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Background: To establish simple screening tests to suspect Alzheimer's disease (AD) pathology, the clinical sign "head-turning sign" (HTS), which is a patient's behavior of turning their head towards their partner to seek assistance with questions posed by the examiner during the interview, and the simple screening questionnaire for dementia named "Neucop-Q" were validated in participants diagnosed with amyloid and tau positron emission tomography (PET). Methods: We enrolled 155 patients: 47 cognitive normal, 36 with mild cognitive impairment, 64 with dementia, and 8 with psychiatric disorders. All participants underwent Neucop-Q [three questions: Consciousness/self-awareness of cognitive disabilities (C) normal/impaired (nor/imp), Pleasure/pastime (P) nor/imp, and News/knowledge on current topics (N) nor/imp] and amyloid/tau PET. Additionally, we measured plasma amyloid β (Aβ) 42/40 ratio, phosphorylated tau 181 (pTau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NFL) levels and compared with HTS and Neucop-Q results. Results: The specificity and positive predictive value (PPV) of HTS positivity (HTSpos) were the highest (amyloid PET: 0.930 and 0.870, tau PET: 0.944 and 0.957, respectively), while Cimp and Nimp had a high negative predictive value (NPV) for amyloid PET (negativity) (0.750 and 0.725). Pimp showed high specificity for predicting non-AD tau positivity among non-AD participants without amyloid PET positivity (0.854). To validate these findings with PET results, we examined the correlation between well-established AD blood biomarkers and results obtained from these screening tests. HTSpos, Cimp, and Nimp were strongly associated with Aβ42/40 ratio (P < 0.0001, P = 0.0022, and P = 0.001), pTau181 (P < 0.0001, P = 0.0095, and P = 0.001), GFAP (P = 0.0372, P = 0.0088, and P = 0.0002), and amyloid PET Centiloid (P < 0.0001, P = 0.0210, and P = 0.0006), whereas Pimp increased neuroinflammation (GFAP; P = 0.0061) and was associated with non-AD tauopathy. The combination of Neucop-Q questions showed that Cimp/Pnor/Nimp subjects have the highest specificity and PPV (0.972 and 0.833) and were strongly associated with Aβ42/40 ratio (P = 0.0006), pTau181 (P = 0.0006), and amyloid PET Centiloid (P < 0.0001). Conclusion: HTSpos, Cimp, and Nimp have diagnostic utility in suspecting MCI due to AD and AD, and Pimp has diagnostic value in non-AD tauopathy. HTSpos, Cimp, and Nimp were associated with biomarkers of Aβ pathology. HTS and Neucop-Q may serve as powerful first-line screening in memory clinics. Trial registration: UMIN Clinical Trials Registry (UMIN-CTR) under registration numbers 000032027 (Registration date: 2018/03/31) and 000030248 (Registration date: 2018/01/01). [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to investigate the characteristics of individuals with amyloid levels below the threshold. To achieve this, we differentiated between two groups: those with global amyloid negativity but focal deposition [G(–)F(+)] and those without focal deposition [G(–)F(–)]. Materials and methods: A total of 2,677 participants were diagnosed with cognitive unimpairment (CU) or mild cognitive impairment (MCI). MRI-based regional centiloid (CL) values were used to establish threshold values for each brain region. After applying a cutoff of 20 rdcCL to identify amyloid positivity, participants who were globally amyloid-negative were grouped into three categories: those who showed focal amyloid uptake [G(–)F(+)], individuals without focal amyloid deposition but with relatively high CL(HC) levels comparable to those in the focal uptake group [G(–)F(–) HC)], and those with relatively low CL(LC) levels [G(–)F(–) LC]. We compared the neuropsychological test results and brain structural changes between these groups using ANCOVA. Results: The G(–)F(+) group demonstrated a lower cortical thickness (P < 0.001) than the G(–)F(–) HC group. In neuropsychological tests, the G(–)F(+) group exhibited lower the Seoul Verbal Learning Test delayed recall (SVLT-DR) and Mini Mental State Examination (MMSE), and showed progressed clinical status in the clinical dementia rating–sum of boxes (CDR-SOB) compared to the G(–)F(–) HC group (P < 0.001). The subsequent sensitivity analyses confirmed the persistence of these findings. Conclusions: Individuals with focal amyloid deposition [G(–)F(+)] exhibited higher rates of cognitive impairment compared to patients with similar levels of amyloid, underscoring the importance of monitoring the progression of focal uptake, even when it remains below the amyloid threshold. [ABSTRACT FROM AUTHOR]

Vascular dysfunction is implicated in the pathophysiology of Alzheimer's disease (AD). While sodium is essential for maintaining vascular function, its role in AD pathology remains unclear. We included 353 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI), assessing serum sodium levels, cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers, magnetic resonance imaging (MRI), and cognitive function. An independent sample (N = 471) with available CSF sodium‐related proteins and AD biomarkers was also included. Associations between serum sodium levels and AD pathology, neurodegeneration, and cognition were evaluated using linear regression models. Spearman's correlation analyses assessed the relationships between CSF sodium‐related proteins and AD biomarkers. Higher serum sodium levels were associated with increased AD pathology, reduced hippocampal volume, and greater cognitive decline (all p < 0.05). The relationship between serum sodium and amyloid PET was evident in several AD‐susceptible brain regions, including the neocortex and limbic system. Individuals with high serum sodium exhibited higher tau pathology, lower hippocampal volume, and more severe cognitive decline per unit increase in amyloid PET compared to those with low serum sodium (all p < 0.05). Among the 14 CSF sodium‐related proteins, which were inter‐correlated, six were significantly correlated with CSF AD pathology and amyloid PET, while two were correlated with hippocampal volume and cognitive function, with sodium channel subunit beta‐2 (SCN2B) and sodium channel subunit beta‐3 (SCN3B) showing the strongest correlations. These findings underscore the crucial role of serum sodium in AD progression, highlighting a potential network of sodium dysregulation involved in AD pathology. Targeting sodium may offer a novel therapeutic approach to slowing AD progression, particularly by impeding the progression of amyloid‐related downstream events. [ABSTRACT FROM AUTHOR]

IntroductionWe used sex and apolipoprotein E ε4 (APOE ε4) carrier status as predictors of pathologic burden in early-onset Alzheimer's disease (EOAD).MethodsWe included baseline data from 77 cognitively normal (CN), 230 EOAD, and 70 EO non-Alzheimer's disease (EOnonAD) participants from the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS). We stratified each diagnostic group by males and females, then further subdivided each sex by APOE ε4 carrier status and compared imaging biomarkers in each stratification. Voxel-wise multiple linear regressions yielded statistical brain maps of gray matter density, amyloid, and tau PET burden.ResultsEOAD females had greater amyloid and tau PET burdens than males. EOAD female APOE ε4 non-carriers had greater amyloid PET burdens and greater gray matter atrophy than female ε4 carriers. EOnonAD female ε4 non-carriers also had greater gray matter atrophy than female ε4 carriers.DiscussionThe effects of sex and APOE ε4 must be considered when studying these populations.HighlightsNovel analysis examining the effects of biological sex and apolipoprotein E ε4 (APOE ε4) carrier status on neuroimaging biomarkers among early-onset Alzheimer's disease (EOAD), early-onset non-AD (EOnonAD), and cognitively normal (CN) participants. Female sex is associated with greater pathology burden in the EOAD cohort compared to male sex. The effect of APOE ε4 carrier status on pathology burden was the most impactful in females across all cohorts.

The elimination of amyloid‐beta (Aβ) plaques in Alzheimer's disease patients after treatment with anti‐Aβ antibodies such as lecanemab and aducanumab is supported by a substantially decreased signal in amyloid positron emission tomography (PET) imaging. However, this decreased PET signal has not been matched by a similar substantial effect on cognitive function. There may be several reasons for this, including short treatment duration and advanced disease stages among the patients. However, one aspect that has not been investigated, and the subject of this study, is whether antibody engagement with amyloid plaques inhibits the binding of amyloid‐PET ligands, leading to a false impression of Aβ removal from the brain. In the present study, tg‐ArcSwe mice received three injections of RmAb158, the murine version of lecanemab or phosphate‐buffered saline (PBS) before the administration of the amyloid‐PET radioligand [11C]PiB, followed by isolation of brain tissue. Autoradiography showed that RmAb158‐ and PBS‐treated mice displayed similar [11C]PiB binding. Moreover, the total Aβ1–40 levels, representing the major Aβ species of plaques in the tg‐ArcSwe model, as well as soluble triggering receptor on myeloid cells 2 (sTREM2) levels, were similar in both groups. Interestingly, the concentration of soluble Aβ aggregates was decreased in the RmAb158‐treated group, along with a small but significant decrease in the total Aβ1–42 levels. In conclusion, this study indicates that the binding of [11C]PiB to Aβ accurately mirrors the load of Aβ plaques in the brain, aligning with how amyloid‐PET is interpreted in clinical studies of anti‐Aβ antibodies. However, early treatment effects on soluble Aβ aggregates and Aβ1–42 levels were not detected. [ABSTRACT FROM AUTHOR]

Objective: This study aims to assess the utility of newly developed objective methods for the evaluation of intracranial abnormal amyloid deposition using PET/CT histogram without use of cortical ROI analyses. Methods: Twenty-five healthy volunteers (HV) and 38 patients with diagnosed or suspected dementia who had undergone 18F-FPYBF-2 PET/CT were retrospectively included in this study. Out of them, 11C-PiB PET/CT had been also performed in 13 subjects. In addition to the conventional methods, namely visual judgment and quantitative analyses using composed standardized uptake value ratio (comSUVR), the PET images were also evaluated by the following new parameters: the skewness and the mode-to-mean ratio (MMR) obtained from the histogram of the brain parenchyma; Top20%-map highlights the areas with high tracer accumulation occupying 20% volume of the total brain parenchymal on the individual's CT images. We evaluated the utility of the new methods using histogram compared with the visual assessment and comSUVR. The results of these new methods between 18F-FPYBF-2 and 11C-PiB were also compared in 13 subjects. Results: In visual analysis, 32, 9, and 22 subjects showed negative, border, and positive results, and composed SUVR in each group were 1.11 ± 0.06, 1.20 ± 0.13, and 1.48 ± 0.18 (p < 0.0001), respectively. Visually positive subjects showed significantly low skewness and high MMR (p < 0.0001), and the Top20%-Map showed the presence or absence of abnormal deposits clearly. In comparison between the two tracers, visual evaluation was all consistent, and the ComSUVR, the skewness, the MMR showed significant good correlation. The Top20%-Maps showed similar pattern. Conclusions: Our new methods using the histogram of the brain parenchymal accumulation are simple and suitable for clinical practice of amyloid PET, and Top20%-Map on the individual's brain CT can be of great help for the visual assessment. [ABSTRACT FROM AUTHOR]

Background: Amyloid positron emission tomography (PET) scans provide in vivo evidence of Alzheimer's disease (AD); however, their high cost limits their use in standard clinical care. Event related potentials (ERPs) may represent an inexpensive and non-invasive additional method for detecting AD pathology. Objective: We investigated whether ERPs, along with neuropsychological data, serve as predictors of amyloid PET status in patients with memory complaints. Methods: Veterans aged 50–100 were recruited from a memory disorders clinic. Participants underwent a neuropsychological battery and an ERP auditory oddball protocol. Twenty-eight patients had a positive amyloid PET scan, and thirty-nine patients had a negative scan. Results: ERP-P200 target amplitude and P200 standard latency were predictors of amyloid PET status. When submitting to ROC analysis, P200 standard latency exhibited the highest specificity and sensitivity in predicting amyloid PET positivity, correctly classifying the amyloid PET status for 86% of patients. Conclusions: ERP-P200 measures are strong indicators of amyloid-β presence in patients from a memory disorder clinic. Increased P200 amplitude and decreased P200 latency in patients with a positive amyloid PET scan may be attributed to hyperactivation of perceptual bottom-up processes compensating for AD-related synaptic loss in the fronto-parietal networks. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Spatial extent‐based measures of how far amyloid beta (Aβ) has spread throughout the neocortex may be more sensitive than traditional Aβ‐positron emission tomography (PET) measures of Aβ level for detecting early Aβ deposits in preclinical Alzheimer's disease (AD) and improve understanding of Aβ's association with tau proliferation and cognitive decline. METHODS: Pittsburgh Compound‐B (PIB)‐PET scans from 261 cognitively unimpaired older adults from the Harvard Aging Brain Study were used to measure Aβ level (LVL; neocortical PIB DVR) and spatial extent (EXT), calculated as the proportion of the neocortex that is PIB+. RESULTS: EXT enabled earlier detection of Aβ deposits longitudinally confirmed to reach a traditional LVL‐based threshold for Aβ+ within 5 years. EXT improved prediction of cognitive decline (Preclinical Alzheimer Cognitive Composite) and tau proliferation (flortaucipir‐PET) over LVL. DISCUSSION: These findings indicate EXT may be more sensitive to Aβ's role in preclinical AD than level and improve targeting of individuals for AD prevention trials. Highlights: Aβ spatial extent (EXT) was measured as the percentage of the neocortex with elevated Pittsburgh Compound‐B.Aβ EXT improved detection of Aβ below traditional PET thresholds.Early regional Aβ deposits were spatially heterogeneous.Cognition and tau were more closely tied to Aβ EXT than Aβ level.Neocortical tau onset aligned with reaching widespread neocortical Aβ. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Commercially available plasma p‐tau217 biomarker tests are not well studied in ethnically diverse samples. METHODS: We evaluated associations between ALZPath plasma p‐tau217 and amyloid‐beta positron emission tomography (Aβ‐PET) in Hispanic/Latino (88% of Cuban or South American ancestry) and non‐Hispanic/Latino older adults. One‐ and two‐cutoff ranges were derived and evaluated to assess agreement with Aβ‐PET. RESULTS: A total of 239 participants underwent blood draw and Aβ‐PET (age 70.8 ± 7.8, 55.2% female, education 15.6 ± 3.4 years, 48.9% Hispanic/Latino, 94.9% white). Plasma p‐tau217 showed excellent discrimination of Aβ‐PET positive and negative participants (visual read: AUC = 0.91 [0.87–0.95], p < 0.001; Centiloids quantification: AUC = 0.90 [0.86–0.94]). There was a greater percent agreement between low p‐tau217 and negative Aβ‐PET (95.8%) than high p‐tau217 and positive Aβ‐PET (86.3%). Analyses within ethnicity‐specific subgroups suggested similar p‐tau217 performance. DISCUSSION: Plasma p‐tau217 (ALZPath) relates to brain Aβ in Hispanic/Latino and non‐Hispanic/Latino older adults. Independent validation and replication are necessary to establish reference ranges and inform appropriate contexts of use across ethno‐racially diverse populations. HIGHLIGHTS: Plasma p‐tau217 (ALZPath) and Aβ‐PET were measured in Hispanic/Latino and non‐Hispanic/Latino older adults.Plasma p‐tau217 accurately discriminated Aβ‐PET positive and negative participants.Applying a two‐cutoff "intermediate" plasma p‐tau217 approach could reduce need for more invasive and costly testing.Plasma p‐tau217 associations with Aβ‐PET were strong within both Hispanic/Latino and non‐Hispanic/Latino groups. [ABSTRACT FROM AUTHOR]

PurposeThis study aimed to investigate the characteristics of individuals with amyloid levels below the threshold. To achieve this, we differentiated between two groups: those with global amyloid negativity but focal deposition [G(–)F(+)] and those without focal deposition [G(–)F(–)].Materials and methodsA total of 2,677 participants were diagnosed with cognitive unimpairment (CU) or mild cognitive impairment (MCI). MRI-based regional centiloid (CL) values were used to establish threshold values for each brain region. After applying a cutoff of 20 rdcCL to identify amyloid positivity, participants who were globally amyloid-negative were grouped into three categories: those who showed focal amyloid uptake [G(–)F(+)], individuals without focal amyloid deposition but with relatively high CL(HC) levels comparable to those in the focal uptake group [G(–)F(–) HC)], and those with relatively low CL(LC) levels [G(–)F(–) LC]. We compared the neuropsychological test results and brain structural changes between these groups using ANCOVA.ResultsThe G(–)F(+) group demonstrated a lower cortical thickness (P < 0.001) than the G(–)F(–) HC group. In neuropsychological tests, the G(–)F(+) group exhibited lower the Seoul Verbal Learning Test delayed recall (SVLT-DR) and Mini Mental State Examination (MMSE), and showed progressed clinical status in the clinical dementia rating–sum of boxes (CDR-SOB) compared to the G(–)F(–) HC group (P < 0.001). The subsequent sensitivity analyses confirmed the persistence of these findings.ConclusionsIndividuals with focal amyloid deposition [G(–)F(+)] exhibited higher rates of cognitive impairment compared to patients with similar levels of amyloid, underscoring the importance of monitoring the progression of focal uptake, even when it remains below the amyloid threshold.

Quantitative susceptibility mapping (QSM) has been used to study susceptibility changes that may occur based on tissue composition and mineral deposition. Iron is a primary contributor to changes in magnetic susceptibility and of particular interest in applications of QSM to neurodegeneration and aging. Iron can contribute to neurodegeneration through inflammatory processes and via interaction with aggregation of disease-related proteins. To better understand the local susceptibility changes observed on QSM, its signal has been studied in association with other imaging metrics such as positron emission tomography (PET). The associations of QSM and PET may provide insight into the pathophysiology of disease processes, such as the role of iron in aging and neurodegeneration, and help to determine the diagnostic utility of QSM as an indirect indicator of disease processes typically evaluated with PET. In this review we discuss the proposed mechanisms and summarize prior studies of the associations of QSM and amyloid PET, tau PET, TSPO PET, FDG-PET, 15O-PET, and F-DOPA PET in evaluation of neurologic diseases with a focus on aging and neurodegeneration.

Abstract Background Mounting data suggests that herpes simplex virus type 1 (HSV-1) is involved in the pathogenesis of AD, possibly instigating amyloid-beta (Aβ) accumulation decades before the onset of clinical symptoms. However, human in vivo evidence linking HSV-1 infection to AD pathology is lacking in normal aging, which may contribute to the elucidation of the role of HSV-1 infection as a potential AD risk factor. Methods To shed light into this question, serum anti-HSV IgG levels were correlated with 18F-Florbetaben-PET binding to Aβ deposits and blood markers of neurodegeneration (pTau181 and neurofilament light chain) in cognitively normal older adults. Additionally, we investigated whether associations between anti-HSV IgG and AD markers were more evident in APOE4 carriers. Results We showed that increased anti-HSV IgG levels are associated with higher Aβ load in fronto-temporal regions of cognitively normal older adults. Remarkably, these cortical regions exhibited abnormal patterns of resting state-functional connectivity (rs-FC) only in those individuals showing the highest levels of anti-HSV IgG. We further found that positive relationships between anti-HSV IgG levels and Aβ load, particularly in the anterior cingulate cortex, are moderated by the APOE4 genotype, the strongest genetic risk factor for AD. Importantly, anti-HSV IgG levels were unrelated to either subclinical cognitive deficits or to blood markers of neurodegeneration. Conclusions All together, these results suggest that HSV infection is selectively related to cortical Aβ deposition in normal aging, supporting the inclusion of cognitively normal older adults in prospective trials of antimicrobial therapy aimed at decreasing the AD risk in the aging population.

Abstract Background Reduced clearance of cerebrospinal fluid (CSF) has been suggested as a pathological feature of Alzheimer’s disease (AD). With extensive documentation in non-human mammals and contradictory human neuroimaging data it remains unknown whether the nasal mucosa is a CSF drainage site in humans. Here, we used dynamic PET with [1-11C]-Butanol, a highly permeable radiotracer with no appreciable brain binding, to test the hypothesis that tracer drainage from the nasal pathway reflects CSF drainage from brain. As a test of the hypothesis, we examined whether brain and nasal fluid drainage times were correlated and affected by brain amyloid. Methods 24 cognitively normal subjects (≥ 65 years) were dynamically PET imaged for 60 min. using [1-11C]-Butanol. Imaging with either [11C]-PiB or [18F]-FBB identified 8 amyloid PET positive (Aβ+) and 16 Aβ- subjects. MRI-determined regions of interest (ROI) included: the carotid artery, the lateral orbitofrontal (LOF) brain, the cribriform plate, and an All-turbinate region comprised of the superior, middle, and inferior turbinates. The bilateral temporalis muscle and jugular veins served as control regions. Regional time-activity were used to model tracer influx, egress, and AUC. Results LOF and All-turbinate 60 min AUC were positively associated, thus suggesting a connection between the brain and the nose. Further, the Aβ+ subgroup demonstrated impaired tracer kinetics, marked by reduced tracer influx and slower egress. Conclusion The data show that tracer kinetics for brain and nasal turbinates are related to each other and both reflect the amyloid status of the brain. As such, these data add to evidence that the nasal pathway is a potential CSF drainage site in humans. These data warrant further investigation of brain and nasal contributions to protein clearance in neurodegenerative disease.

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disease that primarily affects people above the age of 60 all around the world. As of now, the cause is unknown and there is no effective cure. The pathological changes of AD have occurred many years before the onset of the disease, and current treatment techniques can only delay the progression of the disease. Because disease-modifying therapies may be most beneficial in the early stages of AD, the clinical significance of an early diagnosis is emphasized. So far, a variety of imaging technologies and related biomarkers have been used to identify and monitor AD, but there are many imaging technologies; finding the most effective imaging technology can assist medical personnel in interpreting the early stages of AD and can also improve patient treatment opportunities. This is, therefore, the main purpose and background of this study. Methods: PubMed and other repositories were used in this study to conduct a literature search with various keywords, and relevant articles were reviewed. In this review, different neuroimaging techniques are reviewed which are considered advanced tools to help establish the diagnosis, and in addition, the diagnostic utility, advantages, and limitations of contemporary AD imaging techniques are discussed. Results: The results of the literature review and synthesis show that the prevalence of several in vivo biomarkers helps distinguish affected individuals from healthy controls in the early stages of the disease. Additionally, each current imaging method has its advantages and disadvantages, so no single imaging method is the best diagnostic modality. Conclusions: This article also reviews and draws conclusions on better ways to use the imaging techniques to improve the likelihood of an early diagnosis of AD. It is suggested that future research could focus on expanding the use of imaging technologies and on identifying novel biomarkers manifesting the earliest stages of AD pathology. [ABSTRACT FROM AUTHOR]

Background: Impaired glymphatic flow on the Alzheimer's disease (AD) spectrum may be evaluated using diffusion tensor image analysis along the perivascular space (DTI-ALPS). Objective: We aimed to validate impaired glymphatic flow and explore its association with gray matter volume, cognitive status, and cerebral amyloid deposition on the AD spectrum. Methods: 80 participants (mean age, 76.9±8.5 years; 57 women) with AD (n = 65) and cognitively normal (CN) (n = 15) who underwent 3T brain MRI including DTI and/or amyloid PET were included. After adjusting for age, sex, apolipoprotein E status, and burden of white matter hyperintensities, the ALPS-index was compared according to the AD spectrum. The association between the ALPS-index and gray matter volume, cognitive status, and quantitative amyloid from PET was assessed. Results: The ALPS-index in the AD was significantly lower (mean, 1.476; 95% CI, 1.395–1.556) than in the CN (1.784;1.615–1.952; p = 0.026). Volumes of the entorhinal cortex, hippocampus, temporal pole, and primary motor cortex showed significant associations with the ALPS-index (all, p < 0.05). There was a positive correlation between the ALPS-index and MMSE score (partial r = 0.435; p < 0.001), but there was no significant correlation between the ALPS-index and amyloid SUVRs (all, p > 0.05). Conclusions: Decreased glymphatic flow measured by DTI-ALPS in AD may serve as a marker of neurodegeneration correlating with structural atrophy and cognitive decline. [ABSTRACT FROM AUTHOR]

Introduction: We comprehensively evaluated how self- and informant-reported neuropsychiatric symptoms (NPS) were differentially associated with cerebral amyloid-beta (Aβ) PET levels in older adults without dementia. Methods: Two hundred and twenty-one participants (48% female, age = 73.4 years ± 8.4, Clinical Dementia Rating = 0 [n = 184] or 0.5 [n = 37]) underwent an Aβ-PET scan (florbetapir or PIB), comprehensive neuropsychological testing, and self-reported (Geriatric Depression Scale – 30 item [GDS-30]) and informant-reported interview (Neuropsychiatric Inventory Questionnaire [NPI-Q]) of NPS. Cerebral Aβ burden was quantified using centiloids (CL). NPI-Q and GDS-30 queried the presence of NPS within 4 subdomains and 6 subscales, respectively. Regression models examined the relationship between NPS and Aβ-PET CL. Results: Both higher self- and informant-reported NPS were associated with higher Aβ burden. Among specific NPI-Q subdomains, informant-reported changes in depression, anxiety, and irritability were all associated with higher Aβ-PET. Similarly, self-reported (GDS-30) subscales of depression, apathy, anxiety, and cognitive concern were associated with higher Aβ-PET. When simultaneously entered, only self-reported cognitive concern was associated with Aβ-PET in the GDS-30 model, while both informant-reported anxiety and depression were associated with Aβ-PET in the NPI-Q model. Clinical status moderated the association between self-reported NPS and Aβ-PET such that the positive relationship between self-perceived NPS and Aβ burden strengthened with increasing functional difficulties. Conclusions: In a cohort of older adults without dementia, both self- and informant-reported measures of global NPS, particularly patient-reported cognitive concerns and informant-reported anxiety and depression, corresponded with cerebral Aβ burden. NPS may appear early in the prodromal disease state and relate to initial AD proteinopathy burden, a relationship further exaggerated in those with greater clinical severity. Plain Language Summary: This study examines how patients' and their caregivers' report of neuropsychiatric symptoms are associated with amyloid burden, of the primary markers of risk for amyloid burden, in older adults without dementia. Amyloid burden was measured using a PET-CT scan, and neuropsychological symptoms were measured with a self-reported and an informant-reported questionnaire. We found that neuropsychiatric symptoms were associated with amyloid burden in older adults without dementia, and these relationships were stronger in older adults with greater cognitive and functional impairment. In particular, caregivers' report of anxiety, depression, and irritability and patients' report of cognitive concerns were associated with greater amyloid burden. Neuropsychiatric symptoms, observed by both the patient and the informant, may be promising first identifiers of the neuropathology associated with Alzheimer's disease and related dementias. Although neuropsychiatric symptoms have been characterized in persons with dementia, we do not yet have a clear understanding of how neuropsychiatric symptoms appear in non-dementia stages or which instruments may be the most sensitive screening tools for neuropsychiatric symptoms in older adults without dementia. These older adults without dementia may exist in a window of opportunity for behavioral and pharmacologic interventions that may prevent or slow clinical progression. [ABSTRACT FROM AUTHOR]

Background: Amyloid-β (Aβ) plaques play a pivotal role in Alzheimer's disease. The current positron emission tomography (PET) is expensive and limited in availability. In contrast, blood-based biomarkers (BBBMs) show potential for characterizing Aβ plaques more affordably. We have previously proposed an MRI-based hippocampal morphometry measure to be an indicator of Aβ plaques. Objective: To develop and validate an integrated model to predict brain amyloid PET positivity combining MRI feature and plasma Aβ42/40 ratio. Methods: We extracted hippocampal multivariate morphometry statistics from MR images and together with plasma Aβ42/40 trained a random forest classifier to perform a binary classification of participant brain amyloid PET positivity. We evaluated the model performance using two distinct cohorts, one from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the other from the Banner Alzheimer's Institute (BAI), including prediction accuracy, precision, recall rate, F1 score, and AUC score. Results: Results from ADNI (mean age 72.6, Aβ+ rate 49.5%) and BAI (mean age 66.2, Aβ+ rate 36.9%) datasets revealed the integrated multimodal (IMM) model's superior performance over unimodal models. The IMM model achieved prediction accuracies of 0.86 in ADNI and 0.92 in BAI, surpassing unimodal models based solely on structural MRI (0.81 and 0.87) or plasma Aβ42/40 (0.73 and 0.81) predictors. CONCLUSIONS: Our IMM model, combining MRI and BBBM data, offers a highly accurate approach to predict brain amyloid PET positivity. This innovative multiplex biomarker strategy presents an accessible and cost-effective avenue for advancing Alzheimer's disease diagnostics, leveraging diverse pathologic features related to Aβ plaques and structural MRI. [ABSTRACT FROM AUTHOR]

Background: Standard methods for deriving Centiloid scales from amyloid PET images are time-consuming and require considerable expert knowledge. We aimed to develop a deep learning method of automating Centiloid scale calculations from amyloid PET images with 11C-Pittsburgh Compound-B (PiB) tracer and assess its applicability to 18F-labeled tracers without retraining. Methods: We trained models on 231 11C-PiB amyloid PET images using a 50-layer 3D ResNet architecture. The models predicted the Centiloid scale, and accuracy was assessed using mean absolute error (MAE), linear regression analysis, and Bland–Altman plots. Results: The MAEs for Alzheimer's disease (AD) and young controls (YC) were 8.54 and 2.61, respectively, using 11C-PiB, and 8.66 and 3.56, respectively, using 18F-NAV4694. The MAEs for AD and YC were higher with 18F-florbetaben (39.8 and 7.13, respectively) and 18F-florbetapir (40.5 and 12.4, respectively), and the error rate was moderate for 18F-flutemetamol (21.3 and 4.03, respectively). Linear regression yielded a slope of 1.00, intercept of 1.26, and R2 of 0.956, with a mean bias of −1.31 in the Centiloid scale prediction. Conclusions: We propose a deep learning means of directly predicting the Centiloid scale from amyloid PET images in a native space. Transferring the model trained on 11C-PiB directly to 18F-NAV4694 without retraining was feasible. [ABSTRACT FROM AUTHOR]

Background: Reduced clearance of cerebrospinal fluid (CSF) has been suggested as a pathological feature of Alzheimer's disease (AD). With extensive documentation in non-human mammals and contradictory human neuroimaging data it remains unknown whether the nasal mucosa is a CSF drainage site in humans. Here, we used dynamic PET with [1-11C]-Butanol, a highly permeable radiotracer with no appreciable brain binding, to test the hypothesis that tracer drainage from the nasal pathway reflects CSF drainage from brain. As a test of the hypothesis, we examined whether brain and nasal fluid drainage times were correlated and affected by brain amyloid. Methods: 24 cognitively normal subjects (≥ 65 years) were dynamically PET imaged for 60 min. using [1-11C]-Butanol. Imaging with either [11C]-PiB or [18F]-FBB identified 8 amyloid PET positive (Aβ+) and 16 Aβ- subjects. MRI-determined regions of interest (ROI) included: the carotid artery, the lateral orbitofrontal (LOF) brain, the cribriform plate, and an All-turbinate region comprised of the superior, middle, and inferior turbinates. The bilateral temporalis muscle and jugular veins served as control regions. Regional time-activity were used to model tracer influx, egress, and AUC. Results: LOF and All-turbinate 60 min AUC were positively associated, thus suggesting a connection between the brain and the nose. Further, the Aβ+ subgroup demonstrated impaired tracer kinetics, marked by reduced tracer influx and slower egress. Conclusion: The data show that tracer kinetics for brain and nasal turbinates are related to each other and both reflect the amyloid status of the brain. As such, these data add to evidence that the nasal pathway is a potential CSF drainage site in humans. These data warrant further investigation of brain and nasal contributions to protein clearance in neurodegenerative disease. [ABSTRACT FROM AUTHOR]

Background: Mounting data suggests that herpes simplex virus type 1 (HSV-1) is involved in the pathogenesis of AD, possibly instigating amyloid-beta (Aβ) accumulation decades before the onset of clinical symptoms. However, human in vivo evidence linking HSV-1 infection to AD pathology is lacking in normal aging, which may contribute to the elucidation of the role of HSV-1 infection as a potential AD risk factor. Methods: To shed light into this question, serum anti-HSV IgG levels were correlated with 18F-Florbetaben-PET binding to Aβ deposits and blood markers of neurodegeneration (pTau181 and neurofilament light chain) in cognitively normal older adults. Additionally, we investigated whether associations between anti-HSV IgG and AD markers were more evident in APOE4 carriers. Results: We showed that increased anti-HSV IgG levels are associated with higher Aβ load in fronto-temporal regions of cognitively normal older adults. Remarkably, these cortical regions exhibited abnormal patterns of resting state-functional connectivity (rs-FC) only in those individuals showing the highest levels of anti-HSV IgG. We further found that positive relationships between anti-HSV IgG levels and Aβ load, particularly in the anterior cingulate cortex, are moderated by the APOE4 genotype, the strongest genetic risk factor for AD. Importantly, anti-HSV IgG levels were unrelated to either subclinical cognitive deficits or to blood markers of neurodegeneration. Conclusions: All together, these results suggest that HSV infection is selectively related to cortical Aβ deposition in normal aging, supporting the inclusion of cognitively normal older adults in prospective trials of antimicrobial therapy aimed at decreasing the AD risk in the aging population. [ABSTRACT FROM AUTHOR]

Background: Although brain activities in Alzheimer's disease (AD) might be evaluated MRI and PET, the relationships between brain temperature (BT), the index of diffusivity along the perivascular space (ALPS index), and amyloid deposition in the cerebral cortex are still unclear. Purpose: To investigate the relationship between metabolic imaging measurements and clinical information in patients with AD and normal controls (NCs). Study Type: Retrospective analysis of a prospective dataset. Population: 58 participants (78.3 ± 6.8 years; 30 female): 29 AD patients and 29 age‐ and sex‐matched NCs from the Open Access Series of Imaging Studies dataset. Field Strength/Sequence: 3T; T1‐weighted magnetization‐prepared rapid gradient‐echo, diffusion tensor imaging with 64 directions, and dynamic 18F‐florbetapir PET. Assessment: Imaging metrics were compared between AD and NCs. These included BT calculated by the diffusivity of the lateral ventricles, ALPS index that reflects the glymphatic system, the mean standardized uptake value ratio (SUVR) of amyloid PET in the cerebral cortex and clinical information, such as age, sex, and MMSE. Statistical Tests: Pearson's or Spearman's correlation and multiple linear regression analyses. P values <0.05 were defined as statistically significant. Results: Significant positive correlations were found between BT and ALPS index (r = 0.44 for NCs), while significant negative correlations were found between age and ALPS index (rs = −0.43 for AD and − 0.47 for NCs). The SUVR of amyloid PET was not significantly associated with BT (P = 0.81 for AD and 0.21 for NCs) or ALPS index (P = 0.10 for AD and 0.52 for NCs). In the multiple regression analysis, age was significantly associated with BT, while age, sex, and presence of AD were significantly associated with the ALPS index. Data Conclusion: Impairment of the glymphatic system measured using MRI was associated with lower BT and aging. Level of Evidence: 3 Technical Efficacy Stage: 1 [ABSTRACT FROM AUTHOR]

Abstract INTRODUCTION Commercially available plasma p‐tau217 biomarker tests are not well studied in ethnically diverse samples. METHODS We evaluated associations between ALZPath plasma p‐tau217 and amyloid‐beta positron emission tomography (Aβ‐PET) in Hispanic/Latino (88% of Cuban or South American ancestry) and non‐Hispanic/Latino older adults. One‐ and two‐cutoff ranges were derived and evaluated to assess agreement with Aβ‐PET. RESULTS A total of 239 participants underwent blood draw and Aβ‐PET (age 70.8 ± 7.8, 55.2% female, education 15.6 ± 3.4 years, 48.9% Hispanic/Latino, 94.9% white). Plasma p‐tau217 showed excellent discrimination of Aβ‐PET positive and negative participants (visual read: AUC = 0.91 [0.87–0.95], p

IntroductionThe Centiloid scale was developed to harmonise the quantification of β-amyloid (Aβ) PET images across tracers, scanners, and processing pipelines. However, several groups have reported differences across tracers and scanners even after centiloid conversion. In this study, we aim to evaluate the impact of different pre and post-processing harmonisation steps on the robustness of longitudinal Centiloid data across three large international cohort studies.MethodsAll Aβ PET data in AIBL (N = 3315), ADNI (N = 3442) and OASIS3 (N = 1398) were quantified using the MRI-based Centiloid standard SPM pipeline and the PET-only pipeline CapAIBL. SUVR were converted into Centiloids using each tracer's respective transform. Global Aβ burden from pre-defined target cortical regions in Centiloid units were quantified for both raw PET scans and PET scans smoothed to a uniform 8 mm full width half maximum (FWHM) effective smoothness. For Florbetapir, we assessed the performance of using both the standard Whole Cerebellum (WCb) and a composite white matter (WM)+WCb reference region. Additionally, our recently proposed quantification based on Non-negative Matrix Factorisation (NMF) was applied to all spatially and SUVR normalised images. Correlation with clinical severity measured by the Mini-Mental State Examination (MMSE) and effect size, as well as tracer agreement in 11C-PiB-18F-Florbetapir pairs and longitudinal consistency were evaluated.ResultsThe smoothing to a uniform resolution partially reduced longitudinal variability, but did not improve inter-tracer agreement, effect size or correlation with MMSE. Using a Composite reference region for 18F-Florbetapir improved inter-tracer agreement, effect size, correlation with MMSE, and longitudinal consistency. The best results were however obtained when using the NMF method which outperformed all other quantification approaches in all metrics used.ConclusionsFWHM smoothing has limited impact on longitudinal consistency or outliers. A Composite reference region including subcortical WM should be used for computing both cross-sectional and longitudinal Florbetapir Centiloid. NMF improves Centiloid quantification on all metrics examined.

BACKGROUND: We compared the ability of several plasma biomarkers versus amyloid positron emission tomography (PET) to predict rates of memory decline among cognitively unimpaired individuals. METHODS: We studied 645 Mayo Clinic Study of Aging participants. Predictor variables were age, sex, education, apolipoprotein E (APOE) ε4 genotype, amyloid PET, and plasma amyloid beta (Aβ)42/40, phosphorylated tau (p‐tau)181, neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and p‐tau217. The outcome was a change in a memory composite measure. RESULTS: All plasma biomarkers, except NfL, were associated with mean memory decline in models with individual biomarkers. However, amyloid PET and plasma p‐tau217, along with age, were key variables independently associated with mean memory decline in models combining all predictors. Confidence intervals were narrow for estimates of population mean prediction, but person‐level prediction intervals were wide. DISCUSSION: Plasma p‐tau217 and amyloid PET provide useful information about predicting rates of future cognitive decline in cognitively unimpaired individuals at the population mean level, but not at the individual person level. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The implications of positive tau positron emission tomography (T) with negative beta amyloid positron emission tomography (A) are not well understood. We investigated cognitive performance in participants who were T+ but A‐. METHODS: We evaluated 98 participants from the Mayo Clinic who were T+ and A‐. Participants were matched 2:1 to A‐ and T‐ cognitively unimpaired (CU) controls. Cognitive test scores were compared between different groups. RESULTS: The A‐T+ group demonstrated lower performance than the A‐T‐ group on the Mini‐Mental Status Exam (MMSE) (p < 0.001), Wechsler Memory Scale‐Revised Logical Memory I (p < 0.001) and Logical Memory II (p < 0.001), Auditory Verbal Learning Test (AVLT) delayed recall (p = 0.004), category fluency (animals p = 0.005; vegetables p = 0.021), Trail Making Test A and B (p < 0.001), and others. There were no significant differences in demographic features or apolipoprotein E (APOE) e4 genotype between CU A‐T+ and CI A‐T+. DISCUSSION: A‐T+ participants show an association with lower cognitive performance. [ABSTRACT FROM AUTHOR]

It is poorly known how Aβ and tau accumulations associate at the spatiotemporal level in the in vivo human brain to impact cognitive changes in older adults prior to AD symptoms onset. In this study, we used a graph theory-based spatiotemporal analysis to characterize the cortical patterns of Aβ and tau deposits and their relationship with cognitive changes in the Harvard Aging Brain Study (HABS) cohort. We found that the temporal accumulations of interlinked Aβ and tau pathology display distinctive spatiotemporal correlations associated with early cognitive decline. Notably, we observed that baseline Aβ deposits—Thal amyloid phase II—related to future increase of tau deposits, Braak stages I–IV, both displaying linkage to the decline in multi-domain cognitive scores. We also found unimodal tau-to-tau and cognitive impairment associations in broad areas of Braak stages I–IV. The unimodal Aβ-to-Aβ progressions were not associated with cognitive changes. Our results revealed a multifaceted correlation of the spatiotemporal Aβ and tau associations with cognitive decline over time, in which tau-to-tau and tau–Aβ interactions, and not Aβ independently, might be critical contributors to clinical trajectories toward AD in older adults. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes mellitus (T2DM) affects ∼25% of Veterans, a prevalence rate double that of the general population. T2DM is associated with greater dementia risk and has been shown to exacerbate the impact of Alzheimer's disease (AD) risk factors on declines in daily functioning; however, there are few studies that investigate these patterns in older Veterans. Objective: This study sought to determine whether T2DM moderates the association between amyloid-β (Aβ) positron emission tomography (PET) and 1-year change in everyday functioning in older Veterans. Methods: One-hundred-ninety-eight predominately male Vietnam-Era Veterans without dementia from the Department of Defense-Alzheimer's Disease Neuroimaging Initiative (DoD-ADNI) with (n = 74) and without (n = 124) T2DM completed Aβ PET imaging and everyday functioning measures, including the Clinical Dementia Rating–Sum of Boxes (CDR-SB) and Everyday Cognition (ECog). Linear mixed effects models tested the moderating role of T2DM on the association between Aβ PET and 1-year change in everyday functioning. Results: The 3-way T2DM×Aβ PET×time interaction was significant for CDR-SB (p < 0.001) as well as the Memory (p = 0.007) and Language (p = 0.011) subscales from the ECog. Greater amyloid burden was associated with greater increases in functional difficulties, but only in Veterans with T2DM. Conclusions: Higher Aβ was only associated with declines in everyday functioning over 1 year in Veterans with T2DM. Given that people with T2DM are more likely to have co-occurring cerebrovascular disease, the combination of multiple neuropathologies may result in faster declines. Future studies should examine how diabetes duration, severity, and medications impact these associations. [ABSTRACT FROM AUTHOR]

Previous work has associated polymorphisms in the dopamine transporter gene (rs6347 in DAT1 / SLC6A3) and brain derived neurotrophic factor gene (Val66Met in BDNF) with atrophy and memory decline. However, it is unclear whether these polymorphisms relate to atrophy and cognition through associations with Alzheimer's disease pathology. We tested for effects of DAT1 and BDNF polymorphisms on cross-sectional and longitudinal β-amyloid (Aβ) and tau pathology (measured with positron emission tomography (PET)), hippocampal volume, and cognition. We analyzed a sample of cognitively normal older adults (cross-sectional n = 321) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). DAT1 and BDNF interacted to predict Aβ-PET, tau-PET, and hippocampal atrophy. Carriers of both "non-boptimal" DAT1 C and BDNF Met alleles demonstrated greater pathology and atrophy. Our findings provide novel links between dopamine and neurotrophic factor genes and AD pathology, consistent with previous research implicating these variants in greater risk for developing AD. • DAT1 and BDNF polymorphisms relate to Aβ and tau pathology in healthy older adults. • Carriers of both DAT1 CC and BDNF Met exhibit higher Aβ and tau. • DAT1 CC and BDNF Met are also linked with greater hippocampal atrophy. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Alzheimer's disease studies often lack ethnic diversity. METHODS: We evaluated associations between plasma biomarkers commonly studied in Alzheimer's (p‐tau181, GFAP, and NfL), clinical diagnosis (clinically normal, amnestic MCI, amnestic dementia, or non‐amnestic MCI/dementia), and Aβ‐PET in Hispanic and non‐Hispanic older adults. Hispanics were predominantly of Cuban or South American ancestry. RESULTS: Three‐hundred seventy nine participants underwent blood draw (71.9 ± 7.8 years old, 60.2% female, 57% Hispanic of which 88% were Cuban or South American) and 240 completed Aβ‐PET. P‐tau181 was higher in amnestic MCI (p = 0.004, d = 0.53) and dementia (p < 0.001, d = 0.97) than in clinically normal participants and discriminated Aβ‐PET[+] and Aβ‐PET[‐] (AUC = 0.86). P‐tau181 outperformed GFAP and NfL. There were no significant interactions with ethnicity. Among amnestic MCI, Hispanics had lower odds of elevated p‐tau181 than non‐Hispanic (OR = 0.41, p = 0.006). DISCUSSION: Plasma p‐tau181 informs etiological diagnosis of cognitively impaired Hispanic and non‐Hispanic older adults. Hispanic ethnicity may relate to greater likelihood of non‐Alzheimer's contributions to memory loss. Highlights: Alzheimer's biomarkers were measured in Hispanic and non‐Hispanic older adults.Plasma p‐tau181 related to amnestic cognitive decline and brain amyloid burden.AD biomarker associations did not differ between Hispanic and non‐Hispanic ethnicity.Hispanic individuals may be more likely to have non‐Alzheimer causes of memory loss. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Overlooking the heterogeneity in Alzheimer's disease (AD) may lead to diagnostic delays and failures. Neuroanatomical normative modeling captures individual brain variation and may inform our understanding of individual differences in AD‐related atrophy. METHODS: We applied neuroanatomical normative modeling to magnetic resonance imaging from a real‐world clinical cohort with confirmed AD (n = 86). Regional cortical thickness was compared to a healthy reference cohort (n = 33,072) and the number of outlying regions was summed (total outlier count) and mapped at individual‐ and group‐levels. RESULTS: The superior temporal sulcus contained the highest proportion of outliers (60%). Elsewhere, overlap between patient atrophy patterns was low. Mean total outlier count was higher in patients who were non‐amnestic, at more advanced disease stages, and without depressive symptoms. Amyloid burden was negatively associated with outlier count. DISCUSSION: Brain atrophy in AD is highly heterogeneous and neuroanatomical normative modeling can be used to explore anatomo‐clinical correlations in individual patients. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to investigate the association between very late-onset schizophrenia-like psychosis (VLOSLP), a schizophrenia spectrum disorder with an onset of ≥60 years, and Alzheimer's disease (AD) using biomarkers. Design: Retrospective cross-sectional study. Setting: Neuropsychology clinic of Osaka University Hospital in Japan. Participants: Thirty-three participants were classified into three groups: eight AD biomarker-negative VLOSLP (VLOSLP−AD), nine AD biomarker-positive VLOSLP (VLOSLP+AD), and sixteen amnestic mild cognitive impairment due to AD without psychosis (aMCI−P+AD) participants. Measurements: Phosphorylated tau levels in the cerebrospinal fluid and 18F-Florbetapir positron emission tomography results were used as AD biomarkers. Several scales (e.g. the Mini-Mental State Examination (MMSE), Wechsler Memory Scale-Revised (WMS-R) Logical Memory (LM) I and II, and Neuropsychiatric Inventory (NPI)-plus) were conducted to assess clinical characteristics. Results: Those in both VLOSLP−AD and +AD groups scored higher than those in aMCI−P+AD in WMS-R LM I. On the other hand, VLOSLP+AD participants scored in between the other two groups in the WMS-R LM II, with only VLOSLP−AD participants scoring significantly higher than aMCI−P+AD participants. There were no significant differences in sex distribution and MMSE scores among the three groups or in the subtype of psychotic symptoms between VLOSLP−AD and +AD participants. Four VLOSLP−AD and five VLOSLP+AD participants harbored partition delusions. Delusion of theft was shown in two VLOSLP−AD patients and five VLOSLP+AD patients. Conclusion: Some VLOSLP patients had AD pathology. Clinical characteristics were different between AD biomarker-positive and AD biomarker-negative VLOSLP, which may be helpful for detecting AD pathology in VLOSLP patients. [ABSTRACT FROM AUTHOR]

Imaging of amyloid deposition using PET has been available in research studies for 2 decades and has been approved for clinical use by the U.S. Food and Drug Administration, the European Medicines Agency, and other regulatory agencies around the world. Amyloid PET is a crucial tool for the diagnosis of Alzheimer disease, as it allows the noninvasive detection of amyloid plaques, a core neuropathologic feature that defines the disease. The clinical use of amyloid PET is expected to increase with recent accelerated approval in the United States of aducanumab, an antiamyloid monoclonal antibody, for the treatment of mild cognitive impairment and mild dementia due to Alzheimer disease. However, amyloid pathology can also be found in cognitively unimpaired older adults and in patients with other neurodegenerative disorders. The aim of this review is to provide an up-to-date overview of the application of amyloid PET in neurodegenerative diseases. We provide an in-depth analysis of the clinical, pathologic, and imaging correlates; a comparison with other available biomarkers; and a review of the application of amyloid PET in clinical trials and clinical utility studies.

Abstract Background The mismatch between the limited availability versus the high demand of participants who are in the pre-dementia phase of Alzheimer’s disease (AD) is a bottleneck for clinical studies in AD. Nevertheless, potential enrollment barriers in the pre-dementia population are relatively under-reported. In a large European longitudinal biomarker study (the AMYPAD-PNHS), we investigated main enrollment barriers in individuals with no or mild symptoms recruited from research and clinical parent cohorts (PCs) of ongoing observational studies. Methods Logistic regression was used to predict study refusal based on sex, age, education, global cognition (MMSE), family history of dementia, and number of prior study visits. Study refusal rates and categorized enrollment barriers were compared between PCs using chi-squared tests. Results 535/1856 (28.8%) of the participants recruited from ongoing studies declined participation in the AMYPAD-PNHS. Only for participants recruited from clinical PCs (n = 243), a higher MMSE-score (β = − 0.22, OR = 0.80, p

Abstract INTRODUCTION Overlooking the heterogeneity in Alzheimer's disease (AD) may lead to diagnostic delays and failures. Neuroanatomical normative modeling captures individual brain variation and may inform our understanding of individual differences in AD‐related atrophy. METHODS We applied neuroanatomical normative modeling to magnetic resonance imaging from a real‐world clinical cohort with confirmed AD (n = 86). Regional cortical thickness was compared to a healthy reference cohort (n = 33,072) and the number of outlying regions was summed (total outlier count) and mapped at individual‐ and group‐levels. RESULTS The superior temporal sulcus contained the highest proportion of outliers (60%). Elsewhere, overlap between patient atrophy patterns was low. Mean total outlier count was higher in patients who were non‐amnestic, at more advanced disease stages, and without depressive symptoms. Amyloid burden was negatively associated with outlier count. DISCUSSION Brain atrophy in AD is highly heterogeneous and neuroanatomical normative modeling can be used to explore anatomo‐clinical correlations in individual patients.

Carriers of mutations responsible for dominantly inherited Alzheimer disease provide a unique opportunity to study potential imaging biomarkers. Biomarkers based on routinely acquired clinical MR images, could supplement the extant invasive or logistically challenging) biomarker studies. We used 1104 longitudinal MR, 324 amyloid beta, and 87 tau positron emission tomography imaging sessions from 525 participants enrolled in the Dominantly Inherited Alzheimer Network Observational Study to extract novel imaging metrics representing the mean (μ) and standard deviation (σ) of standardized image intensities of T1‐weighted and Fluid attenuated inversion recovery (FLAIR) MR scans. There was an exponential decrease in FLAIR‐μ in mutation carriers and an increase in FLAIR and T1 signal heterogeneity (T1‐σ and FLAIR‐σ) as participants approached the symptom onset in both supramarginal, the right postcentral and right superior temporal gyri as well as both caudate nuclei, putamina, thalami, and amygdalae. After controlling for the effect of regional atrophy, FLAIR‐μ decreased and T1‐σ and FLAIR‐σ increased with increasing amyloid beta and tau deposition in numerous cortical regions. In symptomatic mutation carriers and independent of the effect of regional atrophy, tau pathology demonstrated a stronger relationship with image intensity metrics, compared with amyloid pathology. We propose novel MR imaging intensity‐based metrics using standard clinical T1 and FLAIR images which strongly associates with the progression of pathology in dominantly inherited Alzheimer disease. We suggest that tau pathology may be a key driver of the observed changes in this cohort of patients. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Alzheimer's disease (AD) blood tests are likely to become increasingly important in clinical practice, but they need to be evaluated in diverse groups before use in the general population. METHODS: This study enrolled a community‐based sample of older adults in the St. Louis, Missouri, USA area. Participants completed a blood draw, Eight‐Item Informant Interview to Differentiate Aging and Dementia (AD8®), Montreal Cognitive Assessment (MoCA), and survey about their perceptions of the blood test. A subset of participants completed additional blood collection, amyloid positron emission tomography (PET), magnetic resonance imaging (MRI), and Clinical Dementia Rating (CDR®). RESULTS: Of the 859 participants enrolled in this ongoing study, 20.6% self‐identified as Black or African American. The AD8 and MoCA correlated moderately with the CDR. The blood test was well accepted by the cohort, but it was perceived more positively by White and highly educated individuals. DISCUSSION: Studying an AD blood test in a diverse population is feasible and may accelerate accurate diagnosis and implementation of effective treatments. Highlights: A diverse group of older adults was recruited to evaluate a blood amyloid test.The enrollment rate was high and the blood test was well accepted by participants.Cognitive impairment screens have moderate performance in a diverse population.Alzheimer's disease blood tests are likely to be feasible for use in real‐world settings. [ABSTRACT FROM AUTHOR]

Background: The mismatch between the limited availability versus the high demand of participants who are in the pre-dementia phase of Alzheimer's disease (AD) is a bottleneck for clinical studies in AD. Nevertheless, potential enrollment barriers in the pre-dementia population are relatively under-reported. In a large European longitudinal biomarker study (the AMYPAD-PNHS), we investigated main enrollment barriers in individuals with no or mild symptoms recruited from research and clinical parent cohorts (PCs) of ongoing observational studies. Methods: Logistic regression was used to predict study refusal based on sex, age, education, global cognition (MMSE), family history of dementia, and number of prior study visits. Study refusal rates and categorized enrollment barriers were compared between PCs using chi-squared tests. Results: 535/1856 (28.8%) of the participants recruited from ongoing studies declined participation in the AMYPAD-PNHS. Only for participants recruited from clinical PCs (n = 243), a higher MMSE-score (β = − 0.22, OR = 0.80, p <.05), more prior study visits (β = − 0.93, OR = 0.40, p <.001), and positive family history of dementia (β = 2.08, OR = 8.02, p <.01) resulted in lower odds on study refusal. General study burden was the main enrollment barrier (36.1%), followed by amyloid-PET related burden (PCresearch = 27.4%, PCclinical = 9.0%, X2 = 10.56, p =.001), and loss of research interest (PCclinical = 46.3%, PCresearch = 16.5%, X2 = 32.34, p <.001). Conclusions: The enrollment rate for the AMYPAD-PNHS was relatively high, suggesting an advantage of recruitment via ongoing studies. In this observational cohort, study burden reduction and tailored strategies may potentially improve participant enrollment into trial readiness cohorts such as for phase-3 early anti-amyloid intervention trials. The AMYPAD-PNHS (EudraCT: 2018–002277-22) was approved by the ethical review board of the VU Medical Center (VUmc) as the Sponsor site and in every affiliated site. [ABSTRACT FROM AUTHOR]

To develop a method for predicting amyloid positron emission tomography (PET) positivity based on multiple regression analysis of quantitative susceptibility mapping (QSM). This prospective study included 39 patients with suspected dementia from four centers. QSM images were obtained through a 3-T, three-dimensional radiofrequency-spoiled gradient-echo sequence with multiple echoes. The cortical standard uptake value ratio (SUVR) was obtained using amyloid PET with 18F-flutemetamol, and susceptibility in the brain regions was obtained using QSM. A multiple regression model to predict cortical SUVR was constructed based on susceptibilities in multiple brain regions, with the constraint that cortical SUVR and susceptibility were positively correlated. The discrimination performance of the Aβ-positive and Aβ-negative cohorts was evaluated based on the predicted SUVR using the area under the receiver operating characteristic curve (AUC) and Mann–Whitney U test. The correlation coefficients between true and predicted SUVR were increased by incorporating the constraint, and the AUC to discriminate between the Aβ-positive and Aβ-negative cohorts reached to 0.79 (p < 0.01). These preliminary results suggest that a QSM-based multiple regression model can predict amyloid PET positivity with fair accuracy. [ABSTRACT FROM AUTHOR]

Identification of biomarkers for the early stages of Alzheimer's disease (AD) is an imperative step in developing effective treatments. Cerebral blood flow (CBF) is a potential early biomarker for AD; generally, older adults with AD have decreased CBF compared to normally aging peers. CBF deviates as the disease process and symptoms progress. However, further characterization of the relationships between CBF and AD risk factors and pathologies is still needed. We assessed the relationships between CBF quantified by arterial spin-labeled magnetic resonance imaging, hypertension, APOE ε 4, and tau and amyloid positron emission tomography in 77 older adults: cognitively normal, subjective cognitive decline, and mild cognitive impairment. Tau and amyloid aggregation were related to altered CBF, and some of these relationships were dependent on hypertension or APOE ε 4 status. Our findings suggest a complex relationship between risk factors, AD pathologies, and CBF that warrants future studies of CBF as a potential early biomarker for AD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurological memory loss syndrome that eventually leads to incapacity to perform everyday chores and death. Since no known cure for this disease exists, it's crucial to catch it early, before symptoms appear. This study used Florbetapir PET (specifically AV-45 PET scans) as a neuroimaging biomarker to develop a 3-Dimensional Ensemble Net for Alzheimer's multi-class categorization. Our research is the first to examine the outcomes of three different feature extraction methods in depth (3D Subject, 3D Slice and 3D Patch Extraction Approach). Alzheimer detection through AV45 PET scans and 3-Dimensional slice neuroimaging computation technique was further done using three distinct Slicing algorithms (Subset Slice Algorithm (SSA), Uniform Slice Algorithm (USA), and Interpolation Zoom Algorithm (IZA). We tested the classification accuracy of a 3D patch-based technique with numerous patches varying from small to medium to huge dimensions. In this study, we used Amyloid- Positron Emission Tomography (AV45-PET) scans from the ADNI repository to create 3-Dimensional Ensemble Net model. Averaging, registering according to a standard template, and skull removal were used to pre-process the raw AV45-PET scans. The rotation method was used to augment these scans even more. Ensembling of two separate 3D-ConvNets was done for the 3D Subject-based computation technique. For the 3D Patch based computing approach, many non-overlapping patches ranging from 32, 40, 48, 56, 64, 72, 80, and 88 were retrieved and given to the Ensemble Net. Three unique algorithms were devised to extract slices from an AV45-PET scan and integrate them back to form a 3D volume in the 3D Slice based technique. Our results showed that (1) The three-class classification accuracy of our Ensemble Net model utilizing AV-45 PET images was 92.13% (maximum accuracy attained so far as per our knowledge). (2) The 3-Dimensional Patch extraction proposition was most accurate in Alzheimer's categorization using Florbetapir PET images, followed by Subject-approach, then 3D Slice approach, with performance accuracy of 92.13, 91.01, and 90.44%, respectively. (3) The accuracy of the Ensemble Net network employing the 3D Patch computational approach was highest for larger patches (Dimensions as 72, 80, 88), next moderate patches (Dimensions as 56, 64, 48), and finally smaller patches (Dimensions as 32, 40). Higher dimension patches were classified correctly 92.13% of the time, whereas medium patches were correctly classified 80.89% of the time, and small patches were classified 74.63% of the time. (4) In terms of three-class classification accuracy, using 3D-Slice based approach, uniform slice extraction and interpolation zoom technique with 90.44 and 88.2% accuracy outperformed subset slice selection, with 81.46% performance accuracy. Using the Ensemble Net model and a 3D patch-based feature extraction approach, we efficiently labeled Alzheimer's disease in a three-class categorization using amyloid PET scans with an accuracy of 92.13. Accuracy. The proposed model is examined using several neuroimaging feature computation approaches, stating that 3D-patch based Ensemble Net outperforms 3D-subject based Ensemble Net model and 3D-slice level model in terms of performance accuracy. In addition, a series of experiments were conducted for 3D-patch based approach with numerous patch dimensions varying from small to moderate to big sized patches in order to investigate impact of patch size on Alzheimer's classification accuracy. While for 3D-Slice based approach, to determine which strategy was optimal, the slice-level technique was evaluated using three distinct algorithms revealing that uniform slice method and interpolation selection method outperforms subset slice method. [ABSTRACT FROM AUTHOR]

Abstract Rationale Amyloid-β (Aβ) pathology is one of the earliest detectable brain changes in Alzheimer’s disease pathogenesis. In clinical practice, trained readers will visually categorise positron emission tomography (PET) scans as either Aβ positive or negative. However, adjunct quantitative analysis is becoming more widely available, where regulatory approved software can currently generate metrics such as standardised uptake value ratios (SUVr) and individual Z-scores. Therefore, it is of direct value to the imaging community to assess the compatibility of commercially available software packages. In this collaborative project, the compatibility of amyloid PET quantification was investigated across four regulatory approved software packages. In doing so, the intention is to increase visibility and understanding of clinically relevant quantitative methods. Methods Composite SUVr using the pons as the reference region was generated from [18F]flutemetamol (GE Healthcare) PET in a retrospective cohort of 80 amnestic mild cognitive impairment (aMCI) patients (40 each male/female; mean age = 73 years, SD = 8.52). Based on previous autopsy validation work, an Aβ positivity threshold of ≥ 0.6 SUVrpons was applied. Quantitative results from MIM Software’s MIMneuro, Syntermed’s NeuroQ, Hermes Medical Solutions’ BRASS and GE Healthcare’s CortexID were analysed using intraclass correlation coefficient (ICC), percentage agreement around the Aβ positivity threshold and kappa scores. Results Using an Aβ positivity threshold of ≥ 0.6 SUVrpons, 95% agreement was achieved across the four software packages. Two patients were narrowly classed as Aβ negative by one software package but positive by the others, and two patients vice versa. All kappa scores around the same Aβ positivity threshold, both combined (Fleiss’) and individual software pairings (Cohen’s), were ≥ 0.9 signifying “almost perfect” inter-rater reliability. Excellent reliability was found between composite SUVr measurements for all four software packages, with an average measure ICC of 0.97 and 95% confidence interval of 0.957–0.979. Correlation coefficient analysis between the two software packages reporting composite z-scores was strong (r 2 = 0.98). Conclusion Using an optimised cortical mask, regulatory approved software packages provided highly correlated and reliable quantification of [18F]flutemetamol amyloid PET with a ≥ 0.6 SUVrpons positivity threshold. In particular, this work could be of interest to physicians performing routine clinical imaging rather than researchers performing more bespoke image analysis. Similar analysis is encouraged using other reference regions as well as the Centiloid scale, when it has been implemented by more software packages.

Abstract Amyloid PET imaging has been crucial for detecting the accumulation of amyloid beta (Aβ) deposits in the brain and to study Alzheimer’s disease (AD). We performed a genome-wide association study on the largest collection of amyloid imaging data (N = 13,409) to date, across multiple ethnicities from multicenter cohorts to identify variants associated with brain amyloidosis and AD risk. We found a strong APOE signal on chr19q.13.32 (top SNP: APOE ɛ4; rs429358; β = 0.35, SE = 0.01, P = 6.2 × 10–311, MAF = 0.19), driven by APOE ɛ4, and five additional novel associations (APOE ε2/rs7412; rs73052335/rs5117, rs1081105, rs438811, and rs4420638) independent of APOE ɛ4. APOE ɛ4 and ε2 showed race specific effect with stronger association in Non-Hispanic Whites, with the lowest association in Asians. Besides the APOE, we also identified three other genome-wide loci: ABCA7 (rs12151021/chr19p.13.3; β = 0.07, SE = 0.01, P = 9.2 × 10–09, MAF = 0.32), CR1 (rs6656401/chr1q.32.2; β = 0.1, SE = 0.02, P = 2.4 × 10–10, MAF = 0.18) and FERMT2 locus (rs117834516/chr14q.22.1; β = 0.16, SE = 0.03, P = 1.1 × 10–09, MAF = 0.06) that all colocalized with AD risk. Sex-stratified analyses identified two novel female-specific signals on chr5p.14.1 (rs529007143, β = 0.79, SE = 0.14, P = 1.4 × 10–08, MAF = 0.006, sex-interaction P = 9.8 × 10–07) and chr11p.15.2 (rs192346166, β = 0.94, SE = 0.17, P = 3.7 × 10–08, MAF = 0.004, sex-interaction P = 1.3 × 10–03). We also demonstrated that the overall genetic architecture of brain amyloidosis overlaps with that of AD, Frontotemporal Dementia, stroke, and brain structure-related complex human traits. Overall, our results have important implications when estimating the individual risk to a population level, as race and sex will needed to be taken into account. This may affect participant selection for future clinical trials and therapies.

Cognitive decline is common in chronic kidney disease (CKD). While the evidence of vascular cognitive impairment in this population is robust, the role of Alzheimer's pathology is unknown. We evaluated serum cystatin C-estimated glomerular filtration rate (eGFR), brain amyloid-β positron emission tomography (PET) imaging, and cognitive function in 166 participants from The 90+ Study. Mean age was 93 years (range 90-107) and 101 (61%) were women; 107 participants had normal cognitive status while 59 participants had cognitive impairment no dementia (CIND) or dementia. Mean ± standard deviation cystatin C was 1.59 ± 0.54 mg/L with eGFR 40.7 ± 18.7 ml/min/1.73m2. Higher amyloid-β burden was associated with dementia, but not with age, diabetes, hypertension, or cardiovascular disease. We found no association between brain amyloid-β burden and cystatin C eGFR. We previously reported that kidney function was associated with cognition and cerebral microbleeds in the same cohort of oldest-old adults (90+ years old). Collectively, these findings suggest that microvascular rather than Alzheimer's pathology drives CKD-associated cognitive dysfunction in this population.

Background: Standard methods for deriving Centiloid scales from amyloid PET images are time-consuming and require considerable expert knowledge. We aimed to develop a deep learning method of automating Centiloid scale calculations from amyloid PET images with 11C-Pittsburgh Compound-B (PiB) tracer and assess its applicability to 18F-labeled tracers without retraining. Methods: We trained models on 231 11C-PiB amyloid PET images using a 50-layer 3D ResNet architecture. The models predicted the Centiloid scale, and accuracy was assessed using mean absolute error (MAE), linear regression analysis, and Bland–Altman plots. Results: The MAEs for Alzheimer’s disease (AD) and young controls (YC) were 8.54 and 2.61, respectively, using 11C-PiB, and 8.66 and 3.56, respectively, using 18F-NAV4694. The MAEs for AD and YC were higher with 18F-florbetaben (39.8 and 7.13, respectively) and 18F-florbetapir (40.5 and 12.4, respectively), and the error rate was moderate for 18F-flutemetamol (21.3 and 4.03, respectively). Linear regression yielded a slope of 1.00, intercept of 1.26, and R2 of 0.956, with a mean bias of −1.31 in the Centiloid scale prediction. Conclusions: We propose a deep learning means of directly predicting the Centiloid scale from amyloid PET images in a native space. Transferring the model trained on 11C-PiB directly to 18F-NAV4694 without retraining was feasible.

• Biomarker tests for Alzheimer's disease (AD) pathology are proliferating. • Pre-test counseling (PTC) for AD biomarker testing is an emerging role for nurses. • Key functions of PTC include disease-specific education and emotional support. • Nurse-led PTC yields rich exchanges with patients and family members and promotes informed decision-making. Biomarker testing for Alzheimer's disease and related disorders (ADRD) brings new opportunities for nurses to foster shared decision-making by leading pre-test counseling (PTC) for patients and families. Audio-recordings of 18 nurse-led PTC sessions were analyzed to characterize questions posed by patient and family members dyads considering whether to pursue amyloid positron emission tomography. Sessions lasted 20 to 75 minutes and generated rich discussion of the purpose and potential implications of amyloid imaging. Dyads posed questions regarding: basic neuroanatomy; the spectrum of normal cognitive aging to dementia; clinical phenotypes and pathological hallmarks of ADRD; secondary prevention of ADRD; and advance planning. In response, PTC facilitators provided disease-specific education, clarification of overt misconceptions, caregiver support, and emotion de-escalation. Nurses conducting PTC for AD biomarker testing should be equipped to answer questions about topics both directly and indirectly related to testing, and also provide emotional support. [ABSTRACT FROM AUTHOR]