June 24, 2022

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Elderly depression is associated with reduced Aβ (cortical amyloid) burden

Elderly depression is associated with reduced Aβ (cortical amyloid) burden

 


Elderly depression is associated with reduced Aβ (cortical amyloid) burden.  Depression is closely related to memory dysfunction, not dependent on amyloid?

Keywords: senile depression, Aβ (amyloid), cognition, depressive symptoms, mild cognitive impairment, Alzheimer’s disease.

 


01 Summary

background

To assess the role of cortical amyloid deposits as a factor leading to increased risk of memory dysfunction and dementia associated with senile depression.

method

From the ADNI depression study, 119 currently diagnosed [potential information: Depression now, will it develop into Alzheimer’s disease in the future] elderly participants with severe depression (LLD) and 119 non-depressive (ND) cognitive functions For unimpaired participants, matching age, gender, and APOE genotype were obtained from the ADNI database [Dementia differs in gender].

results

33% of elderly depression participants (LLD group) met the criteria for ADNI mild cognitive impairment (MCI). Compared with the control group (ND group), the overall amyloid (Aβ) accumulation in the LLD group was less (p = 0.05). The positive rate of amyloid in the LLD group was 19.3%, and that in the ND group was 31.1% (p = 0.02). Among LLD participants, the overall level of Aβ was not related to the number of lifetime depression episodes, lifetime depression duration, lifetime SSRI drug use duration, or lifetime depression untreated duration (p> 0.21). The overall level of Aβ was associated with poor memory performance (p = 0.05). Similar results also appeared in secondary analyses, such as comparing LLD participants with unimpaired cognitive function, and comparing the LLD group with the ND group including participants with mild cognitive impairment.

in conclusion

Contrary to expectations, Aβ deposition in the LLD group was less than that in the ND group, and Aβ deposition was not related to the history of depression. Aβ is related to memory, but there is no difference in this relationship between LLD and ND [Statistics? ]. Our results show that [observe the data indicators related to the research and their influencing factors? ], the memory deficits and accelerated cognitive decline reported in previous studies in elderly depression are not due to the accumulation of cortical Aβ. [That is: senile depression has nothing to do with Aβ deposition, senile depression cannot transform dementia, it is not a high risk factor for dementia]

 

 


02 Introduction

The subsyndromic symptoms of depression in the elderly and major depression are the most commonly reported associated with faster cognitive decline in the future (1-8), faster conversion to dementia (9, 10), and higher incidence of dementia The risk factors of (11). Specifically, the subsyndromic symptoms of depression are associated with a 2.4-fold increase in the risk of dementia (12), while major depression is associated with a nearly 4.3-fold increase in the risk of dementia (13). Due to these common findings, increased a β deposition in LLD is considered to be a potential way to increase the risk of dementia in this patient population (14) [Depression (a β deposition? Potential pathway?) is a high risk factor for dementia].

The accumulation of Aβ plaques in the brain is widely considered to be one of the main factors leading to memory and other cognitive dysfunctions in patients with dementia (AD) due to neuronal degeneration and cortical atrophy (15-17). The initial support for the possible link between LLD and increased Aβ deposition was in an autopsy study, which found the relationship between amyloid plaques in the brains of dementia patients with a history of depression (18, 19), and the relationship between plasma Aβ40 and Aβ The study of cerebrospinal fluid (CSF) β42 levels also showed changes in Aβ metabolism levels in patients with LLD (20-22). PET studies have shown that compared with the control group, cortical amyloid deposits in LLD patients are increased (23,24), and there is an association between amyloid binding and the clinical features of LLD, which further supports a β as a link between LLD and dementia The underlying mechanisms of the association include increased resistance to treatment (25) and severity of apathy (26). Studies using PET imaging have also found a positive correlation between amyloid burden and depressive symptoms in the elderly subsyndromes (27,28), including a higher risk of depression over time (29) and cognition The function is worse (30). PET imaging has also been used to examine the relationship between amyloid deposition and depressive symptoms in MCI samples, showing increased amyloid deposition and increased risk of dementia (31-34).

The pathological evidence for increased Aβ in LLD patients has been unclear. Some studies have shown that history of depression or current depression is not associated with increased Aβ (35). In addition, many published studies have shown that the increase in Aβ levels in LLD is limited by a small sample size. Only two studies (29,34) evaluated the APOE genotype in group comparisons, which is significant considering the known association between APOE and AD risk. In addition, most previous studies have incomplete depression and treatment history, and a particularly relevant study has shown that SSRI treatment may be associated with pathological reduction of Aβ (36). In addition, only two studies (30,34) evaluated the relationship between Aβ and memory performance and showed mixed results. Considering that memory dysfunction is the core of the diagnosis of dementia, it is particularly important to assess the relationship between Aβ and LLD memory function.

The purpose of this study was to determine whether LLD is associated with increased Aβ accumulation, and to assess the relationship between Aβ deposition and memory performance and characteristics of depression history, including the use of SSRI. Based on previous studies, we predict that LLD participants will have a higher amyloid deposition level than ND control participants with unimpaired cognitive function.

In addition, we expect that in LLD and ND participants, greater Aβ accumulation may be associated with poor memory function. For our LLD study sample, we hypothesized that in the LLD sample, the lifetime duration of depression, untreated depression, and the number of discrete depressive episodes are positively correlated with Aβ, while lifetime use of SSRI treatment is negatively correlated with Aβ.

 

 


03 Methods and materials

Participant

Participants were included in the main analysis to evaluate the relationship between LLD and β pet SUVR including 119 elderly patients with major depressive disorder participating in the neuroimaging of Alzheimer’s disease-depression project (ADNI-D) and 119 non-depressive (ND) ) Cognitive No individual participated in the Alzheimer’s Disease Neuroimaging Study (ADNI). In the sensitivity analysis, we also compared individuals with LLD and ND, limiting the sample to participants in each group who were not cognitively impaired. In addition, we also compared LLD and ND participants, and matched the proportion of MCI participants in each group according to ADNI’s criteria for judging MCI. Participants with mild cognitive impairment were excluded from the ND group in a preliminary analysis to provide the most conservative point of comparison of Aβ PET SUVR measurements between groups, because major depression has always been associated with memory impairment and is independent of AD (37,38) . All participants provided written informed consent when participating in the study. This study was conducted in accordance with the Helsinki Declaration on the Protection of Human Subjects, and its procedures were approved by the institutional review board of each study site.

For LLD participants, the inclusion criteria include the current diagnosis of major depression (MDD), unipolar, no psychotic features, 17 reported HDRS(39) symptoms with severity ≥15, and current episodes lasting at least 6 weeks. MDD is diagnosed by practicing clinical psychologists using Structured Clinical Interviews (SCID) Mental Disorder Diagnosis and Statistics Manual-IV (40). Other axis I disorders and major current neurological diseases, such as epilepsy, Parkinson’s disease, traumatic brain injury, or cortical stroke, exclude individuals from participation. Those who were diagnosed with dementia or had evidence of dementia (under the age of 25 in the minimum mental status examination [MMSE]) were also excluded from participation. If the study’s inclusion criteria are met and consent is obtained, participants will perform DNA and RNA bank blood draws (APOE genotyping), MRI imaging, and AV-45 (florbetapir) amyloid PET imaging.

The data of the current study of the ND control group comes from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (ADNI.loni.usc.edu). ADNI was initiated in 2003 by the National Institute of Aging (NIA), the National Institute of Biomedical Imaging and Bioengineering (NIBIB), the Food and Drug Administration (FDA), private pharmaceutical companies and non-profit organizations. ADNI’s research was conducted in accordance with the Declaration of Helsinki, and the relevant procedures were approved by the institutional review committees of all participating sites. All participants provided written informed consent at the time of registration. Criteria for participants with unimpaired cognition include MMSE score> 24, Global Clinical Dementia Rating Scale (CDR) score = 0.0, neuropsychological assessment based on the original WMS-R Logical Memory II score adjusted by education, and no evidence of memory impairment. MCI standards include mild mental state score> 24, overall CDR score 0.5, and WMS-R logical memory II is lower than the education correction standard score.

The exclusion criteria of the ADNI study at baseline include: 1) the presence of major depressive disorder or significant depressive symptoms (Geriatric Depression Scale [GDS] score> 6); 2) modified Hutchinson’s ischemia score> 5; 3) major nerves Or mental illness; 4) Large doses of nerve depressants or chronic sedatives or hypnotics, anti-Parkinson drugs and the use of narcotic analgesics. ND participants were matched with LLD participants in terms of age, gender, APOE ε4 positivity, reference area a β PET uptake (whole cerebellum), and PET image smoothing parameters (as an alternative to scanner type). ND participants are also restricted to GDS scores <3 points. In one of the two sensitivity analyses, both the LLD and ND groups were restricted to participants with unimpaired cognitive function and matched on the same variables as the main analysis. In the second sensitivity analysis, MCI participants were included in two groups, LLD participants matched the diagnosis of ND participants (MCI ratio), delayed logical memory, education, and the variables used for matching in the primary analysis. The matching procedure uses a propensity score (41).

process

After the initial screening of the telephone interview, the inclusion criteria were evaluated and demographic data were obtained, and eligible participants were transferred to the corresponding psychiatric department website, whether it was the clinical psychiatric evaluation of the University of Pittsburgh or the University of California, San Francisco (DSM disorder) Structured clinical interview; SCID), history of depression and cognitive assessment. Participants were then evaluated at the University of Pittsburgh Medical Center or the ADNI Research Center at the University of California, San Francisco, where they underwent core ADNI research protocols (including cognitive testing, DNA and RNA blood draws, MRI and PET imaging).

 

 


04 Measurement

memory

The assessment of language learning and memory uses the Webster Memory Scale-Revised. The logical memory test is used to evaluate the learning and memory of the story with the number of recalled story elements as the result measurement index (42). The severity and history of depression. The Elderly Depression Scale (43) and the 17-item Hamilton Depression Rating Scale (39) were used to assess the severity of depressive symptoms at baseline. The history of depression was collected by self-reported retrospective measures and verified by the clinical study coordinator. The time of depression for each person is coded in months. In addition, participants recorded all the treatments sought and the duration of each treatment, including the use of antidepressants. The basic structure of the NIMH life map method (NIMH- lcm) was used to develop a historical retrospective measurement of depression (44).

The burden of amyloid. Four 5-minute frames were collected 50-70 minutes after injection and pre-processed as described previously (45). The structural MRI images at the same time were processed with FreeSurfer v5.3. The total cortical SUVR is calculated by creating an average value of the frontal, cingulate, temporal, and parietal regions relative to the entire cerebellum. The positive status of Aβ in the cortical summary area was> 1.11, which was 2 standard deviations higher than the average (46) of cognitively normal individuals. Individual cortical areas divided by the entire cerebellum were also examined. Finally, for voxel analysis, the average value of the entire cerebellum is used to normalize the intensity of the florbetapir image in the native space at the voxel level. The co-registered structural MRI image of late-life depression amyloid 10 is nonlinearly bent into the MNI template space, and this conversion is applied to the florbetapir image.

APOE genotype. Commercial reagents (FlexiGene, Qiagen, Valencia, CA, USA) were used to extract DNA from blood samples. Two apolipoprotein e SNPs, especially rs7412 and rs429358, were analyzed for allelic discrimination using TaqMan reagent (Applied Biosystems, Foster City, CA, USA). Then the genotyping results are integrated into the algorithm to determine the ε2, ε3, or ε4 genotype. In this study, genotype was analyzed as a dichotomous variable (presence or absence of 3|4 or 4|4 genotypes, that is, the ε4 allele, which is usually associated with an increased risk of AD).

Data and analysis

The continuous measurement Mann-Whitney test and the classification measurement Fisher exact test were used to analyze the differences in demographic characteristics between the LLD group and the ND group. Because the LLD participants came from two PET imaging sites and the ND participants came from 33 imaging sites. 9 scanner types/models, we used the statistical model to measure the cerebellar amyloid and pet image smoothing features that did not account for the cerebellar amyloid in the observation group The differences and restrictions on website changes due to the type of scanner.

We compare the models that summarize scanner information by scanner type and smoothing characteristics. According to the Akaike information criterion, a covariant model with smooth characteristics is selected as a better fitting and more concise model. Robust linear regression and non-parametric bootstrap permutation tests were used to test the differences between groups in overall and regional Aβ accumulation. The independent variables in the model include age, gender, APOE status (with at least one APOE ε4 allele versus ε4 non-carrier), whole cerebellar Aβ uptake, PET image smoothing features, and depression group (LLD versus late-life depression amyloid 11 ND). Logistic regression was used to analyze the differences between the Aβ-positive groups.

Then, we assessed whether memory performance is related to Aβ deposition. In our LLD-specific analysis, the effects of the history characteristics of depression (duration of depression, untreated depression, duration of SSRI treatment, and duration of depression) on the overall Aβ SUVR were also determined by robust linear regression and ranking The test was evaluated. Voxelwise analysis was performed in SPM12 using the same covariates. The false discovery rate (FDR) is used to correct the p value of the difference in the correction area a β accumulation group. The p-values ​​affected by historical features of depression were adjusted using Holm’s correction (47). All p-values ​​are two-tailed and are significant at the α = 0.05 level. Use R package (v3.6.0, http:/www.r.project.org/) for statistical analysis.

Results

Participants included 119 LLD and 119 cognitively unimpaired ND individuals. The average age was 71.4 years (SD = 5.6), the average years of education were 16.4 years (SD = 2.2), 63.9% were women, and 26.9% were APOE+. There was no difference in these characteristics between the LLD group and the ND group (Table 1). 33% of the LLD group met the MCI criteria, and the Hamilton depression score averaged 18.2 points (SD = 2.6). According to the design, the LLD group reported more severe depressive symptoms than the ND group (LLD = 7.3, ND = 0.56; p <0.001), and performed worse on the logical memory delay recall test (LLD = 11.2, ND = 13.3; p <0.001) ). There was no difference between the two groups in the measurement of overall mental state (the average MMSE of the two groups = 29.1; p = 0.45). Regarding the historical characteristics of depression, the average lifetime length of depression in the LLD group is 263.4 months (SD = 223.8), the average life span is untreated late-life depression amyloid 12 depression 139.1 months (SD = 190.0), and the average life span The length of SSRI treatment was 56.8 months (SD = 92.8) and the average life span of depressive episodes was 2.5 (SD = 1.8).

Compared with the ND group with unimpaired cognitive function, the overall a β deposition in the LLD group was significantly reduced (β = -0.04, p = 0.05), and the positive rate of a β was significantly lower (19.3% vs. 31.1%; Figure 2 and Figure 3 Shows regional differences in Aβ SUVR and whole brain. Other important predictors of β positivity include increased age (log or = 0.09, p <0.01), female gender (log or = 1.08, p = 0.01), and APOE positivity (log or = 1.47, p <0.01) (Table 2). Individual region of interest (ROI) comparisons between groups and adjusted multiple comparisons (Supplementary Table 1), β deposition in the LLD group significantly reduced the frontal pole (β = -0.063, p < Measure), lingual gyrus (β = 0.34, p <measure), tail (β = -0.06, p = 0.02) and rostral anterior cingulate (β = -0.06, p = 0.02), and fusiform gyrus (β = -0.04, p = 0.02) medial orbitofrontal cortex (β = -0.05, p = 0.02, lateral orbitofrontal (β = -0.04, p = 0.05, supramarginal (β = -0.04, p = 0.02), intermediate temporary (β= -0.04, p = 0.04, side hippocampus (β = -0.03, p = 0.04), pericalcarine (β = -0.04, p = 0.0), hippocampus (β = -0.03, p = 0.04), isthmus cingulate (β= -0.04, p = 0.04), temporal pole (β = 0.03, p = 0.04), lower parietal lobe (β = -0.05, p = 0.05). In the LLD group, amyloid positive and SUVR related to MCI diagnosis No difference (p> 0.23).

Sensitivity analysis

When the ND control group matched the MCI status (Supplementary Table 2), LLD showed a reduction in overall Aβ SUVR (β = -0.05, p = 0.02), and amyloid 13 reduction in elderly depression with amyloid positive (19.3% vs 39.5%; log OR = -1.27, p = 0.002). Only comparing LLD patients with unimpaired cognitive function and ND patients with unimpaired cognitive function (Supplementary Table 3), there was no significant difference in the comparison of SUVR between the groups (β = -0.03, p = 0.39), However, the positive rate of amyloid was significantly lower than that of the control group (16.2% vs 30.0%; log OR = -1.12, p = 0.03).

The relationship between memory performance and amyloid deposition

After adjusting for age, gender, education level, and depression group, Aβ SUVR was associated with memory loss (β = -3.29, p =0.05; Figure 4), and this relationship was not different in the depression group (p=0.25). After considering age, gender, education level, Aβ SUVR and MCI diagnosis, depression was significantly associated with memory decline (β = 1.32, p = 0.01).

Depressive characteristics in the LLD group

After considering age, gender, education level and APOE status, and adjusting for multiple comparisons, the lifetime duration of depression (β = 0.00, p> 0.99), and the untreated duration of depression (β = 0.00, p> 0.99); The lifetime depressive episode (β = 0.0001, p> 0.99) and the length of life SSRI treatment (β = 0.0002, p = 0.22) were not related to Aβ PET SUVR (Figure 5).

 

 


05 Discussion

This study assessed the differences between groups in amyloid deposits in large, well-characterized samples of elderly people with and without major depression. Contrary to the higher amyloid deposition rate in the LLD group predicted by the literature based on accelerated cognitive decline (9) and neurodegeneration (24) in elderly depression patients, the LLD group was significantly lower than that of the ND participants. Total amyloid deposition rate and amyloid positive rate. When observing the regional deposition of amyloid, the difference is particularly obvious in the frontal pole, rostral and anterior cingulate, medial orbitofrontal, and temporal middle cortex. Our results also show that the amyloid load is related to the memory performance of the sample, but not to the characteristics of the history of depression. Before discussing our results, it is worth noting that our decision to compare the mixed cognitive state LLD group (cognitive not, MCI) cognitive is not controlled in the main analysis is for the most stringent restrictions in the identification of tissue differences may indicate starch in the sample Accumulation increased because MDD has been shown to have an impact on memory performance and functional status independent of advertisements (37 years old, 48). Therefore, relying solely on cognitively matched samples may lead to a higher incidence of AD pathology in the control group. Each of our findings will be discussed below.

In our preliminary analysis, we compared the LLD sample (33% of whom had mild cognitive impairment) with a non-depressed control group without mild cognitive impairment. Our results showed that the burden of amyloid in the LLD group was reduced. Comparing the LLD group with a non-depressive control group that matched the MCI ratio, and got similar results. We found that reducing pre-amyloid depression samples will not be claimed by literature as a risk factor for late life depression in LLD. Amyloid 15 accelerates cognitive decline and the development of MCI and dementia (49) 1, 9, LLD and advertising (50) diseases , And CSF Research β(19). As expected, these differences between the groups (lower and positive amyloid deposits in the LLD group) became more pronounced when the Cognitive Status Matched Comparable Objects (MCI) were added to the analysis. However, when only LLD and ND participants with normal cognition were analyzed, the SUVR comparison was no longer significant, and the amyloid positive difference still existed. Collectively, these results suggest that other non-amyloid-mediated pathways may be related to the accelerated cognitive decline and dementia risk reported by LLD. It is worth noting that most of the previous work supporting the link between LLD and increased amyloid has not been done in in vivo amyloid PET imaging, nor has it included a large number of clinically depressed patients with demographic, genetic, and clinical Compare the controls with matching features.

It is also possible that the mechanism of major depression reduces amyloid deposits. In particular, decreased cerebral blood flow or decreased metabolism may limit the uptake of amyloid in the most severe areas of depression—especially areas such as the cingulate gyrus and the orbital prefrontal cortex. However, in our data, we did not see any history of depression significantly associated with amyloid, which would support this hypothesis. Similarly, we did not find that depression treatment, especially the length of SSRI treatment, was related to the reduction of amyloid accumulation in the sample. We also noticed that in this sample, most LLD participants are early-onset and have a long-term history of depression, and late-onset depression may be more strongly associated with increased amyloid load.

In the entire sample of LLD and ND, we also reported the link between amyloid load and decreased memory performance. These results are notable for the fact that the link between cognition and amyloid is usually weak in individuals with normal cognition (51), and most of our samples are not cognitively impaired. In addition, we also reported the expected connection between memory performance and depression, with LLD participants performing poorly on memory tests. However, we did not find an interaction between amyloid positivity and depressive state and memory performance. In summary, we can conclude that the effect of depression on memory function, independent of amyloid, may be an important factor in the risk of cognitive decline in the future. This relationship may be the direct impact of depression on cognitive and functional status, or it may be due to other factors, such as cortical atrophy associated with depressive symptoms (52). In addition, for individuals with other neurodegenerative processes, including amyloid deposits, this additional effect of depression may accelerate cognitive decline and transform into dementia more quickly.

Although our results are strong and there are several possible explanations for the etiology considered, there are still some limitations. In particular, the cross-sectional nature of the data provided does not allow assessment of the longitudinal cognitive function or future amyloid status of the two groups of patients. In other words, compared with ND participants, the LLD group may still experience accelerated cognitive decline after several years of follow-up, or become amyloid positive more quickly over time. In addition, our results show that individuals with mild cognitive impairment due to AD also have LLD. There may be two different factors that cause cognitive dysfunction, which may have sampling bias.

Therefore, individuals with a greater burden of amyloid and related effects on memory performance are more likely to be diagnosed with dementia earlier and are excluded from this study.

In addition, although the designed protocol limits the influence of specific parts of PET image acquisition, and our method minimizes these potential influences in our analysis, given that our imaging data comes from multiple parts, the imaging acquisition of specific parts may be affected. Affect our results. To the best of our knowledge, this study is the first to investigate the difference in amyloid in a large sample of patients with clinical depression and elderly people with ND with matching APOE status. Given the known link between apolipoprotein e and amyloid accumulation, we believe that this is a key factor to consider when evaluating the link between amyloid and depression. Our sample also meets the current criteria for major depression, and reports a long-term history of depression and various treatments for depression, which is also a key consideration for assessing differences in amyloid between groups.

Although we did not evaluate the longitudinal results in this study, our results indicate that the increased cortical amyloid burden is not the main factor in the reported increased risk of major depression-related dementia in the elderly (13). This conclusion is strengthened due to the lack of a link between the characteristics of depression and the history of amyloid burden treatment. On the contrary, our research found that depression is closely related to memory dysfunction and is not dependent on amyloid, which suggests that LLD may increase the cognition and function of individuals who also suffer from mild cognitive impairment or early neurodegenerative diseases. Burden, accelerate the progress of dementia.

 

 

 

 

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