Proactive M2 blockade prevents cognitive decline in GRK5-deficient APP transgenic mice via enhancing cholinergic neuronal resilience.

Alzheimer's disease (AD) poses an immense challenge in healthcare, lacking effective therapies. This study investigates the potential of anthranilamide derivative (AAD23), a selective M2 receptor antagonist, in proactively preventing cognitive impairments and cholinergic neuronal degeneration in G protein-coupled receptor kinase-5-deficient Swedish APP (GAP) mice. GAP mice manifest cognitive deficits by 7 months and develop senile plaques by 9 months. A 6-month AAD23 treatment was initiated at 5 months and stopped at 11 months before behavioral assessments without the treatment. AAD23-treated mice exhibited preserved cognitive abilities and improved cholinergic axonal health in the nucleus basalis of Meynert akin to wildtype mice. Conversely, vehicle-treated GAP mice displayed memory deficits and pronounced cholinergic axonal swellings in the nucleus basalis of Meynert. Notably, AAD23 treatment did not alter senile plaques and microgliosis. These findings highlight AAD23's efficacy in forestalling AD-related cognitive decline in G protein-coupled receptor kinase-5-deficient subjects, attributing its success to restoring cholinergic neuronal integrity and resilience, enhancing resistance against diverse degenerative insults.

Association between retinal microvascular abnormalities and late-life brain amyloid-ß deposition: the ARIC-PET study.

BACKGROUND: Retinal microvascular signs are accessible measures of early alterations in microvascular dysregulation and have been associated with dementia; it is unclear if they are associated with AD (Alzheimer's disease) pathogenesis as a potential mechanistic link. This study aimed to test the association of retinal microvascular abnormalities in mid and late life and late life cerebral amyloid. METHODS: Participants from the ARIC-PET (Atherosclerosis Risk in Communities-Positron Emission Tomography) study with a valid retinal measure (N = 285) were included. The associations of mid- and late-life retinal signs with late-life amyloid-ß (Aß) by florbetapir PET were tested. Two different measures of Aß burden were included: (1) elevated amyloid (SUVR > 1.2) and (2) continuous amyloid SUVR. The retinal measures' association with Aß burden was assessed using logistic and robust linear regression models. A newly created retinal score, incorporating multiple markers of retinal abnormalities, was also evaluated in association with greater Aß burden. RESULTS: Retinopathy in midlife (OR (95% CI) = 0.36 (0.08, 1.40)) was not significantly associated with elevated amyloid burden. In late life, retinopathy was associated with increased continuous amyloid standardized value uptake ratio (SUVR) (ß (95%CI) = 0.16 (0.02, 0.32)) but not elevated amyloid burden (OR (95%CI) = 2.37 (0.66, 9.88)) when accounting for demographic, genetic and clinical risk factors. A high retinal score in late life, indicating a higher burden of retinal abnormalities, was also significantly associated with increased continuous amyloid SUVR (ß (95% CI) = 0.16 (0.04, 0.32)) independent of vascular risk factors. CONCLUSIONS: Retinopathy in late life may be an easily obtainable marker to help evaluate the mechanistic vascular pathway between retinal measures and dementia, perhaps acting via AD pathogenesis. Well-powered future studies with a greater number of retinal features and other microvascular signs are needed to test these findings.

Osteoclasts Link Dysregulated Peripheral Degradation Processes and Accelerated Progression in Alzheimer's Disease.

Background: The amyloid-ß (Aß) enhances the number and activity of blood monocyte-derived osteoclasts (OCs). Individuals with osteoporosis (OP) face an increased risk of developing dementia or Alzheimer's disease (AD). Despite this association, the contribution of bone-resorbing OCs to the progression of AD pathology remains unclear. Objective: Our objective was to investigate the potential impacts of OCs on the development of AD pathology. Methods: We conducted targeted analysis of publicly available whole blood transcriptomes from patients with AD to characterize the blood molecular signatures and pathways associated with hyperactive OCs. In addition, we used APP23 transgenic (APP23 TG) AD mouse model to assess the effects of OCs pharmacological blockade on AD pathology and behavior. Results: Patients with AD exhibited increased osteoclastogenesis signature in their blood cells, which appears to be positively correlated with dysfunction of peripheral clearance of Aß mediated by immune cells. Long-term anti-resorptive intervention with Alendronate inhibited OC activity in APP23 mice, leading to improvements in peripheral monocyte Aß-degrading enzyme expression, Aß-deposition, and memory decline. Conclusions: Our findings suggest that OCs have a disease-promoting role in the development and progression of AD, possibly linked to their modulation of peripheral immunity. These findings guide future research to further elucidate the connection between OP and AD pathogenesis, highlighting the potential benefits of preventing OP in alleviating cognitive burden.

Obstructive Sleep Apnea and Alzheimer's Disease Pathology: Is Sleep Architecture the Missing Key?

Impairments of the sleep architecture due to disrupted sleep in individuals with obstructive sleep apnea (OSA) may result in reduced slow wave sleep (SWS), intermittent hypoxemia, and excessive day time sleepiness- all factors that have been shown to impact Alzheimer's disease (AD) risk. In this commentary, we comment on the work by Cavuoto and colleagues in which they examine the associations between nocturnal hypoxemia or sleep disruptions (during SWS) and amyloid-ß burden in individuals with OSA. We review the findings in the context of other similar studies and highlight the strengths and weaknesses of these published studies. We note the importance of examining these relationships longitudinally with a large sample size, including considering sleep health disparities, vascular components, and multiple cognitive domain tests.

Modified RCTU Score: A Semi-Quantitative, Visual Tool for Predicting Alzheimer's Conversion from aMCI.

This research evaluated the modified RCTU score, derived from amyloid PET scans, for predicting the progression from amnestic Mild Cognitive Impairment (aMCI) to Alzheimer's Disease (AD). aMCI patients underwent baseline evaluations, including amyloid PET. AD conversion was identified through neuropsychological tests after observation. The RCTU was modified by segmenting frontal, parietal, and temporal lobes into left and right, resulting in seven areas. Scores from both modified and conventional RCTU were analyzed and compared. Among 45 patients, 12 progressed to AD (over 17.8 ± 6.8 months). AD converters showed higher scores in modified RCTU scores. Modified RCTU score had strong correlations with amyloid SUVR (r > 0.7). Modified RCTU sum score was the significant covariate of AD conversion. Modified RCTU could determine the asymmetry of amyloid deposits. We demonstrated that symmetric deposits of amyloid showed a higher risk for AD conversion when analyzed using modified RCTU. The modified RCTU score is a promising method for predicting AD conversion, correlating strongly with amyloid SUVR.

Neuropathological and sociodemographic factors associated with the cortical amyloid load in aging and Alzheimer's disease.

Alzheimer's disease (AD) is the leading cause of dementia and is characterized by a progressive decline in cognitive abilities. A pathological hallmark of AD is a region-specific accumulation of the amyloid-beta protein (Aß). Here, we explored the association between regional Aß deposition, sociodemographic, and local biochemical factors. We quantified the Aß burden in postmortem cortical samples from parietal (PCx) and temporal (TCx) regions of 27 cognitively unimpaired (CU) and 15 AD donors, aged 78-100 + years. Histological images of Aß immunohistochemistry and local concentrations of pathological and inflammatory proteins were obtained at the "Aging, Dementia and TBI Study" open database. We used the area fraction fractionator stereological methodology to quantify the Aß burden in the gray and white matter within each cortical region. We found higher Aß burdens in the TCx of AD octogenarians compared to CU ones. We also found higher Aß loads in the PCx of AD nonagenarians than in AD octogenarians. Moreover, AD women exhibited increased Aß deposition compared to CU women. Interestingly, we observed a negative correlation between education years and Aß burden in the white matter of both cortices in CU samples. In AD brains, the Aß40, Aß42, and pTau181 isoforms of Aß and Tau proteins were positively correlated with the Aß burden. Additionally, in the TCx of AD donors, the proinflammatory cytokine TNFα showed a positive correlation with the Aß load. These novel findings contribute to understanding the interplay between sociodemographic characteristics, local inflammatory signaling, and the development of AD-related pathology in the cerebral cortex.

Descripción de un método de cuantificación diferente para la carga de amiloide (DPDload) y validación de SPECT/TC en amiloidosis cardíaca / Description of a different quantification method for amyloid burden (burdenDPD) and validation of SPECT/CT in cardiac amyloidosis

Introducción Los radiotrazadores con afinidad ósea como el [99mTc]Tc-DPD han demostrado una alta sensibilidad y especificidad en el diagnóstico no invasivo de la amiloidosis cardíaca (AC) por transtirretina (ATTR-AC). Este estudio tiene como objetivo validar el uso de la SPECT/TC y evaluar la utilidad de la cuantificación de la captación (cargaDPD) en el tejido miocárdico como información potencial sobre la carga amiloide. Métodos Se trata de un análisis retrospectivo de 46 pacientes con sospecha de AC, en el que 23 casos con ATTR-AC fueron sometidos a dos métodos de cuantificación para estimar la carga amiloide (cargaDPD) a través de imágenes planares y de una SPECT/TC. Resultados La SPECT/TC aportó un valor añadido significativo en el diagnóstico del paciente con AC (p<0,05). La estimación de la carga amiloide comprobó que la pared del VI más afectada es el tabique interventricular en la mayoría de los casos, y la existencia de una relación significativa entre la captación de Perugini y la carga de DPD. Conclusiones Validamos la necesidad de la SPECT/TC como complemento de la imagen planar en el diagnóstico de la AC-TTR. Por su parte, el cálculo de la carga amiloide continúa siendo un área de investigación compleja y requiere de más estudios, con un mayor número de pacientes, que permitan validar un método estandarizado de cuantificación de la carga de amiloide, tanto para el diagnóstico como para el seguimiento del tratamiento (AU)

Background Bone tracers such as [99mTc]Tc-DPD have shown high sensitivity and specificity in the non-invasive diagnosis of transthyretin cardiac amyloidosis (ATTR-AC). This study aims to validate SPECT/CT and assess the usefulness of uptake quantification (burdenDPD) in the myocardial tissue as potential information on the amyloid burden. Methods In a retrospective analysis of 46 patients with suspected CA, 23 cases with ATTR-AC had two quantification methods conducted to estimate amyloid burden (burdenDPD) through planar scintigraphic scans and a SPECT/CT. Results SPECT/CT significantly provided an added value in the patient's diagnosis with CA (P<.05). The estimation of the amyloid burden substantiated that the most affected wall of the LV is the interventricular septum in most cases and the existence of a significant relationship between the Perugini score uptake and the burdenDPD. Conclusions We validate the need for SPECT/CT to complement planar imaging in diagnosing ATTR-AC. For its part, quantifying the amyloid load continues to be a complex area of research. It requires further studies with a larger number of patients to validate a standardized method of amyloid load quantification, both for diagnosis and treatment monitoring (AU)

Quantitative SPECT/CT Parameters in the Assessment of Transthyretin Cardiac Amyloidosis-A New Dimension of Molecular Imaging.

AIMS: Cardiac transthyretin amyloidosis (ATTR) represents the accumulation of misfolded transthyretin in the heart interstitium. Planar scintigraphy with bone-seeking tracers has long been established as one of the three main steps in the non-invasive diagnosis of ATTR, but lately, single-photon emission computed tomography (SPECT) has gained wide recognition for its abilities to exclude false positive results and offer a possibility for amyloid burden quantitation. We performed a systematic review of the existing literature to provide an overview of the available SPECT-based parameters and their diagnostic performances in the assessment of cardiac ATTR. Methods and Methods: Among the 43 papers initially identified, 27 articles were screened for eligibility and 10 met the inclusion criteria. We summarised the available literature based on radiotracer, SPECT acquisition protocol, analysed parameters and their correlation to planar semi-quantitative indices. RESULTS: Ten articles provided accurate details about SPECT-derived parameters in cardiac ATTR and their diagnostic potential. Five studies performed phantom studies for accurate calibration of the gamma cameras. All papers described good correlation of quantitative parameters to the Perugini grading system. CONCLUSIONS: Despite little published literature on quantitative SPECT in the assessment of cardiac ATTR, this method offers good prospects in the appraisal of cardiac amyloid burden and treatment monitoring.

Description of a different quantification method for amyloid burden (DPDload) and validation of SPECT/CT in cardiac amyloidosis.

BACKGROUND: Bone tracers such as 99mTc-DPD have shown high sensitivity and specificity in the non-invasive diagnosis of transthyretin cardiac amyloidosis (ATTR-CA). This study aims to validate SPECT/CT and assess the usefulness of uptake quantification (DPDload) in the myocardial tissue as potential information on the amyloid burden. METHODS: In a retrospective analysis of 46 patients with suspected CA, 23 cases with ATTR-CA had two quantification methods conducted to estimate amyloid burden (DPDload) through planar scintigraphic scans and a SPECT/CT. RESULTS: SPECT/CT significantly provided an added value in the patient's diagnosis with CA (P<.05). The estimation of the amyloid burden substantiated that the most affected wall of the LV is the interventricular septum in most cases and the existence of a significant relationship between the Perugini score uptake and the DPDload. CONCLUSIONS: We validate the need for SPECT/CT to complement planar imaging in diagnosing ATTR-CA. For its part, quantifying the amyloid load continues to be a complex area of research. It requires further studies with a larger number of patients to validate a standardized method of amyloid load quantification, both for diagnosis and treatment monitoring.

Related amyloid burden and cortical atrophy in individuals with subtle cognitive decline.

BACKGROUND AND PURPOSE: Subtle cognitive decline represents a stage of cognitive deterioration in which pathological biomarkers may be present, including early cortical atrophy and amyloid deposition. Using individual items from the Montreal Cognitive Assessment and k-modes cluster analysis, we previously identified three clusters of individuals without overt cognitive impairment: (1) High Performing (no deficits in performance), (2) Memory Deficits (lower memory performance), and (3) Compound Deficits (lower memory and executive function performance). In this study, we sought to understand the relationships found in our clusters between cortical atrophy on MR and amyloid burden on PET. METHODS: Data were derived from the Alzheimer's Disease Neuroimaging Initiative and comprised individuals from our previous analyses with available MR and amyloid PET scans (n = 272). Using multiple-group structural equation modeling, we regressed amyloid standardized uptake value ratio on volumetric regions to simultaneously evaluate unique associations within each cluster. RESULTS: In our Compound Deficits cluster, greater whole cerebral amyloid burden was significantly related to right entorhinal cortical and left hippocampal atrophy, rs  = -.412 (p = .005) and -.304 (p = .049), respectively. Within this cluster, right entorhinal cortical atrophy was significantly related to greater amyloid burden within multiple frontal regions. CONCLUSIONS: The Compound Deficits cluster, which represents a group potentially at higher risk for decline, was observed to have significantly more cortical atrophy, particularly within the entorhinal cortex and hippocampus, associated with whole brain and frontal lobe amyloid burden. These findings point to a pattern of early pathological deterioration that may place these individuals at risk for future decline.

A Single Baseline Amyloid Positron Emission Tomography Could Be Sufficient for Predicting Alzheimer's Disease Conversion in Mild Cognitive Impairment.

OBJECTIVE: Baseline amyloid burden in mild cognitive impairment (MCI) has been linked to conversion to Alzheimer's disease (AD), but the comparison of baseline and longitudinal changes in amyloid burden for predicting AD remains unresolved. The objectives of this study aimed to compare the prognostic ability of baseline and longitudinal changes in amyloid burden in MCI patients. METHODS: Seventy-five individuals with MCI were recruited and examined annually by clinical interviews for a mean follow-up of 24 months (range, 11.6-42.0). [18F]Florbetaben positron emission tomography (PET) scans were performed. T1-weighted 3D volumes were acquired for co-registration, and to define regions of interest. We examined whether baseline and longitudinal amyloid burden changes can improve AD conversion by Cox proportional hazard model analysis and receiver operating characteristic (ROC) curve analysis. RESULTS: Cox proportional hazards model analysis showed that baseline amyloid burden was significantly associated with increased risk of conversion to AD (hazard ratio [HR]=10.0; 95% confidence interval [CI], 1.15-85.39; p=0.04), but longitudinal amyloid burden changes was not (HR=0.2; 95% CI, 0.02-1.18; p=0.07). When predicting AD, longitudinal amyloid burden changes had better ROC accuracy of 65.2% (95% CI, 48.4-82.0) than baseline amyloid burden of 59.6% (95% CI, 40.3-79.0), without statistical significance in pairwise comparison. CONCLUSION: A single baseline amyloid PET could be sufficient in the prediction of AD conversion in MCI.

Association of serum thyroid hormone levels with positron emission tomography imaging in non-demented older adults.

BACKGROUND: Although increasing evidence indicates that even variations in normal range thyroid function are associated with Alzheimer's disease (AD), the association between serum thyroid hormone levels within the reference range and AD biomarkers remains unclear. This study examined whether variations in thyroid hormones within the reference range are associated with brain amyloid burden and cortical glucose metabolism in older adults without dementia. METHODS: One hundred and two non-demented older adults underwent 11 C-Pittsburgh Compound B positron emission tomography (PiB-PET), 18 F-fluorodeoxyglucose (FDG)-PET, and measurement of serum thyroid-stimulating hormone (TSH), free triiodothyronine (T3), and free thyroxine (T4) levels. The discrimination between PiB-negative and PiB-positive subgroup was made on the basis of a subject's cortical uptake value ratio greater than 1.4. The association of serum thyroid hormone levels with global PiB or FDG uptake, and PiB or FDG uptake in each region of interest, including frontal and temporoparietal lobes and posterior cingulate gyrus, was analysed using a multiple regression model with adjustment for covariates, including age, gender, years of education, apolipoprotein E4 status or PiB uptake value. RESULTS: In the PiB-positive subgroup, the serum TSH levels positively associated with the global FDG uptake (ß = 0.471, P = 0.003) and FDG uptake in the frontal and temporoparietal lobes (ß = 0.466, P = 0.003, ß = 0.394, P = 0.012, respectively); the serum-free T3 levels negatively associated with the FDG uptake in the temporoparietal lobe and posterior cingulate region (ß = -0.351, P = 0.033, ß = -0.544, P = 0.002, respectively). The PiB-negative subgroup showed no significant associations. The serum thyroid hormone levels did not correlate with the global PiB uptake and PiB uptake in each region. CONCLUSIONS: The variations in the thyroid hormones within the reference ranges are associated with glucose metabolism, particularly in the specific regions affected by the neuropathologic changes of AD, in non-demented older adults with brain amyloid burden.

Alzheimer's Disease Seen through the Eye: Ocular Alterations and Neurodegeneration.

Alzheimer's Disease (AD) is one of the main neurodegenerative diseases worldwide. Unfortunately, AD shares many similarities with other dementias at early stages, which impedes an accurate premortem diagnosis. Therefore, it is urgent to find biomarkers to allow for early diagnosis of the disease. There is increasing scientific evidence highlighting the similarities between the eye and other structures of the CNS, suggesting that knowledge acquired in eye research could be useful for research and diagnosis of AD. For example, the retina and optic nerve are considered part of the central nervous system, and their damage can result in retrograde and anterograde axon degeneration, as well as abnormal protein aggregation. In the anterior eye segment, the aqueous humor and tear film may be comparable to the cerebrospinal fluid. Both fluids are enriched with molecules that can be potential neurodegenerative biomarkers. Indeed, the pathophysiology of AD, characterized by cerebral deposits of amyloid-beta (Aß) and tau protein, is also present in the eyes of AD patients, besides numerous structural and functional changes observed in the structure of the eyes. Therefore, all this evidence suggests that ocular changes have the potential to be used as either predictive values for AD assessment or as diagnostic tools.

Predicting diagnosis 4 years prior to Alzheimer's disease incident.

This study employed a deep learning longitudinal model, graph convolutional and recurrent neural network (graph-CNN-RNN), on a series of brain structural MRI scans for AD prognosis. It characterized whole-brain morphology via incorporating longitudinal cortical and subcortical morphology and defined a probabilistic risk for the prediction of AD as a function of age prior to clinical diagnosis. The graph-CNN-RNN model was trained on half of the Alzheimer's Disease Neuroimaging Initiative dataset (ADNI, n = 1559) and validated on the other half of the ADNI dataset and the Open Access Series of Imaging Studies-3 (OASIS-3, n = 930). Our findings demonstrated that the graph-CNN-RNN can reliably and robustly diagnose AD at the accuracy rate of 85% and above across all the time points for both datasets. The graph-CNN-RNN predicted the AD conversion from 0 to 4 years before the AD onset at ∼80% of accuracy. The AD probabilistic risk was associated with clinical traits, cognition, and amyloid burden assessed using [18F]-Florbetapir (AV45) positron emission tomography (PET) across all the time points. The graph-CNN-RNN provided the quantitative trajectory of brain morphology from prognosis to overt stages of AD. Such a deep learning tool and the AD probabilistic risk have great potential in clinical applications for AD prognosis.

Hyperbaric oxygen therapy alleviates vascular dysfunction and amyloid burden in an Alzheimer's disease mouse model and in elderly patients.

Vascular dysfunction is entwined with aging and in the pathogenesis of Alzheimer's disease (AD) and contributes to reduced cerebral blood flow (CBF) and consequently, hypoxia. Hyperbaric oxygen therapy (HBOT) is in clinical use for a wide range of medical conditions. In the current study, we exposed 5XFAD mice, a well-studied AD model that presents impaired cognitive abilities, to HBOT and then investigated the therapeutical effects using two-photon live animal imaging, behavioral tasks, and biochemical and histological analysis. HBOT increased arteriolar luminal diameter and elevated CBF, thus contributing to reduced hypoxia. Furthermore, HBOT reduced amyloid burden by reducing the volume of pre-existing plaques and attenuating the formation of new ones. This was associated with changes in amyloid precursor protein processing, elevated degradation and clearance of Aß protein and improved behavior of 5XFAD mice. Hence, our findings are consistent with the effects of HBOT being mediated partially through a persistent structural change in blood vessels that reduces brain hypoxia. Motivated by these findings, we exposed elderly patients with significant memory loss at baseline to HBOT and observed an increase in CBF and improvement in cognitive performances. This study demonstrates HBOT efficacy in hypoxia-related neurological conditions, particularly in AD and aging.

Predicting Brain Amyloid Using Multivariate Morphometry Statistics, Sparse Coding, and Correntropy: Validation in 1,101 Individuals From the ADNI and OASIS Databases.

Biomarker assisted preclinical/early detection and intervention in Alzheimer's disease (AD) may be the key to therapeutic breakthroughs. One of the presymptomatic hallmarks of AD is the accumulation of beta-amyloid (Aß) plaques in the human brain. However, current methods to detect Aß pathology are either invasive (lumbar puncture) or quite costly and not widely available (amyloid PET). Our prior studies show that magnetic resonance imaging (MRI)-based hippocampal multivariate morphometry statistics (MMS) are an effective neurodegenerative biomarker for preclinical AD. Here we attempt to use MRI-MMS to make inferences regarding brain Aß burden at the individual subject level. As MMS data has a larger dimension than the sample size, we propose a sparse coding algorithm, Patch Analysis-based Surface Correntropy-induced Sparse-coding and Max-Pooling (PASCS-MP), to generate a low-dimensional representation of hippocampal morphometry for each individual subject. Then we apply these individual representations and a binary random forest classifier to predict brain Aß positivity for each person. We test our method in two independent cohorts, 841 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and 260 subjects from the Open Access Series of Imaging Studies (OASIS). Experimental results suggest that our proposed PASCS-MP method and MMS can discriminate Aß positivity in people with mild cognitive impairment (MCI) [Accuracy (ACC) = 0.89 (ADNI)] and in cognitively unimpaired (CU) individuals [ACC = 0.79 (ADNI) and ACC = 0.81 (OASIS)]. These results compare favorably relative to measures derived from traditional algorithms, including hippocampal volume and surface area, shape measures based on spherical harmonics (SPHARM) and our prior Patch Analysis-based Surface Sparse-coding and Max-Pooling (PASS-MP) methods.

Unique regional patterns of amyloid burden predict progression to prodromal and clinical stages of Alzheimer's disease.

Although beta-amyloid (Aß) positivity has shown to be associated with higher risk of progression to Alzheimer's disease (AD) in mild cognitive impairment (MCI), information on the time to conversion to manifest dementia cannot be readily deduced from this binary classification. Here, we assessed if regional patterns of Aß deposition measured with 18F-florbetapir may serve as biomarker for progression risk in Aß-positive cognitively normal (CN) and MCI patients, including clinical follow-up data and cerebrospinal fluid (CSF) biomarkers. Voxel-wise group comparisons between age and sex-matched Aß-positive groups (i.e., CN-stables [n = 38] vs. CN-to-MCI/AD progressors [n = 38], MCI-stables [n = 104] versus MCI-to-AD progressors [n = 104]) revealed higher Aß burden in precuneus, subcortical, and parietal regions in CN-to-MCI/AD progressors and cingulate, temporal, and frontal regions in MCI-to-AD progressors. Importantly, these regional patterns predicted progression to advanced stages on the AD spectrum in the short and the long-term beyond global Aß burden and CSF biomarkers. These results suggest that distinct regional patterns of Aß burden are a valuable biomarker for risk of disease progression in CN and MCI.

AMYQ: An index to standardize quantitative amyloid load across PET tracers.

INTRODUCTION: Positron emission tomography (PET) amyloid quantification methods require magnetic resonance imaging (MRI) for spatial registration and a priori reference region to scale the images. Furthermore, different tracers have distinct thresholds for positivity. We propose the AMYQ index, a new measure of amyloid burden, to overcome these limitations. METHODS: We selected 18F-amyloid scans from ADNI and Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL) with the corresponding T1-MRI. A subset also had neuropathological data. PET images were normalized, and the AMYQ was calculated based on an adaptive template. We compared AMYQ with the Centiloid scale on clinical and neuropathological diagnostic performance. RESULTS: AMYQ was related with amyloid neuropathological burden and had excellent diagnostic performance to discriminate controls from patients with Alzheimer's disease (AD) (area under the curve [AUC] = 0.86). AMYQ had a high agreement with the Centiloid scale (intraclass correlation coefficient [ICC] = 0.88) and AUC between 0.94 and 0.99 to discriminate PET positivity when using different Centiloid cutoffs. DISCUSSION: AMYQ is a new MRI-independent index for standardizing and quantifying amyloid load across tracers.

Change in cognitive function according to cholinesterase inhibitor use and amyloid PET positivity in patients with mild cognitive impairment.

BACKGROUND: Cholinesterase inhibitors (ChEIs) are an FDA-approved symptomatic treatment for patients with Alzheimer's disease (AD). Its efficacy in patients with mild cognitive impairment (MCI), however, is controversial. Nonetheless, ChEIs have often been used in patients with MCI. From the perspective that ChEIs were developed based on the pathomechanism of AD, the effect of ChEIs in MCI patients could be different depending on the amyloid burden. In this retrospective observational study, we aimed to investigate the influence of ChEIs and amyloid burden on cognitive change for 1 year in patients with MCI. METHODS: We included 111 patients with MCI with a Clinical Dementia Rating (CDR) score of 0.5, a 1-year follow-up cognitive assessment, and amyloid positron emission tomography (PET) performed within 6 months before or after the baseline cognitive assessment (73 ChEI users and 38 ChEI non-users) from the Neurocognitive Behavior Center of Seoul National University Bundang Hospital. Additionally, those who had a positive amyloid PET scan more than 6 months before the baseline cognitive assessment and those who had a negative amyloid PET scan more than 6 months after the 1-year follow-up cognitive assessment were also included. Among the total 111 patients, 25 ChEI users and 25 ChEI non-users were matched by baseline Mini-Mental State Examination (MMSE) score, age, educational level, CDR Sum of Boxes, and amyloid PET positivity using propensity score matching. Multiple linear regression analysis was performed to assess the influence of ChEI use and amyloid PET positivity on cognitive change for 1 year. Univariate and multivariate logistic regression analyses were performed to evaluate the association between ChEI use and disease progression to CDR 1 at the 1-year follow-up visit. RESULTS: ChEI use or non-use was not associated with cognitive change for 1 year. Amyloid PET positivity or negativity did not change this non-association. Furthermore, progression to CDR 1 was related to low baseline MMSE score (OR 0.606, CI 0.381-0.873), but not with ChEI use or non-use, and not with amyloid PET result. CONCLUSION: ChEI use or non-use was not related to cognitive change at a 1-year follow-up visit in patients with or without amyloid burden. In addition, ChEI use or non-use could not predict disease progression to CDR 1 at 1-year follow-up visit.

Patch-Based Surface Morphometry Feature Selection with Federated Group Lasso Regression.

Collectively, vast quantities of brain imaging data exist across hospitals and research institutions, providing valuable resources to study brain disorders such as Alzheimer's disease (AD). However, in practice, putting all these distributed datasets into a centralized platform is infeasible due to patient privacy concerns, data restrictions and legal regulations. In this study, we propose a novel federated feature selection framework that can analyze the data at each individual institution without data-sharing or accessing private patient information. In this framework, we first propose a federated group lasso optimization method based on block coordinate descent. We employ stability selection to determine statistically significant features, by solving the group lasso problem with a sequence of regularization parameters. To accelerate the stability selection, we further propose a federated screening rule, which can identify and exclude the irrelevant features before solving the group lasso. Here, we use this framework for patch based feature selection on hippocampal morphometry. Shape is characterized through two different kinds of local measures, the radial distance and the surface area determined via tensor-based morphometry (TBM). The method is tested on 1,127 T1-weighted brain magnetic resonance images (MRI) of AD, mild cognitive impairment (MCI) and elderly control subjects, randomly assigned to five independent hypothetical institutions for testing purpose. We examine the association of MRI-based anatomical measures with general cognitive assessment and amyloid burden to identify the morphometry changes related to AD deterioration and plaque accumulation. Finally, we visualize the significance of the association on the hippocampal surfaces. Our experimental results successfully demonstrate the efficiency and effectiveness of our method.