We applied the Petersen criteria for MCI to a population that is destined to develop AD in the future. We employed two different neuropsychological test batteries and found diverse relative prevalences of MCI subtypes. In Group 1, using a composite score in which only 1 of 3 tests had a delayed recall component, no subjects met criteria for single domain amnestic MCI though 3 subjects met criteria for multiple domain amnestic MCI. When this single test was used as the verbal memory measure, 3 subjects met criteria for single domain amnestic MCI out of a total of 17 subjects with MCI. The results of MCI classification in Group 2 were more in-line with what is reported in sporadic AD with 5 of 7 subjects with MCI having memory impairment and 3 of these having single domain amnestic MCI. We feel that the sensitivity of MCI classification to differences in the methods used to quantitate cognition demonstrated in this example highlights a weakness of a classification scheme based largely on neuropsychological test scores.
An alternative explanation to our findings of disproportionate Executive Function/Working Memory Deficits in Group 1 is that persons with FAD experience deficits in this domain to a greater extent than occurs in preclinical sporadic AD. PSEN1
pedigrees in which disproportionate frontal lobe dysfunction occurs have been reported [41
], and we have found that Wisconsin Card Sorting Performance is impaired during the preclinical phase of the illness [42
]. However, group studies in which scores on neuropsychological batteries are compared between mutation carriers and non-carriers do not consistently show disproportionate frontal lobe dysfunction [43
]. When comparing the 30 mutation carriers in our study to 21 non-carriers, mean time to complete the Trails Making Test Part B was greatly prolonged in the non-demented mutation carriers [10
] and this score contributed significantly to the Executive Function/Working Memory composite score. However, frontal lobe function measured using the interference scores on the Stroop and Color Trails tests was not consistently impaired in Group 2, again reinforcing the sensitivity of the MCI classification scheme to specific attributes of the tests and scoring systems employed.
In this population known to be at risk for genetic alterations causing FAD, 43% of non-mutation carriers in Group 2 thought they had cognitive deficits compared to 57% of carriers. Subjective cognitive loss therefore does not appear to be helpful in predicting who will and who will not go on to develop young-onset AD in these families. It is likely that this high rate of cognitive complaints is due in part to anxiety on the part of study participants with regard to their own genetic status and therefore may not apply to the general population presenting to memory clinics. However, it has been shown that subjective cognitive complaints in persons presenting to such tertiary centers are closely related to depression and anxiety and may or may not reflect incipient neurodegenerative disease [26
]. In our population, informant report of cognitive decline was more helpful as it was present in 41% of carriers but only 7% of non-carriers. Many, but not all (5/7) persons with a subtype of MCI had cognitive complaints from either the subject or informant with complaints being present in both the informant and subject in four of the seven. This indicates that in addition to lacking specificity for those with early AD, the sensitivity of such complaints to early disease is less than optimal.
In the Dubois criteria, the requirement for an episodic memory deficit for the diagnosis of probable AD is retained. Though early memory dysfunction is typical of AD, such a deficit is not always the presenting feature. In addition to our data that suggest executive function can be affected early, many other exceptions occur [44
] in that visuospatial deficits (posterior cortical atrophy or PCA [45
]), language deficits (primary progressive aphasia, or PPA [46
]), or even asymmetric motor deficits (akin to those of corticobasal degeneration [47
]) can initially dominate the clinical picture. We anticipate that further refinement of our knowledge regarding biological markers more directly reflecting AD pathology than the cognitive features may obviate the requirement for an episodic memory deficit in the diagnosis of probable AD.
There are multiple limitations to our study that warrant mention. Eighteen subjects were common to Groups 1 and 2 so the two “sub-studies” described here are not completely independent. However, testing was performed at least two years apart and distinct neuropsychological measures were used to define MCI and its subtypes for the two groups. There are additional difficulties with regard to comparing the groups. Group 1 consisted entirely of Mexican nationals living in Mexico tested with an unvalidated battery consisting of English-language measures translated into Spanish. Group 2 was more mixed, consisting of both highly acculturated Mexican-Americans and Mexican nationals of variable educational levels. It is therefore possible that some of the discrepancies seen between groups in MCI subtypes are related to these differences.
A further weakness of our study is that in Group 1, objective evaluations from an unrelated informant were not systematically sought. Therefore, in some cases, our assessment of demented vs. non-demented status relied on subjects' own accounts. As such subjective reports in persons with incipient dementia are not always accurate, there is the possibility that some persons qualifying as mildly demented were included in Group 1.
Another important weakness of our study that we believe reflects weakness inherent in the psychometrically-defined MCI classification scheme is that there can be disagreement as to what tests most accurately reflect a cognitive construct or domain. In our study of Group 1, the tests that constituted the cognitive domains were chosen to be consistent with our previous publication [10
] and may not have been optimal. For example, the inclusion of immediate recall of the Rey-O Figure (which clearly has a memory component) in the Visuospatial domain and tests of verbal fluency (which has an executive component) in the Language domain may have served to dilute differences between domains. However, lacking a “gold standard” of what constitutes a cognitive domain, we feel that no such constructs will be completely without detractors and therefore it is difficult to standardize the current criteria for MCI across clinicians and across centers.
The Dubois criteria represent an important step towards refining our ability to diagnose AD earlier in its course. As the markers proposed in the Dubois criteria are incompletely validated and many other potential modalities exist (e.g. putative amyloid and tau ligands like PIB [48
] and FDDNP [49
]), the authors expect that these criteria will be specified and modified in the future. Though there are some clinical, biochemical, and pathological differences between FAD and sporadic AD of later onset, the similarities are strong enough to support the utility of FAD mutation carriers as a model for presymptomatic AD. The continued study of persons at-risk for FAD will augment our ability to refine the diagnosis of AD in the earliest, presymptomatic stages.
Our data from this population demonstrate the sensitivity of current concepts of MCI to the neuropsychological battery employed and how scores are used to define it. In addition, our data confirm the observation that informant-based cognitive complaints are more predictive of the future development of AD than are such complaints provided by patients and that perhaps the importance of such subjective complaints should be de-emphasized in future criteria defining early AD.