Amyloid-negative Group Research Articles

Biomarker pathway heterogeneity of amyloid-positive individuals.

In amyloid-positive individuals, disease-related biomarker heterogeneity is understudied. We used Subtype and Stage Inference (SuStaIn) to identify data-driven subtypes among cerebrospinal fluid (CSF) amyloid beta (1-42)-positive individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNIGO/2 [n=376]). Variables included: CSF phosphorylated tau (p-tau181), hippocampal and whole-brain volume, logical memory (LM), composite Trail Making Test score, and white matter hyperintensity (WMH) volumes. CSF amyloid-negative, apolipoprotein E ε4 non-carrier cognitively unimpaired controls (n=86) were used to calculate z scores. One subtype (n=145) had early LM changes, with later p-tau and WMH changes. A second subtype (n=88) had early WMH changes, were older, and more hypertensive. A third subtype (n=100) had early p-tau changes, and reflected typical Alzheimer's disease. Some amyloid positive (n=43) individuals were similar to the amyloid-negative group. This work identified heterogeneity in individuals who are conventionally considered homogeneous, which is likely driven by co-pathologies including cerebrovascular disease. Data-driven modeling identified marker heterogeneity in amyloid-positive individuals. Heterogeneity reflected Alzheimer's disease-like, vascular-like, and mixed pathology presentations. Some amyloid-positive individuals were more similar to amyloid-negative controls. Vascular pathology plays a key role in understanding heterogeneity in those on the amyloid pathway.

Risk Factors for Rapid Cognitive Decline in Amyloid-Negative Individuals Without Cognitive Impairment or With Early-Stage Cognitive Loss in Screening Tests.

Although rapid cognitive decline (RCD) is an important unfavorable prognostic factor, not much is known about it, especially in amyloid-negative individuals. The purpose of this study was to investigate risk factors for RCD in amyloid-negative individuals. We retrospectively enrolled 741 individuals who were either cognitively unimpaired or had early-stage cognitive ability loss and who underwent 18F-florbetaben (FBB) (n = 402) or 18F-flutemetamol (FMM) (n = 339) PET/CT. Based on visual and semiquantitative (SUV ratio [SUVR]-based) analysis, the following amyloid-negative groups were established: visual-negative FBB (n = 232), visual-negative FMM (n = 161), SUVR-negative FBB (n = 104), and SUVR-negative FMM (n = 101). Univariable and multivariable logistic regression analyses were performed for RCD using 5 SUVRs, 5 cortical thicknesses, and 5 neuropsychological domains and clinico-demographic factors. In the amyloid-negative groups, a decline in language function was commonly identified as a significant risk factor for RCD (P = 0.0044 in the visual-negative FBB group, P = 0.0487 in the visual-negative FMM group, P = 0.0031 in the SUVR-negative FBB group, and P = 0.0030 in the SUVR-negative FMM group). In addition, declines in frontal/executive function, frontal SUVR, and parietal SUVR; a longer duration of education; and mild cognitive decline in the amyloid-negative groups were also significant risk factors for RCD. Even in amyloid-negative individuals without cognitive impairment or with early-stage cognitive ability loss, those with decreased language and frontal/executive functions on neuropsychological testing are at risk of progression to RCD.

Relationship Between Amyloid Positivity and Sleep Characteristics in the Elderly With Subjective Cognitive Decline.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by a progressive decline in cognition and performance of daily activities. Recent studies have attempted to establish the relationship between AD and sleep. It is believed that patients with AD pathology show altered sleep characteristics years before clinical symptoms appear. This study evaluated the differences in sleep characteristics between cognitively asymptomatic patients with and without some amyloid burden. Sleep characteristics of 76 subjects aged 60 years or older who were diagnosed with subjective cognitive decline (SCD) but not mild cognitive impairment (MCI) or AD were measured using Fitbit® Alta HR, a wristwatch-shaped wearable device. Amyloid deposition was evaluated using brain amyloid plaque load (BAPL) and global standardized uptake value ratio (SUVR) from fluorine-18 florbetaben positron emission tomography. Each component of measured sleep characteristics was analyzed for statistically significant differences between the amyloid-positive group and the amyloid-negative group. Of the 76 subjects included in this study, 49 (64.5%) were female. The average age of the subjects was 70.72±6.09 years when the study started. 15 subjects were classified as amyloid-positive based on BAPL. The average global SUVR was 1.598±0.263 in the amyloid-positive group and 1.187±0.100 in the amyloid-negative group. Time spent in slow-wave sleep (SWS) was significantly lower in the amyloid-positive group (39.4±13.1 minutes) than in the amyloid-negative group (49.5±13.1 minutes) (p=0.009). This study showed that SWS is different between the elderly SCD population with and without amyloid positivity. How SWS affects AD pathology requires further research.

ATN Classification and Clinical Progression of the Amyloid-Negative Group in Alzheimer's Disease Neuroimaging Initiative Participants.

Alzheimer's disease has recently been classified using three biological markers (amyloid [A], tau [T], and neurodegeneration [N]) to help elucidate its progression. We aimed to investigate whether there were differences between cognitive function and the clinical dementia symptoms over time relative to the ATN classification in the amyloid-negative group. In the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort, 310 participants who underwent all the tests required for ATN classification were enrolled. The cognitive function score differences (Alzheimer's Disease Assessment Scale-Cognitive Subscale 13 [ADAS-Cog 13], Clinical Dementia Rating Sum of Boxes [CDR-SOB], and Mini-Mental State Examination [MMSE]) between the groups were analyzed using the analysis of covariance and score changes over time with a linear mixed-effects model. In the cross-sectional analysis, ADAS-Cog 13 scores were higher for A-T-N+ and A-T+N+ than for A-T-N- (p<0.001) and A-T+N- (p<0.001). In the longitudinal analysis, CDR-SOB scores for A-T+N+ deteriorated faster than A-T-N- (p<0.001), A-T+N- (p<0.001) and A-T-N+ (p<0.001). Hippocampal atrophy progressed faster in A-T-N+ (p<0.001) and A-T+N+ (p=0.02) than in A-T-N-. Through this study, we discovered that even in individuals classified as amyloid negative, neurodegeneration with tau deposition exacerbates cognitive decline and worsens clinical symptoms, underscoring the need for continuous monitoring and observation.

44 Can Clinical Trial data Inform our Understanding of the role of Depressive Symptoms in Alzheimer's Disease?

Objective:Neuropsychiatric symptoms concerning mood are common in Alzheimer's disease (AD), but it is unclear if they are etiologically related to AD pathophysiology or due to factors considered to be non-pathogenic, such as small vessel cerebrovascular disease. New generation clinical trials for AD often enroll participants with evidence of AD pathophysiology, indexed by amyloid PET scanning, but who are cognitively asymptomatic. We used screening data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study to examine the extent to which depressive symptoms are associated with amyloid pathophysiology and small vessel cerebrovascular disease, in the form of white matter hyperintensities (WMH).Participants and Methods:The A4 study randomizes cognitively healthy older adults with evidence of amyloid pathophysiology on PET scanning. We used screening data, which included amyloid status (positive, negative) by visual read, amyloid PET standard uptake value ratio (SUVR) in cortical regions, and MRI data acquired in a subset (n=1,197, mean age 71.6 +/- 4.8 years, 57% women) to quantitate total WMH volume. Depressive symptoms were evaluated with the 15-item Geriatric Depression Scale, which we used both as a continuous variable and to define 'depressed' and 'non-depressed' groups, based on a cut score of &gt; 5. We examined whether 1) depressive symptoms and proportion of depressed individuals differed between amyloid positive and negative groups, 2) there is a relationship between amyloid SUVR and depressive symptoms that differs as a function of amyloid positivity status, and 3) there is a relationship between WMH volume and depressive symptoms that differs as a function of amyloid positivity status.Results:Although depressive symptom severity did not differ between groups (t=0.14, p=0.88), a greater proportion of individuals were classified as depressed in the amyloid negative group than the amyloid positive group (3.5% vs. 1.9%, X2=4.60, p=0.032). Increased amyloid SUVR was associated with increased GDS scores among amyloid positive individuals (r=0.117, p=0.002) but not among amyloid negative individuals (r=0.006, p=0.68, Positivity Status x SUVR interaction on GDS: ß=0.817, p=0.029). Increased WMH was associated with higher GDS scores (ß=0.105, p=0.017) but not differentially in amyloid positive and negative participants (Positivity Status x WMH interaction on GDS: ß=-0.010, p=0.243).Conclusions:These analyses have several implications. First, individuals who are screened to participate in a clinical trial but do not have evidence of amyloidosis may be misattributing concerns about underlying AD pathophysiology to depressive symptoms. Second, the severity of AD pathophysiology, indexed by amyloid PET SUVR, may drive a small increase in depressive symptomatology among individuals over visual diagnostic thresholds. Third, small vessel cerebrovascular changes are additionally associated with depressive symptoms but in a manner that is independent of AD pathophysiology. Overall, depressive symptoms and depression are likely multiply determined among prospective clinical trial participants for preclinical AD.

Distinct amyloid-dependent patterns of nigra dopamine depletion in Lewy body diseases.

Concomitant amyloid pathology is not uncommon and contributes to the clinical characteristics of Lewy body disease (LBD). We investigated the effect of amyloid on striatal18F-FP-CIT uptake patterns in LBD, including Parkinson's disease (PD) and dementia with Lewy bodies. We enrolled 125 patients with LBD who underwent18F-florbetaben positron emission tomography (PET) and18F-FP-CIT PET. Patients were divided into amyloid-positive and amyloid-negative groups. We investigated the effect of amyloid on striatal dopamine transporter (DAT) availability, depending on the type of LBD, using general linear models with interaction analysis after controlling for age, sex, education, deep white matter hyperintensity (WMH), periventricular WMH, and cognitive status. There was a significant interaction effect between the disease group and the presence of amyloid on DAT availability in the anterior putamen, posterior putamen, caudate, and ventral striatum. In the presence of amyloid, only the PD group exhibited decreased DAT availability in the anterior and posterior putamen. In both groups, the presence of amyloid was not associated with DAT availability in the caudate and ventral striatum. The presence of amyloid was not directly related to the worse parkinsonian motor symptoms in both groups. However, there was a significant indirect effect of amyloid on parkinsonian motor symptoms, which was mediated by anterior and posterior putaminal DAT availability in the PD group alone. This study demonstrates different amyloid-dependent or amyloid-independent18F-FP-CIT PET patterns in patients with LBD, suggesting distinctive interactions between α-synuclein and amyloid pathology based on the type of LBD.

Evaluation of glymphatic system activity using diffusion tensor image analysis along the perivascular space and amyloid PET in older adults with objectively normal cognition: a preliminary study.

Diffusion tensor image analysis along the perivascular space (DTI-ALPS) is a recently introduced method for the assessment of the glymphatic system without the need for contrast injection. The purpose of our study was to assess the glymphatic system in cognitively normal older adults with or without subjective cognitive decline (SCD) using DTI-ALPS, and correlating with amyloid PET. To evaluate the glymphatic system in cognitively normal older adults using DTI-ALPS, we built a prospective cohort including a total of 123 objectively cognitively normal older adults with or without SCD. The ALPS index was calculated from DTI MRI and was assessed by correlating it with standardized uptake value ratios (SUVRs) from amyloid PET and clinically relevant variables. The study subjects were also divided into amyloid "positive" and "negative" groups based on the result of amyloid PET, and the ALPS indices between those two groups were compared. The ALPS index was not significantly different between the normal and SCD groups (P = 0.897). The mean ALPS index from the amyloid positive and amyloid negative group was 1.31 and 1.35, respectively, which showed no significant difference (P = 0.308). Among the SUVRs from variable cortices, that of the paracentral cortex was negatively correlated with the ALPS index (r = -0.218, P = 0.016). Multivariate linear regression revealed that older age (coefficient, -0.007) and higher SUVR from the paracentral cortex (coefficient, -0.101) were two independent variables with a significant association with a lower ALPS index (P = 0.015 and 0.045, respectively). DTI-ALPS may not be useful for evaluation of the glymphatic system in subjects with SCD. Older age was significantly associated with lower ALPS index. Greater amyloid deposition in the paracentral cortex was significantly associated with lower glymphatic activity in cognitively normal older adults. These results should be validated in future studies on the relationships between ALPS index and other fundamental compartments in glymphatic system, such as perivenous space and the meningeal lymphatic vessels.

A Pilot Study on Cerebral Blood Flow and Mini-Mental State Examination to Predict Amyloid Deposition in Preclinical Alzheimer's Disease.

Earlier differential diagnosis of dementia remains a major challenge. Although amyloid deposition by positron emission tomography is an emerging standard for the diagnosis of Alzheimer's disease, it is too expensive for routine use in clinical settings. We conducted a pilot study on the potential usefulness of single-photon emission computed tomography and the Mini-Mental State Examination to predict amyloid positron emission tomography positivity in preclinical Alzheimer's disease. Eighteen subjects, including 11 with mild cognitive impairment and 7 with subjective cognitive decline, underwent 18F-florbetapir positron emission tomography, 99mTc-ethylcysteinate dimer cerebral perfusion single-photon emission computed tomography, and the Mini-Mental State Examination. For the assessment of amyloid deposition, visual judgment as a qualitative method and a semiautomatic software analysis as a quantitative method were used. Six subjects were judged as amyloid positive, including 4 mild cognitive impairment and 2 subjective cognitive decline subjects. Compared to the amyloid positron emission tomography-negative group, this group showed a statistically significant difference in the Mini-Mental State Examination recall score [2 (1 : 3) vs. 3 (2 : 3), P = .041] and single-photon emission computed tomography findings from the amyloid-negative group. In the mild cognitive impairment subgroup, correlations were found between amyloid deposition and single-photon emission computed tomography indicators, while in the subjective cognitive decline subgroup, only the Mini-Mental State Examination recall score correlated with amyloid deposition. The Mini-Mental State Examination recall score and single-photon emission computed tomography indicators may be worthwhile for further evaluation as predictors of amyloid deposition in the preclinical stage.

Disruption of early visual processing in amyloid-positive healthy individuals and mild cognitive impairment

BackgroundAmyloid deposition is a primary predictor of Alzheimer’s disease (AD) and related neurodegenerative disorders. Retinal changes involving the structure and function of the ganglion cell layer are increasingly documented in both established and prodromal AD. Visual event-related potentials (vERP) are sensitive to dysfunction in the magno- and parvocellular visual systems, which originate within the retinal ganglion cell layer. The present study evaluates vERP as a function of amyloid deposition in aging, and in mild cognitive impairment (MCI).MethodsvERP to stimulus-onset, motion-onset, and alpha-frequency steady-state (ssVEP) stimuli were obtained from 16 amyloid-positive and 41 amyloid-negative healthy elders and 15 MCI individuals and analyzed using time–frequency approaches. Social cognition was assessed in a subset of individuals using The Awareness of Social Inference Test (TASIT).ResultsNeurocognitively intact but amyloid-positive participants and MCI individuals showed significant deficits in stimulus-onset (theta) and motion-onset (delta) vERP generation relative to amyloid-negative participants (all p < .01). Across healthy elders, a composite index of these measures correlated highly (r = − .52, p < .001) with amyloid standardized uptake value ratios (SUVR) and TASIT performance. A composite index composed of vERP measures significant differentiated amyloid-positive and amyloid-negative groups with an overall classification accuracy of > 70%.DiscussionvERP may assist in the early detection of amyloid deposition among older individuals without observable neurocognitive impairments and in linking previously documented retinal deficits in both prodromal AD and MCI to behavioral impairments in social cognition.

Effect of Amyloid on Cognitive Performance in Parkinson's Disease and Dementia with Lewy Bodies.

Concomitant amyloid pathology contributes to the clinical heterogeneity of Lewy body diseases (LBDs). The objective of this study was to investigate the pattern and effect of amyloid accumulation on cognitive dysfunction in Parkinson's disease (PD) and dementia with Lewy bodies (DLB). We retrospectively assessed 205 patients with LBD (91 with DLB and 114 with PD) who underwent 18 F-florbetaben positron emission tomography and divided them into amyloid-positive and amyloid-negative groups depending on global standardized uptake value ratios (SUVRs). We investigated the effect of group on the regional and global SUVRs using general linear models (GLMs) after controlling for age, sex, cognitive status, and score on the Korean version of the Mini-Mental State Examination. Moreover, the effect of amyloid on cognitive function, depending on the type of LBD, was evaluated using GLMs with interaction analysis. In all evaluated regions including the striatum, the DLB group showed a higher SUVR than the PD group. Among amyloid-positive patients, the DLB group had a higher regional SUVR than the PD group in the frontal and parietal cortices. There was a significant interaction effect between amyloid and disease groups in language and memory function. In patients with PD, global amyloid load was negatively associated with language (B=-2.03; P=0.010) and memory functions (B=-1.96; P < 0.001). However, amyloid load was not significantly associated with cognitive performance in the DLB group. Although the burden of amyloid was higher in the DLB group, amyloid accumulation was negatively associated with the memory and language functions in the PD group only. © 2022 International Parkinson and Movement Disorder Society.

Is plasma amyloid-β 1–42/1–40 a better biomarker for Alzheimer’s disease than AβX–42/X–40?

BackgroundA reduced amyloid-β (Aβ)42/40 peptide ratio in blood plasma represents a peripheral biomarker of the cerebral amyloid pathology observed in Alzheimer’s disease brains. The magnitude of the measurable effect in plasma is smaller than in cerebrospinal fluid, presumably due to dilution by Aβ peptides originating from peripheral sources. We hypothesized that the observable effect in plasma can be accentuated to some extent by specifically measuring Aβ1–42 and Aβ1–40 instead of AβX–42 and AβX–40.MethodsWe assessed the plasma AβX–42/X–40 and Aβ1–42/1–40 ratios in an idealized clinical sample by semi-automated Aβ immunoprecipitation followed by closely related sandwich immunoassays. The amyloid-positive and amyloid-negative groups (dichotomized according to Aβ42/40 in cerebrospinal fluid) were compared regarding the median difference, mean difference, standardized effect size (Cohen’s d) and receiver operating characteristic curves. For statistical evaluation, we applied bootstrapping.ResultsThe median Aβ1–42/1–40 ratio was 20.86% lower in amyloid-positive subjects than in the amyloid-negative group, while the median AβX–42/X–40 ratio was only 15.56% lower. The relative mean difference between amyloid-positive and amyloid-negative subjects was −18.34% for plasma Aβ1–42/1–40 compared to −15.50% for AβX–42/X–40. Cohen’s d was 1.73 for Aβ1–42/1–40 and 1.48 for plasma AβX–42/X–40. Unadjusted p-values < 0.05 were obtained after .632 bootstrapping for all three parameters. Receiver operating characteristic analysis indicated very similar areas under the curves for plasma Aβ1–42/1–40 and AβX–42/X–40.ConclusionsOur findings support the hypothesis that the relatively small difference in the plasma Aβ42/40 ratio between subjects with and without evidence of brain amyloidosis can be accentuated by specifically measuring Aβ1–42/1–40 instead of AβX–42/X–40. A simplified theoretical model explaining this observation is presented.

Practice Effect of Repeated Cognitive Tests Among Older Adults: Associations With Brain Amyloid Pathology and Other Influencing Factors.

BackgroundPractice effects (PE), after repeated cognitive measurements, may mask cognitive decline and represent a challenge in clinical and research settings. However, an attenuated practice effect may indicate the presence of brain pathologies. This study aimed to evaluate practice effects on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) scale, and their associations with brain amyloid status and other factors in a cohort of cognitively unimpaired older adults enrolled in the CHARIOT-PRO SubStudy.Materials and Methods502 cognitively unimpaired participants aged 60-85 years were assessed with RBANS in both screening and baseline clinic visits using alternate versions (median time gap of 3.5 months). We tested PE based on differences between test and retest scores in total scale and domain-specific indices. Multiple linear regressions were used to examine factors influencing PE, after adjusting for age, sex, education level, APOE-ε4 carriage and initial RBANS score. The latter and PE were also evaluated as predictors for amyloid positivity status based on defined thresholds, using logistic regression.ResultsParticipants’ total scale, immediate memory and delayed memory indices were significantly higher in the second test than in the initial test (Cohen’s dz = 0.48, 0.70 and 0.35, P < 0.001). On the immediate memory index, the PE was significantly lower in the amyloid positive group than the amyloid negative group (P = 0.022). Older participants (≥70 years), women, non-APOE-ε4 carriers, and those with worse initial RBANS test performance had larger PE. No associations were found between brain MRI parameters and PE. In addition, attenuated practice effects in immediate or delayed memory index were independent predictors for amyloid positivity (P < 0.05).ConclusionSignificant practice effects on RBANS total scale and memory indices were identified in cognitively unimpaired older adults. The association with amyloid status suggests that practice effects are not simply a source of measurement error but may be informative with regard to underlying neuropathology.

Subjective cognitive decline-related worries modulate the relationship between global amyloid load and gray matter volume in preclinical Alzheimer's disease.

Subjective cognitive decline (SCD)-related worries are indicative of an increased risk for developing Alzheimer's disease (AD) dementia. However, the influence of SCD-related worries on the relationship between amyloid and gray matter (GM) atrophy remains unknown. A total of 93 SCD participants underwent 18F-florbetapir PET and T1-weighted MRI scans. SCD individuals were classified into amyloid-positive or amyloid-negative groups based on global amyloid uptake. Three-step statistical analyses were performed: (1) partial correlation analysis was conducted to determine whether global amyloid relates to GM volume in amyloid-positive and amyloid-negative groups; (2) linear regression analysis was conducted to determine whether the interaction term (worries × global amyloid) predicts GM volume; and (3) post hoc subgroup linear regression analysis was conducted to determine the association between amyloid and GM volume in the subgroups with and without worries. Age, sex, education and total intracranial volume were adjusted in all models. We found a negative relationship between global amyloid load and GM volume in the right hemisphere (r = 0.441, p = 0.012) and right temporal cortex (r = 0.506, p = 0.003) in the amyloid-positive group. Moreover, in the amyloid-positive group, a significant worries × amyloid interaction effect on GM volume was found in the bilateral hemisphere (right: pinteraction=0.037; left: pinteraction=0.036), left temporal cortex (pinteraction=0.044) and bilateral frontal cortex (right: pinteraction=0.010; left: pinteraction=0.011). Subsequent post hoc analysis revealed a significant amyloid-GM association only in the subgroup with worries but not in the subgroup without worries. In preclinical AD cases, SCD-related worries may occur as a symptom in those cases where amyloid affects GM to a greater extent and may thus represent a high-risk population for future cognitive decline.

Evaluating cognitive profiles of patients undergoing clinical amyloid-PET imaging.

Episodic memory impairment and brain amyloid-beta are two of the main hallmarks of Alzheimer’s Disease. In the clinical setting, these are often evaluated through neuropsychological testing and amyloid PET imaging, respectively. The use of amyloid PET in clinical practice is only indicated in patients with substantial diagnostic uncertainty due to atypical clinical presentation, multiple comorbidities and/or early age of onset. The relationship between amyloid-beta and cognition has been previously investigated, but no study has examined how neuropsychological features relate to the presence of amyloid pathology in the clinical population that meets the appropriate use criteria for amyloid PET imaging. In this study, we evaluated a clinical cohort of patients (n = 107) who presented at the Imperial Memory Clinic and were referred for clinical amyloid PET and neuropsychological assessment as part of their diagnostic workup. We compared the cognitive performance of amyloid-positive patients (Aβ-pos, n = 47) with that of stable amyloid-negative (stableAβ-neg, n = 26) and progressive amyloid-negative (progAβ-neg, n = 34) patients. The amyloid-positive group performed significantly worse than both amyloid-negative groups in the visuospatial and working memory domains. Episodic memory performance, however, effectively differentiated the amyloid-positive group from the stable but not the progressive amyloid-negative group. On affective questionnaires, the stable amyloid-negative group reported significantly higher levels of depression than the amyloid-positive group. In our clinical cohort, visuospatial dysfunction and working memory impairment were better indicators of amyloid positivity than episodic memory dysfunction. These findings highlight the limited value of isolated cognitive scores in patients with atypical clinical presentation, comorbidities and/or early age of onset.

Cognitive profiles in amyloid‐PET‐eligible patients: A retrospective study

AbstractBackgroundThe early cognitive profile of Alzheimer’s Disease (AD) is typically characterised by predominant impairment in episodic memory, reflecting medial temporal lobe dysfunction. However, little is known about the cognitive profile associated with AD pathology in those patients who meet Appropriate Use Criteria (AUC, Johnson et al., 2013) for Amyloid PET Imaging (API). In this group, AD pathology is frequently associated with an atypical clinical course or presentation. Here, we systematically evaluate the cognitive profiles of AUC‐meeting patients in a real‐world clinical setting, combining the information provided by the neuropsychological assessment with the results of Amyloid PET Imaging.MethodFrom a larger sample of 396 patients who underwent Amyloid PET at the Imperial Memory Centre between December 2013 and June 2019, we included those individuals who also had at least one formal neuropsychological assessment (minimum of 4 tests) within 18 months of API (n=124). Both these were solely conducted for clinical purposes, and API was requested after multidisciplinary team discussion. Cognitive measures in amyloid positive (Aβ+) and negative (Aβ‐) patients were compared using non‐parametric tests.ResultsNeuropsychological assessment preceded Amyloid PET Imaging in most cases, for both amyloid‐positive (n=51, mean age 67.24±9.32 years, 58.8% female) and amyloid‐negative (n=73, mean age 67.9±9.64 years, 41.1% female) groups. Cognitive performance in the amyloid‐positive group was significantly worse in 6 of the 14 cognitive measures taken into account: visuo‐spatial functioning, executive functioning, working memory, verbal learning, verbal delayed recall, and confrontation naming (Figure 1). Verbal learning, verbal delayed recall and confrontation naming were the most frequently impaired measures in the amyloid‐positive group, with around 50% of patients performing below 2 standard deviations. Notably, self‐reported symptoms of depression were significantly higher in the amyloid‐negative (7.3±4.38) than in the amyloid‐positive group (4.68±3.7) (p=.002) (Figure 2).ConclusionsIn a sample of patients attending a tertiary Behavioural Neurology clinic, neuropsychological evaluation revealed worse performance in positive API across a range of domains, particularly verbal memory and confrontation naming, with higher rates of symptoms of depression being reported more frequently in the amyloid negative group.

Practice effect of repeated cognitive tests among older adults: Associations with brain amyloid status and other influencing factors

AbstractBackgroundPractice effects (PE), after repeated cognitive measurements, may mask cognitive decline and remain a major issue in clinical and research settings. However, an attenuated practice effect may indicate cognitive decline or the presence of brain pathologies. Exploring factors that influence PE can inform strategies to distinguish true signal from bias in future research. This study aimed to evaluate practice effects on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) scale, and their associations with brain amyloid status in a cohort of older adults enrolled in the Cognitive Health in Ageing Register: Investigational, Observational, and Trial Studies: Prospective Readiness cOhort Study (CHARIOT‐PRO) Sub‐study.Method502 cognitively healthy participants aged 60‐85 years were assessed with RBANS in both screening and baseline clinic visits (median time gap of 3.5 months). We assessed the reliability of the RBANS scale and tested PE based on differences between test and retest scores in total scale and domain‐specific indices. Multiple linear regressions were used to examine factors influencing PE, after adjusting for age, sex, educational attainment, and APOE‐ε4 carriage. PE and the initial RBANS score were also examined as predictors for amyloid positivity status based on defined thresholds, using logistic regression.ResultThe internal consistency (Cronbach's α=0.64) and test‐retest reliability (r=0.79) of RBANS were good. Participants’ Total Scale, Immediate Memory and Delayed Memory indices were significantly higher in the second test than in the initial test (d=3.8, 7.6 and 3.2, P&lt;0.001). On the Immediate Memory index, the PE was significantly lower in the amyloid positive group than the amyloid negative group (d=6.5 vs 8.6, P=0.028). Older participants (≥70 years), women, non‐APOE‐ε4 carriers, and those with worse initial RBANS test performance had larger PE. In addition, worse performance and lower practice effects in immediate or delayed memory index were independent predictors for amyloid positivity (OR=0.97, P&lt;0.05).ConclusionSignificant practice effects on RBANS total scale and memory indices were influenced by age, sex, APOE‐ε4, initial RBANS scores and amyloid status. The association with amyloid suggests that practice effects are not simply a source of measurement error but may be informative with regard to underlying neuropathology.

Disclosure of Amyloid Status for Risk of Alzheimer Disease to Cognitively Normal Research Participants With Subjective Cognitive Decline: A Longitudinal Study.

This study aimed to investigate the long-term impacts of disclosing amyloid status for a risk of Alzheimer disease (AD) to cognitively normal research participants with subjective cognitive decline (SCD), which represents an initial manifestation of AD. Forty-two participants were classified as the amyloid-positive (n = 10) or amyloid-negative (n = 32) groups. We assessed symptoms of anxiety, depression, and test-related distress at 6, 24, and 52 weeks after results disclosure. No difference was found over time in anxiety, depression, and test-related distress in either group. Although no significant differences were observed between groups in anxiety or depression, the amyloid-negative group had a significantly higher level of test-related distress than the amyloid-positive group at 52 weeks. Disclosing amyloid status to cognitively healthy research participants with SCD did not cause significant long-term psychological risks. However, a theoretical spectrum of subjective concern may exist about cognitive decline in amyloid-negative individuals.

The Effect of Clinical Characteristics and Subtypes on Amyloid Positivity in Patients with Amnestic Mild Cognitive Impairment.

Background and PurposeMild cognitive impairment (MCI) is a prodromal stage of dementia. Amyloid deposits in positron-emission tomography (PET) imaging of MCI patients imply a higher risk for advancing to dementia, with rates of 10%–15% yearly. The purpose of this study was to investigate the clinical characteristics of subgroups of amnestic MCI (aMCI) that may have a higher impact on amyloid positivity.MethodsWe recruited 136 aMCI patients. All patients underwent a 20-minute F-18 florbetaben or flutemetamol PET scan. We classified amyloid PET images as positive or negative according to a semi-quantitative method. We evaluated the amyloid positivity of subgroups of aMCI (early vs. late type, single vs. multiple amnestic type, verbal vs. verbal, and visual amnestic type), and compared baseline clinical characteristics including key risk factors, apolipoprotein E4 (apoE4) genotype, and neuropsychological assessments with amyloid positivity in aMCI.ResultsThe amyloid positivity in total aMCI was 41%. The positivity rate according to subgroup of aMCI were as follow: Late aMCI (49%) vs. early aMCI (33%) (p=0.13), multiple aMCI (40%) vs. single aMCI (38%) (p=0.51), and verbal and visual aMCI (59%) vs. verbal aMCI (35%) (p=0.01), respectively. The mean age and the frequency of apoE4 allele of the amyloid-positive group was higher than that of the amyloid-negative group in aMCI (p<0.01).ConclusionsWe found that the amyloid positivity was related to patterns of clinical subtypes, characteristics, and risk factors in patients with aMCI.

Prediction of Alzheimer's Pathological Changes in Subjective Cognitive Decline Using the Self-report Questionnaire and Neuroimaging Biomarkers.

Background and PurposeSubjective cognitive decline (SCD) may be the first symptomatic stage of Alzheimer's disease (AD). Hence, a screening tool to characterize the patients' complaints and assess the risk of AD is required. We investigated the SCD neuroimaging biomarker distributions and the relevance between the self-report questionnaire and Alzheimer's pathologic changes.MethodsIndividuals aged 50 and above with consistent cognitive complaints without any objective cognitive impairments were eligible for the study. The newly developed questionnaire consisted of 2 parts; 10 questions translated from the ‘SCD-plus criteria’ and a Korean version of the cognitive failure questionnaire by Broadbent. All the subjects underwent physical examinations such as blood work, detailed neuropsychological tests, the self-report questionnaire, brain magnetic resonance imagings, and florbetaben positron emission tomography (PET) scans. Amyloid PET findings were interpreted using both visual rating and quantitative analysis. Group comparisons and association analysis were performed using SPSS (version 18.0).ResultsA total of 31 participants with SCD completed the study and 25.8% showed positive amyloid depositions. The degree of periventricular white matter hyperintensities (WMH) and hippocampal atrophy were more severe in amyloid-positive SCDs compared to the amyloid-negative group. In the self-reported questionnaire, the ‘informant's report a decline’ and ‘symptom's onset after 65 years of age’ were associated with more Alzheimer's pathologic changes.ConclusionsAmyloid-positive SCDs differed from amyloid-negative SCDs on WMH, hippocampal atrophy, and a few self-reported clinical features, which gave clues on the prediction of AD pathology.

Association of Higher Cortical Amyloid Burden With Loneliness in Cognitively Normal Older Adults

Emotional and behavioral symptoms in cognitively normal older people may be direct manifestations of Alzheimer disease (AD) pathophysiology at the preclinical stage, prior to the onset of mild cognitive impairment. Loneliness is a perceived state of social and emotional isolation that has been associated with cognitive and functional decline and an increased risk of incident AD dementia. We hypothesized that loneliness might occur in association with elevated cortical amyloid burden, an in vivo research biomarker of AD. To determine whether cortical amyloid burden is associated with greater loneliness in cognitively normal older adults. Cross-sectional analyses using data from the Harvard Aging Brain Study of 79 cognitively normal, community-dwelling participants. A continuous, aggregate measure of cortical amyloid burden, determined by Pittsburgh Compound B-positron emission tomography (PiB-PET), was examined in association with loneliness in linear regression models adjusting for age, sex, apolipoprotein E ε4 (APOEε4), socioeconomic status, depression, anxiety, and social network (without and with the interaction of amyloid and APOEε4). We also quantified the association of high amyloid burden (amyloid-positive group) to loneliness (lonely group) using logistic regression, controlling for the same covariates, with the amyloid-positive group and the lonely group, each composing 32% of the sample (n = 25). Loneliness, as determined by the 3-item UCLA Loneliness Scale (possible range, 3-12, with higher score indicating greater loneliness). The 79 participants included 43 women and 36 men with a mean (SD) age of 76.4 (6.2) years. Mean (SD) cortical amyloid burden via PiB-PET was 1.230 (0.209), and the mean (SD) UCLA-3 loneliness score was 5.3 (1.8). Twenty-two (28%) had positive APOEε4 carrier status, and 25 (32%) were in the amyloid-positive group with cortical PiB distribution volume ratio greater than 1.2. Controlling for age, sex, APOEε4, socioeconomic status, depression, anxiety, and social network, we found that higher amyloid burden was significantly associated with greater loneliness: compared with individuals in the amyloid-negative group, those in the amyloid-positive group were 7.5-fold (95% CI, 1.7-fold to 34.0-fold) more likely to be classified as lonely than nonlonely (β = 3.3, partial r = 0.4, P = .002). Furthermore, the association of high amyloid burden and loneliness was stronger in APOEε4 carriers than in noncarriers. We report a novel association of loneliness with cortical amyloid burden in cognitively normal older adults, suggesting that loneliness is a neuropsychiatric symptom relevant to preclinical AD. This work will inform new research into the neural underpinnings and disease mechanisms involved in loneliness and may enhance early detection and intervention research in AD.