Abstract
Objectives:
Although dementia is typically considered a disease of cognitive decline, almost all patients present with neuropsychiatric symptoms (NPS) at some stage of their disease. Few studies have assessed the timing of NPS onset in relation to pathological diagnoses of neurodegenerative diseases. We sought to examine the association between the first presenting clinically significant NPS in aging individuals and neuropathological diagnoses of memory disorders.
Design:
This retrospective longitudinal cohort study utilized the National Alzheimer’s Coordinating Center (NACC) dataset, which includes participant data from 37 Alzheimer’s Disease Research Centers collected between 2005-2022.
Participants:
Participants (N=5416) aged 45 years or older with Clinical Dementia Rating-Global ratings of ≤ 1 were included in this analysis. 4033 (74.5%) participants presented with at least one NPS at any NACC visit.
Measurements:
To measure first NPS, the NACCBEHF variable was used, a clinician-rated variable defined as “the predominant symptom that was first recognized as a decline in the subject’s behavior.” Neuropathologic variables included assessments of Alzheimer’s Disease, Frontotemporal Dementia, Lewy Body Dementia, Cerebral Amyloid Angiopathy, Hippocampal Sclerosis, and Cerebrovascular Disease.
Results:
Presentation with any clinically significant first NPS was associated with several neuropathological diagnoses including Alzheimer’s Disease, Frontotemporal Lobar Dementia with TDP-43 pathology, and Lewy Body Dementia. While specific first NPS were associated with Frontotemporal Dementia neuropathology (personality change and disinhibition) and Lewy Body Dementia neuropathology (psychosis and REM behavior disturbance), Alzheimer’s Disease neuropathology was associated with the majority of NPS.
Conclusions:
Since neuropsychiatric symptoms are frequently the first presenting symptom of dementia, their associations with well-defined neuropathological diagnoses may help clinicians predict the subtype of future dementias.
Keywords: Dementia, neuropsychiatric symptoms, autopsy
Introduction:
Dementia is a leading cause of public health burden for older persons and families worldwide. [1] Although dementia is typically considered a disease of cognitive and functional decline, almost all patients with dementia present with neuropsychiatric symptoms (NPS) at some stage of their disease. [2, 3] NPS are not only associated with poorer cognitive performance across a wide range of cognitive domains but may also increase the risk of progression from normal cognition to mild cognitive impairment (MCI) and from MCI to dementia. [4-7]
Relationships between NPS and neuropathological correlates of memory disorders are just beginning to be explored. Several studies have used autopsy data to identify associations between specific NPS during the clinical course of dementia and Alzheimer’s Disease (AD) and corresponding pathologic correlates. [8-11] For example, Lewy Body Dementia (LBD) pathology has been observed to be associated with hallucinations and sleep disturbances, while AD pathology has been observed to be associated with agitation, depression, and psychosis. [10,12] Furthermore, comorbid AD and LBD pathology has been found to be associated with anxiety and irritability. [10] More broadly, research suggests that more severe neuropathologic evidence of brain aging is associated with an increased number of NPS during life. [13]
Despite increased attention to this topic in recent years, research has tended to focus on neuropathologic findings of AD and LBD, with other dementias such as Frontotemporal Lobar Dementia (FTD) remaining underexplored. Moreover, past studies have been indiscriminate to the timing of NPS onset in relation to other NPS or the onset of MCI and dementia. Given that over half of patients who progress to MCI or dementia develop NPS as a first symptom before diagnosis of their memory disorder9, it is imperative to understand whether there is an association between the first clinically significant NPS noted by a clinician during life and neuropathological correlates of memory disorders. Using data from the National Alzheimer’s Coordinating Center (NACC), this study aims to (1) compare the prevalence of neuropathological diagnoses of memory disorders between aging individuals who do and do not present with clinically significant NPS and (2) examine the association between specific first presenting clinically significant NPS in aging individuals and neuropathological diagnoses.
Methods:
Participants and Study Design
This retrospective longitudinal cohort study utilized participant information from the National Alzheimer’s Coordinating Center (NACC) dataset [14]. Data from 37 past and present Alzheimer’s Disease Research Centers (ADRCs) funded by the National Institute on Aging collected between June 20, 2005, and June 26, 2022, was analyzed. All contributing ADRCs were required to obtain written informed consent from their participants and obtain approval from their institutional review board before submitting data to the NACC.
Participant Assessment and Inclusion Criteria
Participants (N=5416) aged 45 years or older were included in this analysis if they had available NACC neuropathologic data for at least one major study outcome (see Figure 1). AD measures from the NACC neuropathologic dataset show good agreement across centers (average weighted κ =.88). [15] To measure NPS, the NACCBEHF variable was used, a clinician-rated variable defined as “the predominant symptom that was first recognized as a decline in the subject’s behavior.” The first visit at which participants presented with a clinician-defined clinically significant NPS was used to define participants’ “first NPS”, and these participants with ≥ 1 first NPS were included in the “NPS group.” Participants who did not present with clinician-defined clinically significant NPS at any NACC visit were included in the “No NPS group”, and data from their initial clinical visit was utilized. The Clinical Dementia Rating (CDR®) [16] Dementia Staging Instrument was also completed by participants at all clinical visits. The CDR-Global (CDR-G) ratings are determined using a semi-structured interview and algorithm and range from 0 (no dementia) to 3 (severe dementia). A CDR-G score of 1 corresponds to the threshold of early dementia, while a CDR-G of 0.5 generally corresponds to MCI. We excluded participants with a CDR-G score of greater than 1 at their relevant visit (first visit for the No NPS group, visit corresponding to first NPS for the NPS group) to assess participants' NPS earlier in the disease course prior to the development of more severe cognitive decline.
Figure 1.
Eligibility criteria for NACC participants included in this analysis (N=5416). Participants were included if they (1) had data for at least one primary neuropathological outcome variable, (2) were ≥ 45 years of age at their relevant clinical visit, or (3) scored ≤ 1 on the Clinical Dementia Rating-Global (CDR-G) at their relevant clinical visit.
Primary Outcome Variables
Neuropathologic variables included assessments of Alzheimer’s Disease (AD), Frontotemporal Lobar Dementia (FTLD), Lewy Body Dementia (LBD), Cerebral Amyloid Angiopathy (CAA), Hippocampal Sclerosis (HS), and Cerebrovascular Disease. Alzheimer’s Disease pathology was assessed via the NIA-AA AD Neuropathologic Change score (ABC score, NACC variable: NPADNC), which is a composite of three components of AD pathology: amyloid-β deposits (“A” for Amyloid), neurofibrillary degeneration (“B” for Braak stage), and neuritic plaques (“C” for CERAD rating of plaque distribution). The ABC score is rated on a severity scale of 0-3 and is associated with cognitive decline in older adults. [17] To measure FTD Pathology, two dichotomous NACC variables were utilized, NPFTDTAU and NPFTDTDP, which assess for presence of FTLD with Tau Pathology and FTLD with TDP-43 pathology respectively, the two most common pathologic classes of FTLD. [18]
LBD pathology was measured by the NACC variable NACCLEWY, which assesses for the presence of Lewy Bodies in the brainstem, limbic system, neocortex, and other unspecified regions. For the purposes of this analysis, this variable was dichotomized such that identification of LBD pathology in any brain region was coded as a positive diagnosis of LBD. CAA pathology was assessed using the NACC variable, NACCAMY, which is a four-point scale ranging from 0-3 assessing the severity of CAA pathology. HS was assessed using the NACC variable, NPHIPSCL, which measures both the presence and laterality of HS. For the purposes of this analysis, this variable was dichotomized, such that identification of any form of HS (left, right or bilateral) was coded as a positive diagnosis for HS. Finally, cerebrovascular changes relevant to vascular brain disease were assessed using two NACC variables: (1) NACCINF, a dichotomous variable assessing for the presence of infarcts and lacunes and (2) NPHEM, a dichotomous variable assessing for the presence of single or multiple hemorrhages.
Statistical Analysis
Data were collected between June 20, 2005, and June 26, 2022. First, we examined the associations between presentation with any NPS during later life and neuropathologic findings and diagnoses across all participants. The neuropathologic diagnosis and/or finding for each participant was the dependent variable, with age at relevant clinical visit, age at death, sex, educational level, APOE ε4 genotype (number of alleles), and NPS group as the independent variables. All variables were treated as dichotomous (yes/no) except for ABC and CAA severity scores, which were treated as ordinal. Separate analyses were run with ABC and CAA scores transformed to dichotomous variables such that a score of 2 (moderate) or 3 (severe) was coded as a positive diagnosis for AD and CAA, respectively. The No NPS group was used as the reference group and odds ratios were calculated for all outcome variables.
Next, to identify whether specific first NPS during the precedent clinical course were associated with neuropathologic findings and diagnoses, we descriptively compared rates of neuropathological diagnoses between each specific first NPS group, using the No NPS group as a reference group. All hypothesis tests were two-sided and were performed at an overall alpha of 0.05. We used R, version 4.2.1 (R Foundation for Statistical Computing), for all analyses.
Results:
Demographics
Table 1 contains demographic characteristics of participants meeting eligibility criteria. A total of 5416 participants were included in the analysis (2499 women [46.1%] and 2917 men [53.9%]; mean [SD] age, 76.2 [10.9] years). A total of 14 participants (0.3%) were American Indian or Native Hawaiian; 46 (0.9%) Asian; 212 (3.9%) Black; 5110 (94.3%) White; and 10 (0.2%) other/unknown race. The mean [SD] education of all participants was 15.7 [3.0]. The mean [SD] number of NACC visits of all participants was 4.7 [3.0] and the mean [SD] time from relevant visit to autopsy was 5.8 [3.3] years.
Table 1.
Demographic characteristics of NACC participants included in this analysis (N=5416). Continuous variables are presented as mean ± SD while categorical variables are presented as column-based percentages. * p<0.05; ** p<0.01.
| NPS Group (N=4033) |
No NPS Group (N=1383) |
|
|---|---|---|
| NACC Visits (Mean ± SD) | 4.81 ± 3.0** | 4.51 ± 3.2 |
| Visit Age (Mean ± SD, years) | 74.7 ± 11.0** | 80.7 ± 9.1 |
| Age at Death (Mean ± SD, years) | 80.2 ± 10.9** | 87.3 ± 9.2 |
| Education (Mean ± SD, years) | 15.6 ± 3.0 | 15.8 ± 3.0 |
| Sex | ||
| Males, N (%) | 2280 (56.5)** | 637 (46.1) |
| Females, N (%) | 1753 (43.5) | 746 (53.9) |
| Race | ||
| White, N (%) | 3811 (94.5) | 1299 (93.9) |
| Black or African American, N (%) | 149 (3.7) | 63 (4.6) |
| Asian, N (%) | 36 (0.9) | 10 (0.7) |
| Other/Unknown, N (%) | 37 (0.9) | 11 (0.8) |
| Number of APOE-ε4 Alleles | ||
| 0 Alleles, N (%) | 1991 (54.2)** | 916 (71.7) |
| 1 Allele, N (%) | 1363 (37.1) | 325 (25.4) |
| 2 Alleles, N (%) | 320 (8.7) | 37 (2.9) |
Of the 5416 eligible participants, 4033 (74.5%) participants presented with at least one clinically significant NPS at any NACC visit. Clinician-defined first NPS responses (NACCBEHF) showed good concordance with Neuropsychiatric Inventory-Questionnaire (NPI-Q) responses (See Supplementary Table 1). Demographic characteristics of participants in the NPS group (N=4033) and No NPS group (N=1383) are presented in Table 1. Compared to the No NPS group, the NPS group was found to be significantly younger at their relevant clinical visit (T=−20.3, p<0.01), younger at death (T=−23.5, p<0.01), more male (X2 = 45.5, p<0.01) and have a higher number of APOE ε4 alleles (X2=134.9, p<0.01) and number of NACC visits (T=3.1, p<0.01). Groups did not differ in education (T=−1.9, p=0.053) or race (white vs. non-white; X2 = 0.63, p = 0.43). We adjusted for age at relevant clinical visit, sex, education, number of APOE alleles, and age at death in our analyses and confirmed that groups did not differ in their elapsed time between their initial clinical visit and autopsy.
Higher Rates of Neuropathology in Participants with NPS
Table 2 presents the distribution of CDR-G scores at participants’ last NACC visit prior to their death. Presentation with any NPS was associated with higher CDR-G scores at the last NACC visit (T=38.4, p<0.01). Table 3 shows comparisons of neuropathologic findings between the NPS group and No NPS group. We first examined the association between presentation with any NPS and ordinal neuropathological variables. Presentation with any NPS was associated with increased AD pathology (T=10.8, p<0.001) and CAA pathology (T=6.1, p<0.001). Next, we compared the prevalence of dichotomous neuropathological diagnoses between groups. The NPS group had a higher prevalence of FTD with TDP-43 pathology, LBD, and HS than the No NPS group (FTD TDP-43: 8.8% vs. 2.4%; LBD: 37.9% vs. 22.0%; HS: 17.0% vs. 10.4%). Prevalence of FTD with Tau pathology and cerebrovascular disease were similar between the NPS group and the No NPS group (FTD Tau: 18.8% vs. 16.8%; Infarcts and Lacunes: 16.7% vs. 21.6%; Hemorrhages: 2.8 vs. 2.7%).
Table 2.
Comparison of Clinical Dementia Rating-Global (CDR-G) scores at participants’ last NACC visit prior to their death. Variables are presented as column-based percentages. **p<0.01
| CDR-G Score at Last NACC Visit |
NPS Group (N=4033) | No NPS Group (N=1383) |
|---|---|---|
| 0 | 121 (3.0%) | 717 (51.8%) |
| 0.5 | 720 (17.9%) | 418 (30.2%) |
| 1 | 1081 (26.8%) | 158 (11.4%) |
| 2 | 983 (24.4%) | 70 (5.1%) |
| 3 | 1128 (28.0%)** | 20 (1.5%) |
Table 3.
Comparison of neuropathological findings between the NPS group and the No NPS group. All variables are presented as column-based percentages. * p<0.05; ** p<0.01.
| NPS Group (N=4033) |
No NPS Group (N=1383) |
|
|---|---|---|
| Alzheimer's Disease ABC Score | ||
| 0 (Not Alzheimer’s Disease) | 334 (12.9%) | 138 (18.5%) |
| 1 (Mild) | 438 (17.0%) | 221 (29.6%) |
| 2 (Intermediate) | 487 (18.9%) | 232 (31.1%) |
| 3 (High) | 1324 (51.3%)** | 156 (20.9%) |
| Cerebral Amyloid Angiopathy Severity | ||
| 0 (None) | 1551 (39.1%) | 674 (49.6%) |
| 1 (Mild) | 1195 (30.1%) | 382 (28.1%) |
| 2 (Moderate) | 785 (19.8%) | 213 (15.7%) |
| 3 (Severe) | 440 (11.1%)** | 90 (6.6%) |
| Frontotemporal Lobar Dementia | ||
| TDP-43 Pathology | 201 (8.8%)** | 15 (2.4%) |
| Tau Pathology | 492 (18.8%) | 125 (16.8%) |
| Lewy Body Dementia | ||
| Yes | 1521 (37.9%)** | 304 (22.0%) |
| Hippocampal Sclerosis | ||
| Yes | 448 (17.0%)** | 79 (10.4%) |
| Cerebrovascular Disease | ||
| Infarcts and Lacunes | 665 (16.7%) | 296 (21.6%) |
| Single or Multiple Hemorrhages | 73 (2.8%) | 20 (2.7%) |
Odds of receiving neuropathologic diagnoses for the NPS group after dichotomizing ordinal variables and adjusting for relevant covariates were: AD (OR: 2.63, 95% CI: 2.14 – 3.24, p<0.001), FTD Tau (OR: 1.14, 95% CI: 0.89 – 1.46, p=0.35), FTD TDP-43 (OR: 2.54, 95% CI: 1.48 – 4.70, p=0.0017), LBD (OR: 2.04, 95% CI: 1.74–2.39, p<0.001), HS (OR: 2.31, 95% CI: 1.74 – 3.11, p<0.001), CAA (OR: 1.50, 95% CI: 1.27 – 1.77, p<0.001), Infarcts and Lacunes (OR: 0.97, 95% CI: 0.82-1.15, p=0.68), and Single or Multiple Hemorrhages (OR: 0.98, 95% CI: 0.57 – 1.76, p=0.94).
Association of specific NPS with neuropathological variables
Figure 2 and Table 4 show comparisons of neuropathologic findings by first NPS. Rates of FTD with TDP-43 pathology were highest in participants with personality change (31.6%) and participants with disinhibition (24.0%). Rates of FTD with Tau Pathology were similarly highest in participants with personality change (35.5%) and participants with disinhibition (27.6%). Rates of LBD were highest in participants with REM sleep behavior disorder (81.4%) and participants with psychosis (58.5%). Odds ratios of receiving neuropathological diagnoses by highly correlated first NPS after adjusting for relevant covariates are presented in Table 5.
Figure 2.
Rates of neuropathological diagnoses by first NPS group. Red dotted lines indicate the prevalence of corresponding pathology in the No NPS group. AD ABC scores and CAA severity scores were dichotomized such that a score of 2 (moderate) or 3 (severe) was coded as a positive diagnosis for AD and CAA, respectively. Alzheimer’s Disease (AD); Frontotemporal Lobar Dementia (FTD); Lewy Body Dementia (LBD); Cerebral Amyloid Angiopathy (CAA); Hippocampal Sclerosis (HS).
Table 4.
Comparison of neuropathological findings and diagnoses by first NPS group. All percentages are presented as column-based representing the proportion of participants in each NPS group with corresponding neuropathologic finding.
| No NPS (N=138 3) |
Apathy (N=120 9) |
Depressi on (N=1218 ) |
Psycho sis (N=188 ) |
Disinhibiti on (N=201) |
Irritabili ty (N=595) |
Agitati on (N=115) |
Personal ity (N=172) |
REM (N=9 9) |
Anxie ty (N=81 ) |
Other (N=15 5) |
|
|---|---|---|---|---|---|---|---|---|---|---|---|
| Alzheimer's Disease | |||||||||||
| ABC Score | |||||||||||
| 0 (Not AD) | 138 (18.5%) | 99 (13.9%) | 104 (13.4%) | 5 (5.0%) | 29 (22.7%) | 34 (8.3%) | 9 (11.3%) | 25 (22.9%) | 12 (14.6 %) | 5 (6.3%) | 12 (11.2%) |
| 1 (Mild) | 221 (29.6%) | 109 (15.3%) | 125 (16.1%) | 15 (15.0%) | 39 (30.5%) | 51 (12.5%) | 10 (12.5%) | 37 (34.0%) | 24 (29.3%) | 16 (20.3%) | 12 (11.2%) |
| 2 (Intermediate) | 232 (31.1%) | 110 (15.5%) | 148 (19.0%) | 29 (29.0%) | 18 (14.1%) | 80 (19.6%) | 14 (17.5%) | 21 (19.3%) | 20 (24.4%) | 23 (29.1%) | 24 (22.4%) |
| 3 (High) | 156 (20.9%) | 393 (55.3%) | 402 (51.6%) | 51 (51.0%) | 42 (32.8%) | 243 (59.6%) | 47 (58.8%) | 26 (23.9%) | 26 (31.7%) | 35 (44.3%) | 59 (55.1%) |
| Frontotemporal Lobar Dementia | |||||||||||
| TDP-43 Pathology | 15 (2.4%) | 61 (9.8%) | 39 (5.8%) | 2 (2.4%) | 30 (24.6%) | 16 (4.3%) | 5 (7.9%) | 36 (31.6%) | 1 (1.3%) | 4 (5.6%) | 7 (7.5%) |
| Tau Pathology | 125 (16.8%) | 156 (21.4%) | 118 (15.1%) | 10 (10.1%) | 39 (28.9%) | 77 (18.9%) | 10 (12.4%) | 43 (35.5%) | 12 (14.5 %) | 11 (13.8%) | 16 (15.2%) |
| Lewy Body Dementia | |||||||||||
| Yes | 304 (22.0%) | 451 (37.6%) | 458 (37.7%) | 110 (58.5%) | 46 (23.4%) | 210 (35.4%) | 40 (35.1%) | 37 (21.6%) | 80 (81.6%) | 35 (43.8%) | 54 (34.8%) |
| Hippocampal Sclerosis | |||||||||||
| Yes | 79 (10.4%) | 137 (18.9%) | 122 (15.4%) | 23 (22.7%) | 30 (22.9%) | 66 (15.9%) | 12 (14.1%) | 20 (17.0%) | 19 (22.6%) | 6 (7.4%) | 13 (12.2%) |
| Cerebral Amyloid Angiopathy Severity | |||||||||||
| 0 (None) | 674 (49.6%) | 463 (39.0%) | 462 (38.4%) | 64 (34.8%) | 97 (48.7%) | 189 (32.5%) | 38 (33.0%) | 94 (56.0%) | 44 (44.4%) | 34 (42.0%) | 66 (43.1%) |
| 1 (Mild) | 382 (28.1%) | 346 (29.1%) | 379 (31.5%) | 63 (34.2%) | 54 (27.1%) | 181 (31.2%) | 44 (38.3%) | 40 (23.8%) | 29 (29.3%) | 25 (30.9%) | 34 (22.2%) |
| 2 (Moderate) | 213 (15.7%) | 240 (20.2%) | 234 (19.5%) | 30 (16.3%) | 36 (18.1%) | 131 (22.6%) | 20 (17.4%) | 24 (14.3%) | 17 (17.2 %) | 16 (19.8%) | 37 (24.2%) |
| 3 (Severe) | 90 (6.6%) | 139 (11.7%) | 128 (10.6%) | 27 (14.7%) | 12 (6.0%) | 80 (13.8%) | 13 (11.3%) | 10 (6.0%) | 9 (9.1%) | 6 (7.4%) | 16 (10.5%) |
| Cerebrovasc ular Disease | |||||||||||
| Infarcts and Lacunes | 296 (21.6%) | 190 (15.9%) | 226 (18.7%) | 25 (13.4%) | 39 (19.5%) | 115 (19.5%) | 13 (11.3%) | 17 (10.1%) | 8 (8.6%) | 10 (12.5%) | 22 (14.3%) |
| Single or Multiple Hemorrhages | 20 (2.8%) | 21 (2.9%) | 20 (2.8%) | 1 (1.0%) | 5 (3.8%) | 10 (2.4%) | 2 (2.4%) | 3 (2.6%) | 4 (5.0%) | 3 (3.9%) | 4 (3.8%) |
Table 5.
Odds of developing neuropathological diagnoses by first NPS group (with participants presenting with no NPS and other NPS participants as the reference group) with covariates of age at relevant clinical visit, sex, education, number of APOE alleles, and age at death. FTD=Frontotemporal Lobar Dementia, LBD=Lewy Body Dementia. * p<0.05; ** p<0.01.
| First NPS Group | Odds of LBD pathology |
Odds of FTD (TDP-43) pathology |
Odds of FTD (Tau) pathology |
|---|---|---|---|
| REM Disorder (N=98) | 7.34 ± 4.44 - 12.79** | 0.14 ± 0.01 - 0.63* | 0.74 ± 0.37 - 1.34 |
| Psychosis (N=188) | 2.96 ± 2.14 - 4.14** | 0.17 ± 0.01 - 0.81 | 0.64 ± 0.31 - 1.20 |
| Personality Change(N=171) | 0.49 ± 0.32 - 0.71** | 4.05 ± 2.50 - 6.45** | 2.19 ± 1.43 - 3.29** |
| Disinhibition (N=197) | 0.57 ± 0.40 - 0.81** | 4.31 ± 2.60 - 6.98** | 1.60 ± 1.03 - 2.42* |
Rates of AD pathology (ABC Score >1) was highest participants with psychosis group (80%) and participants with irritability (79.2%), and elevated rates of AD pathology relative to the No NPS group were found in all groups except for participants with personality change (43.1%) and participants with disinhibition (46.9%). Associations between first NPS and AD with and without vascular pathology were also explored (Supplemental Figure 1). Rates of CAA (severity score >1) was highest in participants with irritability (36.3%) and was elevated in all groups expect for participants with personality change (20.2%).
Discussion:
This analysis leveraged the rich NACC dataset to better understand how presentation with clinically significant NPS during life was associated with neuropathological correlates of memory disorders years later. Our findings support past literature highlighting the strong association between presentation with clinically significant NPS during later life and subsequent development of memory disorders. Across a wide range of neurodegenerative diseases, including AD, FTD with TDP-43 pathology, LBD, HS, and CAA, presentation with any clinically significant NPS was highly correlated with neuropathological diagnoses. The use of objective neuropathological autopsy data rather than clinical findings to measure degree of brain aging was a strength of our study. An additional strength of our analysis is the use of a clinician rated variable to identify first NPS, which contrasts past studies that commonly use NPI-Q scores to evaluate for the presence of any NPS irrespective of the timing or clinical relevance. This variable is particularly useful in that it reflects an expert clinician’s judgment of whether a new NPS is clinically significant, and thus is relevant to clinicians’ everyday practice. Finally, our study is one of the first to assess the association between NPS and neuropathological correlates of less common neurodegenerative pathologies such as CAA and HS, which further emphasizes the clinical relevance of NPS during later life.
Our study also suggests that specific NPS are associated with specific neuropathological diagnoses. Unsurprisingly, patients who presented with disinhibition and personality change were most likely to have neuropathological diagnoses of FTD with TDP-43 and Tau pathology, while patients who presented with psychosis and REM sleep disorders were more likely to have neuropathological diagnoses of LBD. These associations were expected from the literature, [19,20] as the clinical phenotypes of these disorders match the first presenting NPS most associated with their neuropathological correlates. For example, behavior variant type FTD (bvFTD), the most common phenotype of FTD, commonly presents with personality changes that may include disinhibition and loss of emotional reactivity. [19] On the other hand, LBD has a distinct triad of dementia, psychosis, and features of parkinsonism, although REM sleep behavior disorder is another observed feature. [20] While correlation between common clinical features and neuropathological correlates may not be surprising, our restriction to subjects with CDR-G scores of 1 or lower highlights that these NPS may present early in the clinical course of the memory disorder, and thus may provide clinicians with clues to subsequent clinical course.
In contrast to the relatively narrow associations observed between specific NPS and FTD and LBD, a wide variety of NPS were associated with AD pathology. Elevations in AD pathology were observed across the majority of NPS measured, including apathy, depression, psychosis, agitation, irritability, and anxiety. These findings may correspond to our clinical understanding of AD, which is a heterogenous disorder with varying pathophysiology and clinical phenotypes. [21] Moreover, neuropathological findings associated with AD are more widespread in comparison to LBD and FTD, which may also help to explain why AD has less specific associations with NPS. [22] These findings may aid clinicians in the prediction of future dementia and its neuropathological subtypes.
Limitations
Limitations of this analysis include the lack of specificity of the NACCBEHF variable used to measure first NPS, which although useful in its clinical relevance, may be associated with any number of diagnoses during life including non-memory related disorders. Moreover, we could not determine whether the first NPS occurred alongside cognitive complaints or were the earliest presenting symptom in the absence of any cognitive decline, although we excluded participants with CDR scores greater than 1 to ensure that the first NPS occurred early in the disease course prior to the development of severe cognitive decline.
Additional limitations relate to the neuropathological variables used for this analysis. There was great overlap with regards to neuropathological diagnoses, with many participants (43.6%) receiving more than one diagnosis. While the NACC dataset contained several variables that were meant to identify the primary neuropathological diagnosis of each participant, available data for these variables were limited and we opted to analyze the broader variables with large sample sizes to maximize power. Thus, overlapping neuropathological diagnoses may limit the clinical relevance of any one diagnosis. Additionally, post-hoc analyses revealed that the neuropathological variables selected to represent vascular dementia (Lacunes/Infarcts and Hemorrhages) are not highly correlated with the clinical diagnosis of vascular dementia, and in fact, rates of probable or possible vascular dementia diagnoses are quite low in these participants (see Supplemental Table 2).
It is also worth noting that given that the NACC is a referral population, patients included in this analysis may be more likely to develop neuropathology than the general population, and patients with NPS during later life who did not develop neuropathology may be underrepresented in our sample. Finally, the sample included in this analysis was also predominantly white and highly educated, limiting the generalizability of our findings. Additionally, given the low numbers of non-White participants in this cohort, the impact of race on the hypotheses of interest could not be meaningfully assessed owing to lack of power.
Conclusion:
In a well-characterized cohort (NACC), we found that specific first NPS were associated with FTD neuropathology (personality change and disinhibition) and LBD neuropathology (psychosis and REM behavior disturbance), while several NPS were associated with AD neuropathology. Since NPS are frequently the first presenting symptom of dementia, these associations may help clinicians predict the neuropathologic subtype of future dementia.
Supplementary Material
Highlights:
What is the primary question addressed by this study?—The primary question addressed by this study was to examine the association between the first presenting neuropsychiatric symptom (NPS) in aging individuals and neuropathological diagnoses of memory disorders.
What is the main finding of this study?—The main finding of this study was that specific first NPS were associated with Frontotemporal Dementia neuropathology (personality change and disinhibition) and Lewy Body Dementia neuropathology (psychosis and REM behavior disturbance), while many first NPS were associated with Alzheimer’s Disease neuropathology.
What is the meaning of the finding?—The significance of the finding is that since neuropsychiatric symptoms are frequently the first presenting symptom of dementia, their associations with well-defined neuropathological diagnoses may help clinicians predict the subtype of future dementias.
Acknowledgements:
PBR has received support from the National Institute on Aging (AG054771, AG050515) as well as the Richman Family Precision Medicine Center of Excellence in Alzheimer's Disease. The NACC database is funded by NIA/NIH Grant U24 AG072122. NACC data are contributed by the NIA-funded ADRCs: P30 AG062429 (PI James Brewer, MD, PhD), P30 AG066468 (PI Oscar Lopez, MD), P30 AG062421 (PI Bradley Hyman, MD, PhD), P30 AG066509 (PI Thomas Grabowski, MD), P30 AG066514 (PI Mary Sano, PhD), P30 AG066530 (PI Helena Chui, MD), P30 AG066507 (PI Marilyn Albert, PhD), P30 AG066444 (PI John Morris, MD), P30 AG066518 (PI Jeffrey Kaye, MD), P30 AG066512 (PI Thomas Wisniewski, MD), P30 AG066462 (PI Scott Small, MD), P30 AG072979 (PI David Wolk, MD), P30 AG072972 (PI Charles DeCarli, MD), P30 AG072976 (PI Andrew Saykin, PsyD), P30 AG072975 (PI David Bennett, MD), P30 AG072978 (PI Neil Kowall, MD), P30 AG072977 (PI Robert Vassar, PhD), P30 AG066519 (PI Frank LaFerla, PhD), P30 AG062677 (PI Ronald Petersen, MD, PhD), P30 AG079280 (PI Eric Reiman, MD), P30 AG062422 (PI Gil Rabinovici, MD), P30 AG066511 (PI Allan Levey, MD, PhD), P30 AG072946 (PI Linda Van Eldik, PhD), P30 AG062715 (PI Sanjay Asthana, MD, FRCP), P30 AG072973 (PI Russell Swerdlow, MD), P30 AG066506 (PI Todd Golde, MD, PhD), P30 AG066508 (PI Stephen Strittmatter, MD, PhD), P30 AG066515 (PI Victor Henderson, MD, MS), P30 AG072947 (PI Suzanne Craft, PhD), P30 AG072931 (PI Henry Paulson, MD, PhD), P30 AG066546 (PI Sudha Seshadri, MD), P20 AG068024 (PI Erik Roberson, MD, PhD), P20 AG068053 (PI Justin Miller, PhD), P20 AG068077 (PI Gary Rosenberg, MD), P20 AG068082 (PI Angela Jefferson, PhD), P30 AG072958 (PI Heather Whitson, MD), P30 AG072959 (PI James Leverenz, MD).
Footnotes
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Data Availability:
The datasets used and/or analyzed during the current study can be made available from the corresponding author on reasonable request.
Data Statement:
The data has not been previously presented orally or by poster at scientific meetings.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets used and/or analyzed during the current study can be made available from the corresponding author on reasonable request.
The data has not been previously presented orally or by poster at scientific meetings.