imaging literature shows that component processes of the episodic memory system are frequently widely distributed,27,28 it is also clear that lesions of prefrontal cortex and medial temporal structures result in significantly different types of memory deficits. Although the classic amnestic disorder associated with medial temporal lesions is not seen in patients with focal frontal lesions, these patients have impairments in organizing to-be-remembered material, in temporal ordering of memories, and in contextual memory.29-34 Frontal structures play a critical role in the regulation of working memory as well,35 the failure of which can contribute to episodic memory impairment. Because IVD and AD patients differ in the degree of dysfunction in frontal and temporal structures, one might predict that they would also differ in the degree to which memory impairment is related to the functioning of these different structures. If frontal dysfunction predominates in IVD, one might predict that memory failure would primarily correlate with the extent of physiological dysfunction in prefrontal cortex. Conversely, one might predict that in AD patients, in whom temporal lobe dysfunction predominates, memory failure would correlate primarily with temporal lobe dysfunction. A secondary prediction is that the pattern of memory failure would differ between patients in these 2 groups. This hypothesis does not necessitate entirely distinct neuropathological substrates for AD and IVD, because it is clear that AD pathological changes may occur in patients labeled as having “IVD.” Rather, the presence of substantial subcortical cerebrovascular disease may modify the expression of AD pathological changes so that the behavioral features more closely resemble those seen in subcortical frontal syndromes. The purpose of this study was to test this model of memory failure in IVD by attempting to show a specific link between subcortical stroke, cortical glucose metabolism, and memory function. We performed high-resolution [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) studies using a verbal memory task during the period of tracer uptake and then looked for relations between metabolic activity and memory task performance. Our hypothesis was that different brain regions would be related to memory ability in the two conditions—prefrontal cortex in subcortical vascular disease and temporal lobes in AD.