Mild cognitive impairment (MCI) has been defined as a clinical entity whose characteristics were reviewed by Ron Petersen. Persons with MCI have memory impairment beyond what would be expected for age, yet they are not demented. These persons have relatively normal general cognitive function and activities of daily living. When compared to age and education-matched normal persons, measures of learning and delayed recall are significantly impaired. Their CDR will be 0.5.

Other investigators examined selected correlates of MCI. For example, Devanand et al. described olfactory identification deficits in patients with mild cognitive impairment (does this reflect a memory or an olfactory problem?) while Wolf et al. proposed that asymmetrical hippocampal atrophy may be a sign of MCI. Jack et al. reported that patients with MCI have hippocampal volumes which lie intermediate in size between controls and patients with probable AD. Blomberg et al. examined the ability of CSF tau, Aβ40 and Aβ42 to distinguish MCI from AD. Substantial overlap between AD and MCI was observed in all these markers, a finding reflective of the overlap in neuropathological markers presented below. Olichney et al. reported on a late positive event-related potential that peaked at 600 ms in response to a word repetition paradigm. In normals, the evoked potential was large in response to new words, and was greatly diminished with repetition. Fourteen patients with mild cognitive impairment had a smaller word repetition effect with a delayed onset of evoked response. These authors suggest the source of this potential was in the hippocampus. Mufson et al. continued with their studies of neurons with immunohistochemically defined chemical phenotype. Among their findings was the total number of trkA-ir neurons declined significantly from normal to MCI to AD (F92,27)=17.38;p.0.5). A global measure of cognitive function which combined all test scores was significantly related to the number of trkA-ir neurons (Spearman rank correlation=0.38, p=0.048). ANOVA revealed that the total number of p75NTR-ir neurons was significantly decreased in subjects with MCI (31 percent, pThere is no doubt as to the legitimacy of this relatively recently defined constellation of clinical signs. However, several questions arise as to the meaning of this clinical entity. These include: What is its prevalence? Does it represent an early form of clinically diagnosed AD that will inevitably progress to the full blown disease? What are its neuropathological, neurobiological and molecular correlates? Thirty-eight abstracts were devoted to these and other issues related to MCI.

Prevalence of MCI:
Relatively few presentations focused specifically on the prevalence of MCI. Hanninen et al., in a population study of 806 persons between the ages of 60 and 76 in Finland, reported that 52 subjects, 6.5 percent, met the MCI criteria. This percentage is in contrast to the 18-35 percent over age 65 cited by Bullock (referenced to Callaham, 1995). This difference may be a reflection of differences in inclusion criteria. In an extension of other studies Hallikainen et al. reported that women diagnosed as MCI had used estrogen replacement significantly less than cognitively better functioning women (5.5 percent versus 17.5 percent, p=0.004).

Progression of MCI to AD was a topic that attracted the greatest number of presentations. Issues covered dealt with the rate of progression in a sample and characteristics that might be predictive of conversion. Hanninen et al. reported that in a population sample of 806 subjects in Finland, more than 50 percent of cases classed as MCI converted to AD within three to four years. This percentage is in approximate agreement with Petersen's report of a conversion rate of 10-15 percent per year as compared to a rate of 1-2 percent per year for normal subjects of the same age. In further agreement, Nordberg et al. reported a conversion rate of 26 percent over two years. On the other hand, Bullock et al. reported a conversion of 32 percent over a one-year period in a cohort of 88 patients diagnosed with MCI (as defined in the European Consensus Guidelines). Of those that remained stable, the history in some suggested possible vascular aetiology and in others was not suggestive of AD, suggesting that the difference from the Petersen and the Hanninen data may be a consequence of differing definitions of MCI. The issue of differing inclusion criteria was also pointed out by Sadovnick et al. with some criteria having no stipulation of CDR staging.

Petersen suggested that certain features of the initial clinical presentation of MCI subjects, such as apolipoprotein E status, memory performance profile, and MRI-based measurements of the hippocampus, predict which individuals will progress more rapidly from MCI to AD.

Predictors of conversion:
Bennett et al. compared rates of change in global cognitive function (based on 20 cognitive tests) in 159 persons with mild cognitive impairment (MCI) to 464 persons with no cognitive impairment (NCI) and to 63 persons with early AD. The correlation between initial global score and rate of change was r=.17. However, for a memory score the correlation between initial level and rate of change was r=.54. In contrast, Sano et al. assessed seven symptom categories: memory, performance, disorientation, language, depression, behavior, and psychosis in a sample of 67 MCI patients who were followed at six-month intervals. Memory complaint, the most common symptom of individuals with MCI, was not predictive of conversion to AD. However, other specific symptoms, such as disorientation and the total number of symptoms were associated with subsequent conversion to AD.

The use of MRI data as predictors of conversion led to more agreement among studies than did use of psychometric tests. Jack et al. reported that measurement of hippocampal volume can provide predictive information as to which MCI patients will remain cognitively stable and which will convert to AD within a three- to five-year follow-up. Close correlation was seen between the rate of hippocampal atrophy and the probability of clinical decline. Murtha et al. reported a preliminary analysis indicating no difference in atrophy between Time 1 and Time 2 between elderly control subjects and those MCI subjects who did not convert to AD. The converters had a significantly greater change in atrophy than the control group and the nonconverters.

The data of Rossoret al., although not targeted specifically at MCI, are also consistent with a utility of MRI in predicting conversion. Using MRI to examine a cohort of at risk persons with a history of familial Alzheimer's disease with APP and presenilin 1 mutations revealed a presymptomatic phase of tissue loss in patients who subsequently develop the disease.

PET data, especially glucose measures, proved to be uniformly useful in predicting conversion. Nordberg et al. reported that deficits in glucose metabolism predicted clinical outcome in 93 percent of their cases. Mony De Leon reported data from a four-year longitudinal study assessing regional cerebral glucose metabolic (CMRglu) and neuropsychologal predictors of MCI conversion to AD. Subjects received a baseline diagnostic examination that included FDG-PET, MRI and memory tests. FDG-PET scans were coregistered with MRIs and CMRglu was obtained from four subregions of the temporal lobe, the supramarginal gyrus, two subregions of the frontal lobe, the posterior cingulate gyrus and the pons. Compared to the normal control group, the MCI group that converted to AD showed, after scan normalization, widespread metabolic reductions in the hippocampal formation and the temporo-parietal area (>20 percent). Significant reductions in immediate and delayed memory performance were also noted. There were no significant CMRglu or cognitive differences between the MCI group that remained stable at follow-up and the normal control group. Both CMRglu and memory performance predicted conversion to AD. De Leon also reported that entorhinal cortex changes in normal elderly predict the hippocampal and memory changes characteristic of MCI. Hippocampal changes in MCI predict neocortical changes and the clinical diagnosis of AD. Thus, these data indicate that over four years, conversion from MCI (as defined in the de Leon studies) to AD is not inevitable, and that it is possible to predict who may remain stable.

There were also isolated reports of other measures with potential for predicting conversion from MCI to AD. Olichney et al. reported on a positive event-related potential that peaked at 600 ms in response to a word repetition paradigm. Analyses, comparing MCI cases to normals showed that whereas normals and nonconverters showed a reduction of evoked response with repetition, converters did not show this reduction. These authors suggest that, albeit based on a small sample, differences between MCI convertors and nonconvertors indicate that this evoked response measure may be particularly sensitive to early AD pathology. In a separate study Blennow et al. found increased CSF-tau and decreased CSF-Aβ42 levels in MCI patients, to be predictive of conversion to AD with a sensitivity of 88 percent, and a specificity of 80 percent. These data are in stark contrast to the data of Blomberg et al. reported above in which substantial overlap between AD and MCI was observed in these CSF markers.

Although not directly related to MCI, Coleman et al. reported that levels of synaptophysin message in single postmortem neurons declined progressively with immunohistochemical markers of disease state. These data suggest that a longitudinal PET study of a synaptic marker may reveal a quantitative indicator of probability of conversion from MCI to AD.

Neuropathology of MCI:
The neuropathological status of persons with MCI extended over a wide range of involvement when using traditional indices of plaques and neurofibrillary tangles. Joseph Parisi presented neuropathological data from nine brains of persons who had been classified as MCI at the Mayo Clinic, Rochester, Minnesota. Although these nine patients had a single diagnosis of MCI, they presented different neuropathological pictures. Several fell in the range of Braak III-V with plaques that were mostly diffused with a few neuritic plaques. Several more of these MCI cases were Braak II-III with no plaques and were considered to have argyrophilic grain disease. Finally, one case had neurofibrillary tangles only in the medial temporal lobe and was classified as having had NFT-only disease. The finding of a range of Braak scores in a set of cases with a similar level of cognitive impairment is consistent with the consensus report on neuropathological diagnosis of AD that gave a probabalistic definition of the relation between Braak stage and dementia. Bennett reported postmortem data on 85 persons: 27 with MCI, 37 with no cognitive impairment, and 21 with AD. A global measure of AD pathology was created using the average z-scores for neuritic plaques (NP), diffuse plaques (DP), and neurofibrillary tangles (NFT) from three neocortical regions. AD pathology increased linearly across the three groups but accounted for only 23 percent of the variance. This conclusion is consistent with the Mayo Clinic data reported by Parisi (above). Bennett suggested that both the course of cognitive decline and severity of AD pathology in persons with MCI is intermediate to that of NCI and AD, and that performance on tests of episodic memory may be a better predictor of future decline than global cognitive function.

In summary, MCI represents a clinical definition with variable underlying pathology and a primary hippocampal focus. The rate and the probability of conversion to AD, although statistically predictable in a large enough sample, shows considerable individual variability that is probably reflective of variability in underlying pathology and, perhaps, differing basic neurobiological mechanisms. Thus, the present clinical definition of MCI may represent a variety of underlying mechanisms all leading to the final common path of MCI.—Paul Coleman

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