Background
Discrepancy in the dyadic relationship of subjective cognitive change has revealed both increased/heightened awareness and decreased awareness/unawareness in the predementia stages of ...Alzheimer’s Disease (AD). The dyadic relationship is often calculated using the mean discrepancy between an individual and their study partner’s scores on a memory complaints questionnaire. However, participants may display heightened awareness on some questions and unawareness on others, canceling out each other’s effect and masking subtle changes in either direction. Here, we present a new item‐level methodological approach allowing us to examine individual subtle changes in these two awareness dimensions separately. Moreover, we compared them to AD pathology and investigated their ability to predict clinical progression.
Method
A total of 503 ADNI participants (Table.1) with baseline clinical dementia rating (CDR) = 0 and baseline CSF (Aβ1‐42 and t‐tau) were included. A subset (N = 329) had at least two follow‐up CDR time points to compute clinical progression. A traditional score was calculated as the average discrepancy between the partner and participant’s responses on the Everyday Cognition questionnaire, with positive scores indicating heightened awareness and negative scores indicating unawareness. An unawareness (resp., heightened awareness) sub‐score was computed by applying a ceiling (resp., floor) at zero to item‐level differences before averaging. Each measure was compared by AD pathology, adjusted for age and sex. Survival analyses examined the relationship of the new scores with clinical progression.
Result
CSF t‐tau, but not Aβ1‐42, was a significant independent predictor of the traditional and unawareness scores in models adjusting for each other. There was no significant interaction between the two (Table.2). Survival analyses showed a one‐point improvement on the unawareness sub‐score associated with an 84% reduction in progression hazard (HR = 0.16, p<0.001), or equivalently. A one‐point decline and 525% increase in progression hazard, with no significant effect for the heightened awareness score.
Conclusion
Decomposing the traditional awareness score into two sub‐scores, allowed the investigation of the relationship between AD and awareness with more specific, sensitive measures. Of these, the unawareness sub‐score was associated with t‐tau and a strong predictor of clinical progression, providing further support that discordant self‐ and informant‐reported cognitive decline may provide important clinical information.
Background
Awareness of memory impairment has been shown to vary across the AD spectrum with an initial heightened awareness at the preclinical stage, and a subsequent loss of awareness with AD ...progression (Hanseeuw et al.,2020). Whether there are potential differences in the evolution of awareness for cognitive domains other than memory is unknown. In this study, we investigated the evolution of awareness in visuospatial, language, planning, divided attention and organization in cognitively older adults that later progressed versus those who remained stable.
Methods
Our study included 621 cognitively normal (CN) ADNI participants (Tab1). Individuals were considered Stable or Progressors (n = 147) on the basis on the Clinical Dementia Rating scale global score (stable: scores at first and last observation both 0, progression:last score≥0.5). Cognitive complaints were recorded using the Everyday Cognition (ECog) questionnaire, using both participant’s and informant’s average complaints in each of the six subscales: divided attention, language, memory, organization, planning and visuo‐spatial. Generalized linear mixed‐effect models were run to predict complaints within each subscale, using time, the source of complaint (informant vs participant), and their interaction as independent variables, adjusting for age, gender and education. Jonhson‐Neyman Points (JNP) were computed for significant interactions, and simple slopes analyses were performed.
Results
Stable participants displayed a similar evolution of both informant and participant complaints (Fig1, left panels). Among progressors, all models showed significant interactions with participants expressing greater, and subsequent lower complaints than informants (Fig1, right panels). JNP analyses revealed that, while on some subscales this transition occurred only after/close to progression (i.e., divided attention, language, memory and organization), it could be observed years before progression in others (i.e., planning and visuo‐spatial).
Conclusions
Progressive participants expressed greater, and then lower complaints as compared to their informant, demonstrating a transition from heightened to reduced awareness over time. Our results attest that, while most studies are focusing on memory awareness, other domains might also show early changes in awareness. This advocates for including the informant’s appraisal in the examination process, as well as to expand the focus to other cognitive abilities.
Background
Heightened awareness and unawareness of memory decline are known to manifest at different stages in AD, and both have been shown to predict clinical progression. Awareness is often ...measured by the discrepancy between the informant’s and participant’s mean scores on a memory complaints questionnaire. A major limitation of this approach is that a participant may display heightened awareness on some items and unawareness on others, averaging out each’s effect. Here, we present a new item‐level methodological approach, allowing us to examine these two dimensions of awareness (heightened/unawareness). We aimed to compare all these measures and investigate their ability to predict clinical progression.
Method
This study included 438 ADNI participants with CDR global = 0 at the time of their baseline Everyday Cognition (ECog) measurement and at least two follow‐up CDR assessments (Tab.1). Disease progression was defined as the first instance of two consecutive CDR global≥0.5. A traditional awareness score was calculated by subtracting the mean average ECog score between the informant and participant complaints (Fig.1A). An unawareness score was generated by capping item‐level positive differences at zero and then averaging (Fig.1B). Its complementary heightened awareness score was generated by capping negative differences at zero (Fig.1C). For all three measures, baseline group differences were analyzed using Wilcoxon rank‐sum tests. Robust Cox regression models were run to test the association between each baseline measure and progression, adjusted for age, gender, and education.
Result
The progressing (N = 91) and stable (N = 347) groups demonstrated similar scores for traditional (p = .11) and heightened awareness (p = .72). A significant difference was found for unawareness, with progressors displaying more unawareness than stable participants (p<.001;Tab.1,Fig.1). Robust Cox regression models showed a significant association between greater risk of progression and unawareness (p<.001) and a marginal association with lower traditional scores (p = .06). There was not a significant association with heightened awareness (p = .75).
Conclusion
By separating its two dimensions, our novel approach allows us to refine the analysis of awareness and to determine each dimension’s respective contributions to future clinical progression. These findings provide evidence that unawareness rather than heightened awareness is associated with clinical progression and supports the utility of informant report of decline.
Background
Mnemonic anosognosia (i.e., unawareness) is a behavioral condition characterized by a lack of self‐awareness of objective memory decline. In the context of Alzheimer’s Disease (AD), ...unawareness may be a sign of predementia stages. It contributes to disease severity, symptomatology worsening, and caregiver burden and is a good predictor of clinical progression. Here, we use in‐vivo multi‐modal neuroimaging to profile the brain phenotype of individuals presenting altered self‐awareness of memory during aging.
Methods
We used amyloid‐ and tau‐PET (N = 335) and resting‐state fMRI (N = 713) data of individuals from the Anti‐Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4)/Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies (Table1A). The neurocognitive profile of unawareness was characterized using between‐groups comparisons (omnibus and post‐hoc analyses) of the objective (LM delayed memory, and FCSRT free and cued scores) and subjective (MACQ) memory measurements of individuals classified as unaware of their memory impairment, compared to aware, subjective‐complainers and control individuals. To characterize the cortical burden of amyloid and tau and their modulatory effect on functional connectivity networks, we applied whole‐brain voxel‐wise GLM analyses, region‐of‐interest associations, and graph‐theory metrics (e.g., degree centrality).
Results
Unaware and aware individuals perform worse than the control group in objective memory tests, while unaware individuals differ from aware but not from controls in MACQ (Table1B). The unaware group presents elevated amyloid and tau burden in midline core regions of the default mode network (DMN) compared to aware, complainer or control individuals (p‐value<0.05) (Figure1AB). Tau spreading in controls showed significant connectivity toward DMN and lateral and medial occipito‐parietal regions (Figure1C). Unawareness is characterized by an altered network connectivity pattern modulated by tau accumulation in which hyperconnectivity is observed mainly in midline DMN and posterior occipito‐parietal regions (p‐value<0.05) (Figure2A). Degree centrality revealed the main connectivity hubs altered by tau deposits in unaware individuals (e.g., posterior regions) (Figure2B).
Conclusions
Mnemonic anosognosia is an early behavioral biomarker of AD pathology. Unawareness of memory decline leads to distinct brain phenotype, characterized by increased amyloid and tau burden, along with functional network connectivity disruptions, in several areas of the self‐referential brain network, including the posterior cerebral cortex of the human brain.
Background
Better predicting depression following a stressor like COVID‐19 would help identify vulnerable individuals who might benefit the most from early intervention. We examined change in ...depressive symptoms relative to the onset of COVID‐19 and longitudinal trajectories of depressive symptoms post‐pandemic‐onset. As a secondary objective, we examined associations of these changes with stress, resilience, and in vivo AD biomarkers.
Method
Data were analyzed from 101 older adults (cognitively unimpaired at baseline) from the Harvard Aging Brain Study, a longitudinal observational cohort study. Depressive symptoms are assessed annually with the 30‐item Geriatric Depression Scale (GDS), and for these analyses, participants had no/mild self‐reported depression (GDS<11) at the last pre‐COVID examination. GDS‐delta scores were computed using the mean of the post‐COVID‐onset scores subtracted by the last pre‐COVID examination for participants. Levels of resilience (Connor‐Davidson Resilience scale) and stress (Perceived Stress Scale) were assessed within a year after pandemic onset. Cortical amyloid (PiB) and entorhinal (EC) and inferior temporal (IT) tau (FTP) were analyzed using pre‐pandemic acquisition (mean 1.6 years to pandemic onset). We used linear models to predict GDS‐delta and linear mixed effects models to predict GDS trajectory post‐COVID onset from resilience, stress, and the interaction of each with AD biomarkers (PiB and FTP).
Results
GDS‐delta was predicted by resilience (t = ‐4.69, p<0.001) and stress (t = 3.51, p<0.001) such that those with lower resilience and higher stress experienced higher GDS‐delta. EC tau, but not IT tau or cortical amyloid, interacted with stress to predict GDS‐deltas (EC tau*stress: t = 2.04; p = 0.04) indicating that those with higher levels of EC tau and stress experienced higher GDS‐delta. For post‐pandemic‐onset GDS trajectory, no significant longitudinal associations were observed, but there was a marginal interaction between EC‐tau*stress in predicting greater GDS trajectories (t = ‐1.79, p = 0.08).
Conclusion
Results suggest that change in depressive symptoms in elders following a societal stressor is associated with lower resilience and higher stress; this may be exacerbated by concurrent EC tau pathology. Moreover, elevated depressive symptoms in the years following onset of a societal stressor can be partially predicted by increased EC tau and stress, highlighting a vulnerable population who may benefit from preventive interventions throughout a major stressor.
Background
Both the loss of awareness for cognitive decline (a.k.a anosognosia) and neuropsychiatric symptoms (NPS) are commonly seen in patients with Alzheimer’s disease (AD) dementia, even in the ...prodromal stages. Anosognosia and NPS may negatively affect caregiver burden and patient’s activities of daily living. Despite the high impact of these symptoms on patients and their caregivers, our knowledge of how they develop across the AD spectrum is limited. Here, we explored the cross‐sectional and longitudinal associations between anosognosia and NPS in individuals with mild cognitive impairment (MCI).
Method
We included 310 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with a baseline Clinical Dementia Rating global score of 0.5. Everyday Cognition (ECog) questionnaire scores were used to measure complaints from participants and study‐partners at baseline and annually over a mean of 4 years (SD = 3). Anosognosia was defined as the study‐partner having an ECog score ≥2.5/4 and the participant having an ECog score ≤2.5/4 on their baseline measure and their last observation and without having more than 2 consecutive deviating observations during the follow‐up period. The 12 study‐partner‐rated Neuropsychiatric Inventory items determined the presence or absence of specific NPS (see Table 1). The Mini‐Mental State Examination (MMSE), an assessment used to screen for cognitive impairment, was administered annually. Survival analyses were performed to analyze the rate of appearance of NPS over time in individuals with and without anosognosia.
Result
Sixty participants displayed anosognosia, while 250 did not. At baseline, groups had similar lengths of follow‐up. Participants with anosognosia had lower MMSE scores and a higher proportion of amyloid positivity (see Table 1). At baseline, the frequency of agitation and disinhibition was higher in the anosognosia group. Survival analyses showed earlier onset of all NPS in the anosognosia group (see Figure 1). Specifically, aberrant motor behavior, irritability, disinhibition, apathy, agitation, and hallucinations were highly significant.
Conclusion
Loss of awareness for cognitive decline is associated with greater frequency and faster onset of NPS over time in participants with MCI. These results support the hypothesis of a potential common underlying neurophysiological process, a finding that needs to be addressed further in future studies.
Background
Patients with Alzheimer’s disease (AD) often demonstrate anosognosia, which is reduced awareness of cognitive decline. Anosognosia has been associated with tau accumulation (d'Oleire ...Uquillas et al., 2020) and impaired resting‐state functional connectivity (FC) in self‐referential networks (Vannini et al., 2017, Valera‐Bermejo et al., 2022). The explicit links between AD pathological deposits and large‐scale functional networks associated with anosognosia have yet to be elucidated. Here, we sought to examine whether FC plays a modulatory role in the effect of tau on awareness in participants across the AD spectrum.
Method
We included 58 participants from two observational cohorts—44 asymptomatic (Clinical Dementia Rating (CDR) global score = 0) and 14 symptomatic (CDR≥0.5) individuals (Table1). Awareness was measured as the participant‐study partner discrepancy on the Cognitive Function Index. Flortaucipir‐PET was used to quantify tau accumulation, and segregation analysis was applied to resting‐state fMRI data to asses within‐network connectivity. For both modalities, the mean value in each of the Yeo 7 networks was used. First, a linear regression model was performed to assess the association between awareness and group (i.e., symptomatic/asymptomatic). Linear regression models were also used to assess the relationship between awareness and tau in the 7 networks, separately. Finally, we examined the effect of the FC×tau interaction on awareness. All models were adjusted for age, sex, and education.
Result
Holding age, sex, and education constant, mean awareness was 0.18 lower in symptomatic (vs. asymptomatic) participants (p<0.01). Lower awareness was associated with a higher tau burden in all 7 networks (Table2). Interaction effects between tau and FC were observed. Specifically, reduced awareness was associated with high tau burden when the salience network was less functionally connected (Figure1A; β = ‐0.23, p = 0.02) and when the dorsal attention network was more functionally connected (Figure1B; β = 0.70, p = 0.03). For all other networks, the relationship between awareness and tau was not modified by the FC of the same network (Table2).
Conclusion
These findings provide new insights into the neuropathological correlates of anosognosia in AD. It suggests that anosognosia is not only due to local pathology in single brain areas but also to altered connectivity between them, especially within self‐referential networks.
Background
Loss of awareness of cognitive decline (a.k.a. anosognosia) is a common symptom of Alzheimer’s disease (AD) dementia and has also been observed in its predementia stages. Anosognosia is ...thought to be related not only to functional changes in individual brain regions, but also to a disturbance in functional connectivity (FC) between or within networks. This study aimed to investigate how memory awareness relates to resting‐state fMRI segregation (within‐network connectivity) and integration (between‐network connectivity) maps across the AD spectrum.
Method
We included 66 older adults divided in two groups: cognitively normal (CN, n = 49), and symptomatic (mild cognitive impairment or mild AD; n = 17). Memory awareness was measured as the discrepancy between the participant’s and study partner’s scores on the Cognitive Function Instrument. Positive values indicated heightened awareness and negative values indicated unawareness. We assessed whole‐brain connectivity with resting‐state fMRI and computed voxel‐level maps of segregation and integration. General linear models were used to relate the integration or segregation of each voxel to memory awareness (in the total sample and in the two groups separately), adjusted for age, sex, and education. Multiple comparison correction was performed using cluster‐wise Monte Carlo simulations.
Result
Demographics are presented in Table 1. Segregation maps showed that lower awareness was associated with increased connectivity within the frontoparietal network (FPN) and with decreased connectivity within the medial visual, default mode (DMN), and sensory‐motor networks (Figure 1A(i); Table 2A(i)). The relationship with the FPN persisted in the CN and symptomatic groups separately, and an additional negative association between awareness and FC in the salience network was found in the CN group (Figure 1B‐C(i); Table 2B‐C(i)). In integration maps, lower awareness was associated with increased between‐network connectivity of the dorsal attention and DMN, and decreased connectivity of the salience and sensory‐motor networks (Figure 1A(ii); Table 2A(ii)). In the CN group, the sensory‐motor relationship persisted, while the DMN relationship reversed (Figure 1B‐C(ii); Table 2B‐C(ii)).
Conclusion
Anosognosia is characterized by reduced FC patterns featuring disconnection between self‐referential networks (DMN and salience) to other networks and hyperconnectivity within the FPN. Future studies should investigate the pathological underpinnings for these functional changes.
Background
Both loss of awareness for cognitive decline (a.k.a. anosognosia) and neuropsychiatric symptoms (NPS) are common symptoms in Alzheimer’s disease (AD) and have been associated with AD ...pathology. Recent studies have shown a co‐occurrence between these symptoms across the AD spectrum, suggesting shared underlying neurophysiological processes, especially within the default mode network (DMN). Here, we investigated the relationship between NPS and altered awareness and the structural integrity (as assessed with diffusion tensor imaging, DTI) of brain regions supporting the DMN in participants with and without amyloid pathology.
Methods
Three‐hundred participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) underwent an amyloid positron emission tomography (PET), using 18F‐AV45 (florbetapir), and were classified into two groups: amyloid‐positive (A+) and negative (A‐). Individual mean fractional anisotropy (FA) was calculated from tracts overlapping the DMN regions. An awareness index was computed using the discrepancy between Everyday Cognition questionnaire scores from participants and informants. The Neuropsychiatric Inventory Total Score was used to assess the informant‐reported NPS. We compared amyloid groups on demographics and our different measures of interest. Pearson correlations were used to determine associations between measures of interest in each amyloid group. A multivariate multiple regression (MMR) model was performed to determine whether structural brain integrity predicts altered awareness and NPS jointly.
Results
A+ participants were significantly older (74 ± 7 vs. 72 ± 7 for A‐), more impaired (CDR global), and showed lower awareness and diffusion, and greater NPS (all p<0.001, see Table 1). Significant correlations were found between the FA, NPS, and awareness measures in A+ participants, with decreased FA associated with decreased awareness and more NPS. The MMR confirmed these associations between FA, awareness and NPS (p<0.02, see Table 2). The Pillai test revealed that the DTI effect jointly contributed to both models. No significant relationships were observed in the A‐ group.
Conclusion
Our results show that, in amyloid‐positive individuals across the AD spectrum, decreased awareness and increased NPS were related to decreased structural integrity of the DMN. This supports the hypothesis of common neurobiological mechanisms underlying anosognosia and NPS in AD.
Abstract
Background
While memory performance is well studied in preclinical Alzheimer's disease (AD), there are relatively few studies concerning memory errors. However, in the clinical and prodromal ...stages, intrusions are very frequent, and the specific error profile appears to be particularly diacritical compared to other diseases. In this study, we explore whether the specific pattern of errors produced in memory tests can be predicted by AD biomarkers load in asymptomatic individuals at risk for AD.
Method
318 cognitively normal older adults from the INSIGHT‐PreAD cohort were studied. We present here the data for a three‐year follow‐up. Errors were recorded in two types of memory tests, a verbal test (i.e., FCSRT) and a visual test (i.e., DMS48). Given the distribution of the data, we used Zero‐Inflated Generalized Linear Mixed‐effects Models (ZIGLMMs). Concerning verbal intrusions, two types of patterns were studied, either their context of occurrence (free vs. cued recall) or the type of error (semantically related or not). For visual false recognitions we studied the type of error (i.e. Paired, Abstract or Unique).
Result
Participants produced significantly more semantically related intrusions regardless of the level of brain amyloidosis. Regarding context, participants with higher amyloid produced significantly more intrusions in free recall situations. However, there is no effect of the SUVr on those occurring in cued recall. For false recognitions, the level of brain amyloidosis significantly increases the frequency of unrelated errors (semantically and graphically). All together, the SUVr value efficiently predict a specific error pattern.
Conclusion
This study demonstrates that a specific pattern of memory errors can occur even at early stages of AD evolution. Regarding verbal tests, our results show that asymptomatic at‐risk participants tend to exhibit errors in free recall situations, which can be related to an early executive retrieval dysfunction. In visual modality, the results suggest an abolition of familiarity, associated with the internal temporal regions, which are precociously affected in AD. Our results show that a specific error profile is associated with increased brain amyloidosis in cognitively normal elderly participants.
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