'Mixed dementia' can refer to the presence of two or more causes of dementia; however, it generally refers to the coexistence of the clinical and pathologic alterations of both AD and VaD. Tomlinson et al. (1968, 1970) first called attention to this disorder when they suggested that the combined effects of AD histopathologic lesions and cerebral infarctions might lead to intellectual decline. Criteria for the diagnosis of mixed AD/VaD have not been developed; thus, the true frequency is not known. A recent review of autopsy studies found the prevalence of mixed VaD/AD to range from 3.7% to 36% in different autopsy series (Markesbery, 1998). The mean of these studies was 17.7%.
The Canadian Consortium for the Investigation of Vascular Impairment of Cognition found that out of 603 dementia patients, 149 had VaD and, of these, 76 had mixed AD/VaD (Rockwood et al., 2000).
Cohen et al. (1997) reviewed different approaches to the clinical diagnosis of mixed dementia. Characteristics of AD by history, examination, and imaging studies revealing vascular lesions are most commonly used for this diagnosis. A definite diagnosis of mixed AD/VaD is best made by autopsy; however, the presence of the pathologic findings of AD plus vascular lesions occurs quite frequently, and without precise clinical information the clinical role of the vascular lesions is not known.
Approximately one-third of pathologically confirmed AD brains contain vascular lesions (Gearing et al., 1995). Infarcts superimposed on AD could potentially worsen cognitive function, although only a few studies document
Figure 19.1. A Lacunar infarcts in the caudate nucleus and thalamus of a theoretical patient with normal cognitive reserve who shows no evidence of cognitive decline because of the infarcts. B Similar lacunar infarcts in a theoretical patient with neurofibrillary tangles sufficient to be Braak stage II or III and CERAD sparse neuritic plaques, which together could lead to cognitive decline
Figure 19.1. A Lacunar infarcts in the caudate nucleus and thalamus of a theoretical patient with normal cognitive reserve who shows no evidence of cognitive decline because of the infarcts. B Similar lacunar infarcts in a theoretical patient with neurofibrillary tangles sufficient to be Braak stage II or III and CERAD sparse neuritic plaques, which together could lead to cognitive decline this. In a prospective study of autopsied aged nuns (mean age 87 years), 39% met the neuropathologic criteria for AD and had one or more cerebral infarcts (Snowdon et al., 1997). Subjects who met AD neuropathologic criteria and had cerebral infarction were significantly more cognitively impaired than were AD subjects without infarcts. Fewer neurofibrillary tangles and senile plaques appeared to cause dementia in those with brain infarctions than those without infarcts. Nagy et al. (1997) demonstrated that in autopsied mixed AD/VaD patients and in AD patients with other neurodegenerative pathology (Parkinson's disease changes, motor neuron disease, or normal-pressure hydrocephalus), the density of total senile plaques or neuritic plaques was significantly lower in those with AD and other pathologic alterations of the central nervous system compared with AD and no other pathologic changes for any given level of cognitive deficit. This indicates that the combination of two pathologic processes influences the severity of the cognitive deficit.
Brun (2000) suggested that a summation dementia of old age resulted from a combination of AD changes, synapse loss, trauma, and cerebrovascular disease. He placed emphasis on selective incomplete white matter infarcts in the summation dementia of old age.
One interpretation of the above studies is that superimposing vascular lesions in critical brain regions in individuals with declining functional brain reserve can lead to decline in cognitive function. That is, individuals with abundant entorhinal and hippocampal neurofibrillary tangles, such as might be found in Braak stage II or III (Braak and Braak, 1991) and infrequent neocortical senile plaques as described in the CERAD sparse classification (Mirra et al., 1991), who experienced critically located infarcts, could start to show more marked intellectual decline than those without these changes (Figure 19.1). For example, individuals showing mild cognitive impairment might show a greater decline in function following cerebral infarction, which could lead to a diagnosis of dementia. Similarly, subjects with early or mid stage AD, who develop cerebral infarcts, might experience a more rapid decline in cognitive function through further depletion of brain reserve.
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