Abstract
Background
It is unclear whether self or informant-based subjective cognition better distinguishes emotional factors from early stage Alzheimer’s disease (AD).
Methods
447 healthy members of the Arizona Apolipoprotein E (APOE) Cohort and their informants completed both the self and informant paired Multidimensional Assessment of Neurodegenerative Symptoms questionnaire (MANS).
Results
30.6% of members and 26.2% of informants endorsed decline on the MANS. Both self and informant-based decliners had higher scores of psychological distress and slightly lower cognitive scores than nondecliners. Over the next 6.7 years, 20 developed mild cognitive impairment (MCI). Converters were older at entry than nonconverters (63.8[7.0] vs 58.8[7.3] years, p=.003), 85% were APOE e4 carriers (p<.0001), and they self-endorsed decline earlier than informants (58.9[39.2] vs 28.0[40.4] months before MCI; p=.002).
Conclusions
Both self and informant based subjective decline correlated with greater psychological distress, and slightly lower cognitive performance. Those with incident MCI generally self-endorsed decline earlier than informants.
1. Introduction
Subjective cognitive complaints are common, but their clinical significance is not always clear. Stage two of the 1982 Global Deterioration Scale for Primary Degenerative Dementia defines “very mild cognitive decline” as a disease phase in which patients complain of memory loss but have no clinical, psychometric, or functional evidence of decline (1,2). Nonetheless, whether subjective memory complaints represent early stage Alzheimer’s disease (AD) or not has remained highly controversial. Clinical (3) as well as large population-based cross sectional (4) and longitudinal (5) studies have found memory complaints to correlate more closely with psychological factors such as anxiety and depression than with psychometrically objective impairment. More recently, however, a longitudinal study of 2415 German primary care patients age 75 years and older reported greater rates of incident mild cognitive impairment (MCI) and AD at one and three years of followup among those expressing concern about their memory (6). Reisberg et al reported similar results in a cohort of 213 cognitively normal individuals followed for at least 7 years although the baseline characteristics of those with subjective memory complaints revealed them to be older and with lower baseline cognitive performance compared to those without such complaints (7).
By the time individuals with subjective complaints reach a clinical setting, informant reports are often used to validate the patient’s concern, but in the setting of minimal to no objective patient impairment, it is unclear whether the patient or the informant is able to provide the more medically salient history. We therefore sought to compare the responses of individuals and their informants on the Multidimensional Assessment of Neurodegenerative Symptoms questionnaires (MANS) (8), paired self and informant based questionnaires sensitive to the cognitive, behavioral, and movement related problems that are prevalent among patients with early stage AD and related disorders.
2. Methods
2.1 Study participants and enrollment
Cognitively normal residents of Maricopa County age 45–79 years with a family history of dementia were recruited through local media ads into the Arizona APOE cohort, a longitudinal study of cognitive aging (9). Demographic, family, and medical history data were obtained on each individual undergoing APOE genotyping, and identity was coded by a study assistant. All individuals gave their written, informed consent, approved by the Institutional Review Boards of Mayo Clinic and Banner Alzheimer Institute, and agreed to have the results of the APOE test withheld from them as a precondition for their participation in this study. Genetic determination of APOE allelic status was performed using a polymerase chain reaction (PCR) based assay (10).
Screening tests included a medical history, neurologic examination, the Folstein Mini-Mental Status Exam (MMSE; 11), the Hamilton Depression Rating Scale (Ham-D; 12), the Functional Activities Questionnaire (FAQ), Instrumental Activities of Daily Living (IADL), and Structured Psychiatric Interview (13). There were no potentially confounding medical, neurological, or psychiatric problems (such as prior stroke, traumatic brain injury, memory or other form of cognitive impairment, parkinsonism, major depression, or substance abuse). None met the published criteria for MCI (14), AD (15), or any other form of dementia (13), or major depressive disorder (13). On the MMSE, participants had to score at least 27 based on published age and education-based norms (and must have scored at least 1 out of 3 on the recall subtest) (11). On the Ham-D, participants had to score 10 or less (12) at the time of their first visit. All FAQ and IADL questions had to indicate no loss of function.
2.2 Neuropsychological testing
Those fulfilling these requirements were administered an extensive standardized battery of neuropsychological tests that was repeated every two years. The neuropsychological tests within our battery are detailed in reference 16, and encompass four broadly defined cognitive domains. The scores used were as follows:
Memory
Auditory Verbal Learning Test Long Term Memory Score ([LTM], 30 minute delayed recall of a 15 word list, maximum possible is 15); Buschke Free and Cued Selective Reminding Test Total Free (SRT-free) Recall (maximum is 112), Rey-Osterrieth Complex Figure Test Absolute Recall (CFT-recall; maximum possible is 36); the Wechsler Memory Scale-Revised Paragraph Recall (one story, total 30 minute delayed recall); and the Benton Visual Retention Test total number correct (VRT; maximum possible is 10).
Executive
Wisconsin Card Sorting Test Total Errors (WCST-errors; lower scores are better), Paced Auditory Serial Attention Task 3 and 2 second versions total correct (PASAT-3, PASAT-2; mental arithmetic tests in which problems are presented 3 and 2 seconds apart; maximum possible for each is 60); Controlled Oral Word Association Test total words (COWAT; word generation over one minute for each of three letters; no upper limit, higher is better); Category fluency task (total vegetables named in one minute); Trail Making Test parts A (easier) and B (more difficult) total time to connect the alternating numbers and letters; and Age Scaled Scores (a score of 10 is 50th percentile) of the Wechsler Adult Intelligence Scale-Revised (WAIS-R) subtests including Digit Span (DigSp), Mental Arithmetic (WAIS-arithmetic), and Digit Symbol Substitution Age Scaled Score (DSS).
Language
Boston Naming Test (BNT; 60 item), and Token Test total correct (maximum is 44).
Visuospatial
Judgment of Line Orientation total correct (JLO; maximum is 30), Facial Recognition Test Short Form corrected long form score (FRT; 27 matches), WAIS-R Block Design Age Scaled Score (BD), and the CFT copy score (maximum score is 36).
2.3 Behavioral Testing
As noted above, the Ham-D is an examiner-based depression measure (12) used to screen out those with potentially clinically significant depression. Participants also complete the Beck Depression Inventory (17), a generally applicable self-scored depression measure, and Geriatric Depression Scale (18), most appropriate for older age groups. Finally, participants completed the Personality Assessment Inventory (19) which surveys a wide variety of behavioral domains including somatization and anxiety in addition to depression (scores are reported as T-scores).
2.4 Subjective cognitive assessment
All participants and their informants (typically a spouse) completed the paired the Multidimensional Assessment of Neurodegenerative Symptoms questionnaires (MANS) (9). The MANS are paired self and informant based questionnaires comprised of 87 questions that assess changes over the preceding year in daily habits, personality, and motor functioning. It employs a quantitative scale for rating the frequency of a symptom from zero (never) to four (routinely), with intermediate values of one (once), two (occasionally), and three (more than monthly); scores can range from 0–348 with higher scores indicating more frequent and severe symptoms. Any score greater than zero was considered “positive” for endorsed decline on both the MANS-self and MANS-informant questionnaire.
2.5 Statistical analysis
Statistical analyses were performed using computer software SPSS (IBM). Categorical variables (sex ratio and APOE genotype) were examined using the Fisher-exact test, group differences on continuous measures were examined using parametric two-sample independent t-tests, or Mann-Whitney U tests for data that were not normally distributed, defined by MANS-self or MANS-informant being equal to, or greater than, zero. Conversion ratios between the MANS=0 and the MANS>0 groups were compared using chi square. Significance of p=0.05, two-tailed, was used for all analyses. Bonferroni correction was used to adjust for multiple comparisons separately within the behavioral and cognitive categories of results.
2.6 Clinical conversion
Participants were all normal at entry but those who subsequently developed symptomatic cognitive impairment underwent a standard clinical assessment that included a neurological examination with mental status testing, neuropsychological assessment (if not already completed within 6 months of the complaint), brain imaging (CT or MRI), and standard blood tests to exclude common mimics and potentially reversible causes. MCI was diagnosed according to the modified Petersen Criteria adopted by the American Academy of Neurology (14), and Alzheimer’s disease according to 1984 NINCDS/ADRDA criteria (15).
3. Results
Of 2482 individuals who underwent APOE genotyping, 704 completed at least one epoch of neuropsychological testing. Of these, 588 completed the MANS-informant, 572 completed the MANS-self, and 447 completed both the self and informant versions of the MANS and so were included in this analysis. Demographic data are summarized in table 1. Mean age was 59.0 (7.4), education 15.6 (2.4) years, and MMSE score 29.6 (.7). 69% were women, and 40% were APOE e4 carriers. In the MANS-self analysis, there was no difference in age, gender, or e4 carrier proportion between those with scores of zero or greater than zero. In the MANS-informant analysis, however, those with MANS-informant scores greater than zero were older (p=.031), with a higher proportion of e4 carriers (p=.049, Fisher exact test), and less female predominance (p=.001, Fisher exact test). Family history of a first degree relative with dementia was present in 71.8% of the sample. This did not differ by MANS-self response (p=.64, Fisher exact test), but was slightly higher among those whose informant did not report decline (73.9 vs 63.4%, p=.04). 310 scored zero on the MANS-self (no change within the past year) and 137 scored above zero (indicative of some change within the past year). Of those scoring above zero, the mean score was 36.1 (32.4). For both self and informant responses, 85% related to cognitive concerns, 9% to behavioral, and 6% to movement. The most common self-endorsed concerns included losing/misplacing objects and forgetting names; informants reported misplacing/losing items, personality changes, and forgetting events and appointments.
Table 1.
Demographics
| Self = 0 | Self > 0 | p* | Informant = 0 | Informant > 0 | p* | |
|---|---|---|---|---|---|---|
| N | 310 | 137 | 330 | 117 | ||
| Age | 58.7 (6.9) | 59.8 (8.3) | 0.15 | 58.6 (7.0) | 60.3 (8.3) | 0.031 |
| Education | 15.7 (2.4) | 15.5 (2.6) | 0.6 | 15.7 (2.4) | 15.4 (2.5) | 0.16 |
| Female (%) | 219 (70.8%) | 93 (68.1%) | 0.58 | 242 (73.3%) | 66 (56.4%) | 0.0011 |
| APOE e4+ (%) | 136 (43.8%) | 53 (38.4%) | 0.3 | 123 (37.3%) | 56 (47.9%) | 0.049 |
| MMSE | 29.7 (.6) | 29.4 (.8) | <.0001 | 29.6 (.7) | 29.6 (.7) | 0.24 |
| MANS-Self | 0 | 36.1 (32.4) | <.0001 | 6.3 (17.1) | 24.6 (35.0) | <.0001 |
| MANS-Informant | 4.7 (13.0) | 15.0 (28.0) | <.0001 | 0 | 30.0 (28.1) | <.0001 |
unpaired t-tests used to compare groups for continuous data (except for the MMSE, Mann-Whitney U-test) and Fisher’s exact test for categorical data. All p values are two-tailed.
APOE=Apolipoprotein E; MMSE=Mini-mental Status Exam; MANS=Multidimensional Assessment of Neurodegenerative Symptoms
Table 2 shows the results of the cognitive and behavioral tests in the MANS = 0 and MANS > 0 subgroups for both the self-rated and the informant-rated questionnaires. Although all scores are well within normal limits (and many in the superior range), those whose MANS-self scores were greater than zero performed slightly but significantly less well on the MMSE, VRT, WAIS-arithmetic, WCST-errors, and CFT-copy, but after Bonferroni correction, only the MMSE and WAIS-R mental arithmetic differences remained significant. Those whose MANS-informant scores were greater than zero performed less well on CFT-recall, logical memory, WCST-errors, and CFT-copy, but after Bonferrini correction only the CFT recall difference remained significant. Table 2 also shows the results of the behavioral measures. Again, all scores were well within normal ranges. Nonetheless, all four of the four depression measures (Ham-D, Beck, GDS, and PAI-Depression) were significantly higher in the Self > 0 subgroup as were measures of anxiety (PAI-Anxiety), stress (PAI-Stress), and somatization (PAI-Somatization), and all remained significant after Bonferroni correction. Informant based differences were nearly identical on the behavioral measures, and all except the Ham-D and PAI-SOM remained significant after Bonferroni correction.
Table 2.
Psychometric Data
| Self = 0 | Self > 0 | p* | Informant = 0 | Informant > 0 | p* | |
|---|---|---|---|---|---|---|
| Behavioral Data | ||||||
| Hamilton Depression Scale | 1.9 (2.6) | 3.4 (3.7) | <.0001 | 2.1 (2.8) | 2.9 (3.5) | 0.007 |
| Beck Depression Inventory | 3.1 (3.3) | 6.3 (5.1) | <.0001 | 3.7 (4.0) | 5.2 (4.6) | 0.0004 |
| Geriatric Depression Scale | 2.1 (2.6) | 4.4 (4.7) | <.0001 | 2.3 (3.0) | 4.0 (4.5) | <.0001 |
| PAI-Somatization | 45.8 (5.7) | 49.7 (9.6) | <.0001 | 46.5 (6.7) | 48.4 (8.6) | 0.04 |
| PAI-Anxiety | 44.5 (5.7) | 47.2 (7.4) | .0002 | 44.8 (6.0) | 46.7 (7.1) | 0.008 |
| PAI-Depression | 45.0 (6.7) | 48.6 (8.7) | <.0001 | 45.4 (7.4) | 48.4 (7.7) | <.0001 |
| PAI-Stress | 43.4 (6.2) | 46.5 (9.4) | <.0001 | 43.4 (6.2) | 46.5 (10.0) | 0.0006 |
| Cognitive Data | ||||||
| MMSE | 29.7 (.6) | 29.4 (.8) | <.0001 | 29.6 (.7) | 29.6 (.7) | 0.24 |
| AVLT-LTM | 9.2 (3.4) | 9.2 (3.0) | 0.97 | 9.4 (3.4) | 8.7 (3.0) | 0.063 |
| SRT-total free | 87.1 (11.9) | 87.8 (10.9) | 0.72 | 87.8 (11.7) | 85.8 (11.2) | 0.09 |
| CFT-recall | 18.2 (6.6) | 17.7 (5.8) | 0.43 | 18.6 (6.4) | 16.5 (6.1) | 0.0018 |
| Visual Retention Test | 6.9 (1.9) | 6.5 (1.9) | 0.03 | 6.9 (1.9) | 6.5 (2.0) | 0.1 |
| WMS logical memory delay | 12.7 (4.0) | 12.0 (3.8) | 0.13 | 12.9 (3.8) | 11.6 (4.2) | 0.0091 |
| COWA | 45.7 (11.1) | 44.6 (10.2) | 0.46 | 45.9 (10.8) | 43.8 (10.8) | 0.06 |
| Categories-vegetables | 15.5 (4.3) | 14.9 (4.3) | 0.17 | 15.5 (4.1) | 14.9 (4.9) | 0.09 |
| PASAT-3 second | 45.8 (11.9) | 42.9 (13.8) | 0.054 | 45.6 (12.2) | 43.0 (13.2) | 0.059 |
| PASAT-2 second | 34.3 (11.4) | 32.1 (12.2) | 0.066 | 33.8 (11.9) | 33.2 (11.0) | 0.69 |
| WAIS-arithmetic | 11.9 (2.5) | 10.9 (2.7) | 0.0002 | 11.7 (2.6) | 11.3 (2.7) | 0.09 |
| WAIS-digit span | 11.3 (2.8) | 10.5 (2.6) | 0.005 | 11.3 (2.7) | 10.7 (2.8) | 0.17 |
| WAIS-DSS | 12.6 (2.1) | 12.4 (2.2) | 0.57 | 12.7 (2.0) | 12.2 (2.2) | 0.14 |
| WCST-errors | 29.3 (19.5) | 33.2 (19.6) | 0.015 | 29.4 (19.1) | 33.6 (20.7) | 0.045 |
| TMT-A seconds | 28.0 (9.0) | 29.2 (10.6) | 0.54 | 27.9 (9.5) | 29.6 (9.5) | 0.051 |
| TMT-B seconds | 71.0 (27.9) | 76.7 (36.6) | 0.38 | 71.2 (28.8) | 76.7 (35.3) | 0.27 |
| Boston Naming Test | 56.2 (3.5) | 55.9 (3.1) | 0.075 | 56.3 (3.3) | 55.6 (3.7) | 0.078 |
| Token | 42.9 (2.0) | 42.6 (2.1) | 0.071 | 42.9 (1.9) | 42.7 (2.3) | 0.44 |
| Judgment of Line Orientation | 24.9 (3.6) | 24.7 (3.8) | 0.79 | 24.8 (3.7) | 25.0 (3.7) | 0.47 |
| Facial Recognition Test | 46.7 (4.0) | 46.3 (3.5) | 0.15 | 46.6 (3.8) | 46.4 (3.8) | 0.57 |
| CFT-copy | 34.4 (2.4) | 34.1 (2.5) | 0.026 | 34.5 (2.3) | 33.8 (2.7) | 0.008 |
| WAIS-Block Design | 12.1 (2.6) | 11.8 (2.3) | 0.33 | 12.0 (2.5) | 12.0 (2.4) | 0.91 |
Mann-Whitney U tests used to compare groups for continuous data. All p values are two-tailed.
PAI=Personality Assessment Inventory, MMSE=mini-mental state exam, AVLT-LTM=Auditory Verbal Learning Test-Long Term Memory, SRT=Selective Reminding Test, CFT=Complex Figure Test, WMS=Wechsler Memory Scale (revised), COWA=Controlled Oral Word Association Test, PASAT=Paced Auditory Serial Attention Task, WAIS=Wechsler Adult Intelligence Scale (revised), DSS=Digit Symbol Substitution, WCST=Wisconsin Card Sorting Task, TMT=Trail Making Test
Overall followup duration for the cohort was 80.8 (57.4) months over which time, 20 members subsequently met criteria for MCI (mean age at conversion 71.5 [6.6] years). For the MANS-self, 6.9% of those endorsing decline converted while 2.6% of those not endorsing decline did so (O.R. 2.78, p<.05). Similarly, for the MANS-informant, conversion rates for those endorsing or not endorsing decline were 9.4% and 2.2% respectively (O.R. 4.58, p<.05). Those who developed MCI were older at entry than nonconverters (63.8 [7.0] vs 58.8 [7.3] years, p=.003), with a higher proportion of APOE e4 carriers 85% vs 38.2%, p<.0001, Fisher’s exact test) and male gender (55% vs 30%, p=.03, Fisher’s exact test), and they performed less well on multiple memory measures (table 3). Entry MANS-self scores, but not informant scores were slightly higher in MCI converters (p=.034). Self endorsement of decline preceded informant in 11, coincided in eight, and trailed in one. Overall members self-endorsed decline earlier than their informants (58.9[39.2] vs 28.0[40.4] months before MCI; p=.002).
Table 3.
Incident Mild Cognitive Impairment
| Incident MCI (Entry Data) | Nonconverters (Entry Data) | p* | |
|---|---|---|---|
| Demographics | |||
| N | 20 | 427 | |
| Age | 63.8 (7.0) | 58.8 (7.3) | 0.003 |
| Education years | 15.4 (1.7) | 15.6 (2.4) | 0.67 |
| Female (%) | 9 (45%) | 299 (70%) | 0.03 |
| APOE e4 carriers (%) | 17 (85%) | 163 (38.2%) | <0.0001 |
| MANS-Self | 21.8 (34.9) | 10.7 (24.0) | 0.034 |
| MANS-Informant | 15.9 (33.1) | 7.5 (18.8) | 0.39 |
| Behavioral Data | |||
| Hamilton Depression Scale | 3.0 (3.4) | 2.3 (3.0) | 0.36 |
| Beck Depression Inventory | 3.8 (3.5) | 4.1 (4.2) | 0.95 |
| Geriatric Depression Scale | 4.9 (4.0) | 2.7 (3.5) | 0.0079 |
| PAI-Somatization | 46.5 (5.7) | 47.0 (7.4) | 0.95 |
| PAI-Anxiety | 45.3 (5.8) | 45.3 (6.4) | 0.94 |
| PAI-Depression | 46.1 (6.5) | 46.1 (7.6) | 0.43 |
| PAI-Stress | 45.9 (6.2) | 44.3 (7.6) | 0.14 |
| Cognitive Data | |||
| MMSE | 29.4 (.8) | 29.6 (.7) | 0.14 |
| AVLT-LTM | 6.8 (2.6) | 9.3 (3.3) | 0.0007 |
| SRT-total free | 77.7 (12.6) | 87.7 (11.3) | 0.0005 |
| CFT-recall | 16.0 (5.9) | 18.1 (6.4) | 0.11 |
| Visual Retention Test | 5.5 (1.9) | 6.9 (1.9) | 0.002 |
| WMS logical memory delay | 8.2 (5.0) | 12.7 (3.8) | .0003 |
| COWA | 43.5 (9.1) | 45.4 (10.9) | 0.56 |
| Categories-vegetables | 10.8 (3.4) | 15.5 (4.2) | <.0001 |
| PASAT-3 second | 39.5 (18.4) | 45.2 (12.1) | 0.19 |
| PASAT-2 second | 30.1 (15.5) | 33.8 (11.5) | 0.51 |
| WAIS-arithmetic | 11.8 (2.4) | 11.6 (2.6) | 0.67 |
| WAIS-digit span | 11.9 (2.5) | 11.0 (2.8) | 0.14 |
| WAIS-DSS | 12.0 (2.0) | 12.6 (2.1) | 0.22 |
| WCST-errors | 36.6 (19.2) | 30.2 (19.6) | 0.1 |
| TMT-A seconds | 34.3 (10.5) | 28.1 (9.4) | 0.012 |
| TMT-B seconds | 107.4 (47.8) | 71.2 (28.9) | .0013 |
| Boston Naming Test | 55.7 (3.6) | 56.1 (3.4) | 0.65 |
| Token | 43.2 (1.5) | 42.8 (2.0) | 0.69 |
| Judgment of Line Orientation | 24.7 (3.5) | 24.8 (3.7) | 0.8 |
| Facial Recognition Test | 44.6 (3.5)) | 46.6 (3.8) | 0.017 |
| CFT-copy | 32.7 (4.1) | 34.4 (2.3) | 0.063 |
| WAIS-Block Design | 11.7 (2.2) | 12.0 (2.5) | 0.52 |
unpaired t-tests used to compare groups for continuous demographic data and Mann-Whitney U tests for neuropsychological and behavioral data; Fisher’s exact test was used for categorical data. All p values are two-tailed.
PAI=Personality Assessment Inventory, MMSE=mini-mental state exam, AVLT-LTM=Auditory Verbal Learning Test-Long Term Memory, SRT=Selective Reminding Test, CFT=Complex Figure Test, WMS=Wechsler Memory Scale (revised), COWA=Controlled Oral Word Association Test, PASAT=Paced Auditory Serial Attention Task, WAIS=Wechsler Adult Intelligence Scale (revised), DSS=Digit Symbol Substitution, WCST=Wisconsin Card Sorting Task, TMT=Trail Making Test
4. Discussion
In our cohort overall, we found that both self and informant-reported decline correlated with greater psychological distress and mildly lower cognitive performance. Incident MCI converters, however, had higher MANS-self (but not informant) scores and performed worse than nonconverters on memory measures at entry, but not on behavioral measures. These results are generally consistent with previous research. We were also able to compare self and informant endorsed decline showing that both correlated with psychological measures of stress. Self-rated decline on average preceded informant-rated decline among those who developed MCI, but informant rated decline seemed more highly predictive of subsequent conversion in our small sample of converters.
The association of self reported cognitive decline with psychological distress, especially depression, anxiety, and somatization (3–5), has led many to question the clinical relevance of subjective cognition to AD or other neurodegenerative dementias. However, evidence supporting its biological validity is accruing. Several recent cohort studies have shown that subjective decline implies an increased risk of subsequent clinical conversion (6,7), but not all (20). While MRI studies of individuals with subjective memory loss have yielded mixed results (4,21) a recent PiB-PET study compared cognitively normal older adults with higher and lower measurements of cerebral amyloid deposition. Those with more amyloid deposition had the subjective impression of lower memory performance, as well as lower memory scores (22).
In addition to having higher scores on measures of psychological distress, those endorsing subjective decline had slightly but significantly lower scores on some cognitive measures. Informant-based impressions of decline correlated with a similar pattern. In prior studies, declarative memory measures (such as word list retention) have proven to be sensitive to preclinical decline (9), while mental arithmetic tests also declined but much less robustly than memory (23).
The following limitations should be kept in mind when considering the results of our study. First, our results represent those of a group, and despite a small subset with incident MCI, most of those endorsing subjective decline did not develop evidence of objective decline or receive a clinical diagnosis over an average of more than six years of followup. Therefore, one should not infer that everyone with subjective memory complaints necessarily has preclinical AD. Second, because our cohort contains a high proportion of APOE e4 carriers subjective complaints were more likely to indicate early stage AD than would be true in a community-based cohort. On the other hand, ours is also a relatively young cohort and it is possible that subjective decline may have greater significance in older individuals. Finally, the relative lack of correlation between informant-reported decline and incident MCI in this study does not imply that informants are unreliable. Our incident MCI subset was small, and in roughly half the cases, informant reports correlated with subjective reports. Rather, our data suggest that individuals can become self-aware of change before observers detect any signs of decline. Further comparison of self-and informant reports in a larger incident MCI cohort is needed to address this question further.
In summary, subjective decline, whether self or informant-based, can be an early harbinger of objective cognitive decline, but its association with psychological distress makes it clinically challenging to interpret.
Research in Context.
Systematic Review. We searched PubMed with the terms “subjective cognition,” “preclinical Alzheimer’s disease”, “cognitive aging”, “age associated memory impairment”, “mild cognitive impairment”, “apolipoprotein E and cognition” and “global deterioration scale” and searched for studies correlating subjective cognitive concerns in neuropsychologically unimpaired individuals with psychological and cognitive outcomes. We identified several clinical3–7, neuropsychology1–7 and imaging biomarker17,18 studies of particular relevance.
Interpretation. The results of our study show that there is considerable overlap between self and informant based subjective decline and that both correlate not only with measures of psychological distress but also with cognitive measures sensitive to emotionally sensitive executive skills. We also were able, for the first time, to correlate both self and informant reports with clinical outcomes and found that self-reported decline preceded informant-observed decline in roughly half our case and coincided in the other half (with informant reported decline preceding self-reported decline in only a single case). Our findings support both sides of the current argument that subjective decline is indeed highly correlated with psychological distress but that it also seems to contain a clinically relevant signal in some cases making it a potential sign of preclinical Alzheimer’s disease/impending MCI.
Future Directions. Continued followup of our cohort with a larger number of incident MCI and dementia cases, as well as further correlation with AD biomarkers will allow us to better identify those factors that most reliably distinguish a true “biological signal” from “psychological noise” among patients with subjective cognitive complaints in the absence of objective cognitive impairment.
Acknowledgments
Funding support from NIA R01AG031581, NIA P30AG19610, and the Arizona Alzheimer’s Consortium. The authors wish to thank Bruce Henslin, Sandra Yee-Benedetto, Travis Johnson, Marci Zomok, Jessie Jacobsen, Jeanne Young, Jennifer Pichon, Lynn Autry, Allyson Jensen, and Andrea Fowler for expert technical support.
Footnotes
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References
- 1.Reisberg B, Ferris SH, De Leon MJ, Crook T. The global deterioration scale for assessment of primary degenerative dementia. Am J Psychiatry. 1982;139:1136–1139. doi: 10.1176/ajp.139.9.1136. [DOI] [PubMed] [Google Scholar]
- 2.Gauthier S, Reisberg B, Zaudig M, et al. Mild cognitive impairment. Lancet. 2006;367:1262–1270. doi: 10.1016/S0140-6736(06)68542-5. [DOI] [PubMed] [Google Scholar]
- 3.Derouesne C, Lacomplez L, Thibault S, LePoncin M. Memory complaints in young and elderly subjects. Int J Geriatr Psychiat. 1999;14:291–301. [PubMed] [Google Scholar]
- 4.Jorm AF, Butterworth P, Anstey KJ, et al. Memory complaints in a community sample aged 60–64 years: associations with cognitive functioning, psychiatric symptoms, APOE genotype, hippocampus and amygdale volumes, and white matter hyperintensities. Psychol Med. 2004;34:1495–1506. doi: 10.1017/s0033291704003162. [DOI] [PubMed] [Google Scholar]
- 5.Comijs HC, Deeg DJH, Dik MG, Twisk JWR, Jonker C. Memory complaints; the association with psych-affective and health problems and the role of personality characteristics. A 6 year follow-up study. J Affect Disord. 2002;72:157–165. doi: 10.1016/s0165-0327(01)00453-0. [DOI] [PubMed] [Google Scholar]
- 6.Jessen F, Wiese B, Bachman C, et al. Prediction of dementia by subjective memory impairment: effects of severity and temporal association with cognitive impairment. Arch Gen Psychiat. 2010;67:414–422. doi: 10.1001/archgenpsychiatry.2010.30. [DOI] [PubMed] [Google Scholar]
- 7.Reisberg B, Shulman MB, Torossian C, Leng L, Zhu W. Outcome over seven years of healthy adults with and without subjective cognitive impairment. Alz Dem. 2010;6:11–24. doi: 10.1016/j.jalz.2009.10.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Locke DE, Dassel KB, Hall G, Baxter LC, Woodruff BK, Hoffman Snyder C, Miller BL, Caselli RJ. Assessment of patient and caregiver experiences of dementia-related symptoms: development of the Multidimensional Assessment of Neurodegenerative Symptoms questionnaire. Dement Geriatr Cogn Disord. 2009;27:260–72. doi: 10.1159/000203890. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Caselli RJ, Dueck AC, Osborne D, Sabbagh MN, Connor DJ, Ahern GL, Baxter LC, Rapcsak SZ, Shi J, Woodruff BK, Locke DE, Snyder CH, Alexander GE, Rademakers R, Reiman EM. Longitudinal modeling of age-related memory decline and the APOE epsilon4 effect. N Engl J Med. 2009;361:255–63. doi: 10.1056/NEJMoa0809437. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Crook R, Hardy J, Duff K. Single-day apolipoprotein E genotyping. J Neurosci Methods. 1994;53:125–127. doi: 10.1016/0165-0270(94)90168-6. [DOI] [PubMed] [Google Scholar]
- 11.Crum RM, Anthony JC, Bassett SS, Folstein MF. Population-based norms for the mini-mental satae examination by age and education level. JAMA. 1993;269:2386–2391. [PubMed] [Google Scholar]
- 12.Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56–62. doi: 10.1136/jnnp.23.1.56. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4. Washington D.C: American Psychiatric Association; 1994. [Google Scholar]
- 14.Petersen RC, Stevens JC, Ganguli M, Tangalos EG, Cummings JL, DeKosky ST. Practice parameter: early detection of dementia: mild cognitive impairment (an evidence-based review) Report of the Quality Standards Subcommittee of the American Academy of Neurology Neurology. 2001;56:1133–1142. doi: 10.1212/wnl.56.9.1133. [DOI] [PubMed] [Google Scholar]
- 15.McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS/ADRDA work group under the auspices of Department of Health and Human Services task force on Alzheimer’s disease. Neurol. 1984;34:939–944. doi: 10.1212/wnl.34.7.939. [DOI] [PubMed] [Google Scholar]
- 16.Lezak MD, Howieson DB, Loring DW. Neuropsychological Assessment. 4. Oxford University Press; New York: 2004. [Google Scholar]
- 17.Beck AT, Steer RA, Brown GK. Manual for the Beck Depression Inventory-II. San Antonio, TX: Psychological Corporation; 1996. [Google Scholar]
- 18.Yesavage JA, Brink TL, Rose TL, et al. Development and validation of a geriatric depression screening scale: a preliminary report. J Psychiatr Res. 1982–83;17(1):37–49. doi: 10.1016/0022-3956(82)90033-4. [DOI] [PubMed] [Google Scholar]
- 19.Morey L. Personality Assessment Inventory: professional manual. Lutz, FL: Psychological Assessment Resources; 1991. [Google Scholar]
- 20.Mol MEM, van Boxtel MPJ, Willems D, Jolles J. Do subjective memory complaints predict cognitive dysfunction over time? A six-year follow-up of the Maastricht Aging Study. Int J Geriatr Psychiatry. 2006;21:432–441. doi: 10.1002/gps.1487. [DOI] [PubMed] [Google Scholar]
- 21.deGroot JC, de Leeuw FE, Oudkerk M, Hofman A, Jolles J, Breteler MMB. Cerebral white matter lesions and subjective cognitive dysfunction: the Rotterdam scan study. Neurology. 2001;56:1539–1545. doi: 10.1212/wnl.56.11.1539. [DOI] [PubMed] [Google Scholar]
- 22.Perrotin A, Mormino EC, Madison CM, Hayenga AO, Jagust WJ. Subjective cognition and amyloid deposition imagine. Arch Neurol. 2012;69:223–229. doi: 10.1001/archneurol.2011.666. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Caselli RJ, Dueck AC, Locke DE, Hoffman-Snyder CR, Woodruff BK, Rapcsak SZ, Reiman EM. Longitudinal modeling of frontal cognition in APOE epsilon4 homozygotes, heterozygotes, and noncarriers. Neurology. 2011;76:1383–8. doi: 10.1212/WNL.0b013e3182167147. [DOI] [PMC free article] [PubMed] [Google Scholar]