Extracellular vesicle proteome unveils cathepsin B connection to Alzheimer's disease pathogenesis.

Extracellular vesicles (EVs) are membrane vesicles that are released extracellularly and considered to be implicated in the pathogenesis of neurodegenerative diseases including Alzheimer's disease. Here, CSF EVs of 16 ATN-classified cases were subjected to quantitative proteome analysis. In these CSF EVs, levels of 11 proteins were significantly altered during the ATN stage transitions (P < 0.05 and fold-change > 2.0). These proteins were thought to be associated with Alzheimer's disease pathogenesis and represent candidate biomarkers for pathogenic stage classification. Enzyme-linked immunosorbent assay analysis of CSF and plasma EVs revealed altered levels of cathepsin B (CatB) during the ATN transition (seven ATN groups in validation set, n = 136). The CSF and plasma EV CatB levels showed a negative correlation with CSF amyloid-ß42 concentrations. This proteomic landscape of CSF EVs in ATN classifications can depict the molecular framework of Alzheimer's disease progression, and CatB may be considered a promising candidate biomarker and therapeutic target in Alzheimer's disease amyloid pathology.

Progression of Myopic Maculopathy Based on the ATN Classification System.

INTRODUCTION: Myopic maculopathy is a sight-threatening disease, which causes irreversible vision faults and central vision loss. The purpose of this study is evaluating the risk factors of the myopic maculopathy progression according to the ATN classification system. METHODS: Clinic data of 69 high myopia patients aged older than 40 years with a follow-up time of more than 2 years, who underwent fundus photography and OCT examination were retrospectively collected. Fundus changes were evaluated with ATN classification at the first and last follow-up times. The related factors affecting progress including axial length (AL), spherical equivalence (SE), subfoveal choroidal thickness (SFCT), disc-foveal distance (DFD), optic disc tilt, and parapapillary atrophy (PPA) were analyzed. RESULTS: This study included 69 high-myopia patients with mean age 54.29 ± 10.41 years. The progression rate of myopic maculopathy (MM) was approximately 25.56%. Elongated DFD (5.37 ± 0.11 mm vs. 4.86 ± 0.37 mm; p < 0.001) and thinner SFCT (138.52 ± 29.38 µm vs. 184.87 ± 48.72 µm; p = 0.008) at baseline were linked with MM progression. In multiple logistic regression analysis, DFD was a substantial hazard risk factor (adjusted OR = 1.672, 95% CI: 1.135-2.498, p < 0.05) after adjusting for age, AL and SFCT. Receiver operating characteristic curve showed that DFD might serve as a predictor to discriminate the MM progression with a cut-off value of 5.15 mm and a substantial receiver operating characteristic curve area (AUC: 0.794). Compared with the non-progression group, the progression group had older age (p < 0.001), longer AL (p = 0.001), higher optic disc tilt rate (p < 0.001), and higher proportion of pre-existing PPA (p = 0.038) at baseline, the differences were statistically significant. CONCLUSION: Based on the ATN classification system, we found that the progression of MM was related to older age, longer AL, high disc tilt, pre-existing PPA, thinner SFCT, and longer DFD. The parameter of DFD was an important factor affecting the progression of MM, which is considered to have a higher probability of progression when the length is beyond 5.15 mm.

Amyloid-ß levels and cognitive trajectories in non-demented pTau181-positive subjects without amyloidopathy.

Phosphorylated Tau181 (pTau181) in CSF and recently in plasma has been associated with Alzheimer's disease. In the absence of amyloidopathy, individuals with increased total Tau levels and/or temporal lobe atrophy experience no or only mild cognitive decline compared with biomarker-negative controls, leading to the proposal to categorize this constellation as suspected non-Alzheimer's disease pathophysiology (SNAP). We investigated whether the characteristics of SNAP also applied to individuals with increased CSF-pTau181 without amyloidopathy. In this long-term observational study, 285 non-demented individuals, including 76 individuals with subjective cognitive impairment and 209 individuals with mild cognitive impairment, were classified based on their CSF levels of pTau181 (T), total Tau (N), amyloid-ß42 (Aß42) and Aß42/Aß40 ratio (A) into A+T+N±, A+T-N±, A-T+N±, and A-T-N-. The longitudinal analysis included 154 subjects with a follow-up of more than 12 months who were followed to a median of 4.6 years (interquartile range = 4.3 years). We employed linear mixed models on psychometric tests and region of interest analysis of structural MRI data. Cognitive decline and hippocampal atrophy rate were significantly higher in A+T+N± compared to A-T+N±, whereas there was no difference between A-T+N± and A-T-N-. Furthermore, there was no significant difference between A-T+N± and controls in dementia risk [hazard ratio 0.3, 95% confidence interval (0.1, 1.9)]. However, A-T+N± and A-T-N- could be distinguished based on their Aß42 and Aß40 levels. Both Aß40 and Aß42 levels were significantly increased in A-T+N± compared to controls. Long term follow-up of A-T+N± individuals revealed no evidence that this biomarker constellation was associated with dementia or more severe hippocampal atrophy rates compared to controls. However, because of the positive association of pTau181 with Aß in the A-T+N± group, a link to the pathophysiology of Alzheimer's disease cannot be excluded in this case. We propose to refer to these individuals in the SNAP group as 'pTau and Aß surge with subtle deterioration' (PASSED). The investigation of the circumstances of simultaneous elevation of pTau and Aß might provide a deeper insight into the process under which Aß becomes pathological.

Pathologic myopia and severe pathologic myopia: correlation with axial length.

PURPOSE: This study had three aims: (1) correlate axial length (AL), age and best-corrected visual acuity in high myopic patients scored on the ATN grading system; (2) determine AL cut-off values to distinguish between pathologic myopia (PM) and severe PM; and (3) identify clinical differences between PM and severe PM. METHODS: This is a cross-sectional, non-interventional study. All patients underwent complete ophthalmologic examination, ATN grading and multimodal imaging (colour fundus photography, swept-source OCT, fundus autofluorescence, OCT angiography and fluorescein angiography). RESULTS: Six hundred forty-four eyes from 345 high myopic patients were included. The eyes were graded on the ATN system and classified as PM (≥ A2) or severe PM (≥ A3, ≥ T3 and/or N2). Significant between-group (PM vs. severe PM) differences (p < 0.05) were observed on the individual ATN components (atrophic [A], tractional [T] and neovascular [N]), age, BCVA and AL. AL was also linearly correlated with the A, T and N components (r = 0.53, p < 0.01; r = 0.24, p < 0.01; r = 0.20, p < 0.01; respectively). ROC curve analysis showed the optimal AL cut-off value to distinguish between PM at 28 mm (AUC ROC curve: 0.813, specificity: 75%, sensitivity: 75%) and severe PM at 29.50 mm (AUC ROC curve: 0.760, specificity: 75%, sensitivity: 70%). CONCLUSION: AL is the main variable associated with myopic maculopathy. Due to the clinical differences found between PM and severe PM, there is need to create an objective cut-off point to distinguish these two different entities being the optimal cut-off points for AL 28 mm and 29.5 mm, respectively. These objective AL cut-off values should be taken into account for determining a correct follow-up, ophthalmic management and treatment.

Long-term surgical outcomes and prognostic factors of foveal detachment in pathologic myopia: based on the ATN classification.

BACKGROUND: To investigate the long-term surgical outcomes and prognostic factors of foveal detachment (FD) in pathological myopia. METHODS: This retrospective observational study included 59 patients with FD (61 eyes) who underwent pars plana vitrectomy at Shanghai General Hospital between June 2017 and July 2018 with follow-up for at least 24 months. Comprehensive ophthalmic examinations, including best-corrected visual acuity (BCVA) and swept-source optical coherence tomography, were assessed. Preoperative myopic maculopathy was evaluated according to the ATN classification. RESULTS: FD completely resolved in 59 of 61 eyes (96.7%). Mean duration of retinal reattachment was 12.10 ± 8.10 months. Mean logMAR BCVA improved from 1.34 ± 0.52 to 0.83 ± 0.43 at 24 months postoperatively (P < 0.001). Secondary macular hole occurred in 8 eyes (13.1%) with a mean period of 3.4 ± 4.1 weeks after primary surgery. In regression analyses, baseline myopic atrophy maculopathy (MAM) (B = 0.213, P = 0.005) and vitreomacular traction (VMT) (B = 0.292, P = 0.007) were adverse prognostic factors for postoperative BCVA. A more severe MAM revealed a delay in retinal reattachment (B = 5.670, P = 0.002). FD eyes with VMT (OR = 1.309, P = 0.003) or outer lamellar macular hole (O-LMH) (OR = 1.369, P < 0.001) were risk factors for postoperative secondary macular hole. CONCLUSIONS: Vitrectomy was effective in the long-term for treating FD. Careful consideration is needed for those with VMT or O-LMH due to the high risk of secondary macular hole after vitrectomy. FD eyes with more severe MAM tended to have poorer postoperative BCVA and extended periods of retinal reattachment.

Intra- and interobserver concordance of a new classification system for myopic maculopathy.

BACKGROUND: Myopic maculopathy (MM) is one of the major causes of visual impairment and irreversible blindness in eyes with pathologic myopia (PM). However, the classification of each type of lesion associated with MM has not been determined. Recently, a new MM classification system, known as the ATN grading and classification system, was proposed; it is based on the fundus photographs and optical coherence tomography (OCT) images and includes three variable components: atrophy (A), traction (T), and neovascularization (N). This study aimed to perform an independent evaluation of interobserver and intraobserver agreement for the recently developed ATN grading system for MM. METHODS: This was a retrospective study. Fundus photographs and OCT images of 125 patients (226 eyes) with various MMs were evaluated and classified using the ATN grading of the new MM classification system by four blinded and independent evaluators (2 attending ophthalmologists and 2 ophthalmic residents). All cases were randomly re-evaluated by the same observers after an interval of 6 weeks. The kappa coefficient (κ) and 95% confidence interval (CI) were used to determine the interobserver and intraobserver agreement. RESULTS: The interobserver agreement was substantial when considering the maculopathy type (A, T, and N). The weighted Fleiss κ values for each MM type (A, T, and N) were 0.651 (95% CI: 0.602-0.700), 0.734 (95% CI: 0.689-0.779), and 0.702 (95% CI: 0.649-0.755), respectively. The interobserver agreement when considering the subtypes was good or excellent, except for stages A1, A2, and N1, in which the weighted κ value was less than 0.6, with moderate agreement. The intraobserver agreement of types and subtypes was excellent, with κ > 0.8. No significant differences were observed between the attending ophthalmologists and residents for interobserver reliability or intraobserver reproducibility. CONCLUSIONS: The ATN classification allows an adequate agreement among ophthalmologists with different qualifications and by the same observer on separate occasions. Future prospective studies should further evaluate whether this classification can be better implemented in clinical decision-making and disease progression assessments.

Evolution of Macular Bruch Membrane Defects of Patchy Chorioretinal Atrophy in Pathologic Myopia Based on a Recent Classification System.

PURPOSE: The purpose of this study was to analyze the progression of macular Bruch membrane defects (BMD) in highly myopic patients with patchy atrophy (PA); and study its correlation with the enlargement of PA and ATN grading. Setting/Venue: Puerta de Hierro-Majadahonda University Hospital, Madrid, Spain. PATIENTS AND METHODS: This was a cross-sectional, noninterventional study. A series of 451 highly myopic eyes with spherical equivalent > -6.0 D and/or >26 mm of axial length (AL) were included. All patients underwent a complete ophthalmological examination and swept-source optical coherence tomography (SS-OCT), and were graded using the ATN system by 2 masked retina experts that assessed the atrophic (A), tractional (T), and neovascular (N) components. SS-OCT b-scans were employed to study PA and macular BMD at baseline and at a 1-year follow-up, in patients with good foveal fixation. RESULTS: Out of total 451 eyes, 126 eyes (27.9%) had PA (53 patients; 75.4% women). Mean T and N in eyes with PA were 1.1 ± 1.3 and 0.08 ± 0.2, respectively. Sixty-eight of them had >1-year follow-up with a good foveal fixation and enough image quality. From them, BMD were found in 44 eyes (64.7%) at baseline and increased to 59 eyes (86.7%) at a 1-year follow-up. The mean great linear dimension of PA and macular BMD increased with a median of 384.5 ± 462.5 µm (IR 68.0-660.2) and 265.6 ± 418.1 µm (IR 0-331.7), respectively. At 1-year, PA and BMD sizes increase, and were statistically significant (p < 0.001). There was a positive correlation between the growth of macular BMD and the growth of PA (r = 0.490, p < 0.00). T grading correlated significantly with PA growth (p < 0.05). CONCLUSIONS: Macular BMD increase its prevalence and its size over time in highly myopic patients with PA. There is a positive correlation between BMD and PA area growth. New studies with a larger sample size, longer follow-up, and AL elongation correlation are necessary to corroborate our findings.

Revision of Alzheimer's diagnostic criteria or relocation of the Potemkin village.

The recently announced revision of the Alzheimer's disease (AD) diagnostic ATN classification adds to an already existing disregard for clinical assessment the rejection of image-based in vivo assessment of the brain's condition. The revision suggests that the diagnosis of AD should be based solely on the presence of cerebral amyloid-beta and tau, indicated by the "A" and "T". The "N", which stands for neurodegeneration - detected by imaging - should no longer be given importance, except that A+ ± T + = AD with amyloid PET being the main method for demonstrating A+ . We believe this is an artificial and misleading suggestion. It is artificial because it relies on biomarkers whose significance remains obscure and where the detection of "A" is based on a never-validated PET method using a tracer that marks much more than amyloid-beta. It is misleading because many patients without dementia will be falsely classified as having AD, but nonetheless candidates for passive immunotherapy, which may be more harmful than beneficial, and sometimes fatal.

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

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

Where Should I Draw the Line: PET-Driven, Data-Driven, or Manufacturer Cut-Off?

Background: The optimal cut-off for Alzheimer's disease (AD) CSF biomarkers remains controversial. Objective: To analyze the performance of cut-off points standardized by three methods: one that optimized the agreement between 11C-Pittsburgh compound B PET (a-PET) and CSF biomarkers (Aß1-42, pTau, tTau, and Aß1-42/Aß1-40 ratio) in our population, called PET-driven; an unbiased cut-off using data from a healthy research cohort, called data-driven, and that provided by the manufacturer. We also compare changes in ATN classification. Methods: CSF biomarkers measured by the LUMIPULSE G600II platform and qualitative visualization of amyloid positron emission tomography (a-PET) were performed in all the patients. We established a cut-off for each single biomarker and Aß1-42/Aß1-40 ratio that optimized their agreement with a-PET using ROC curves. Sensitivity, Specificity, and Overall Percent of Agreement are assessed using a-PET or clinical diagnosis as gold standard for every cut-off. Also, we established a data-driven cut-off from our cognitively unimpaired cohort. We then analyzed changes in ATN classification. Results: One hundred and ten patients were recruited. Sixty-six (60%) were a-PET positive. PET-driven cut-offs were: pTau > 57, tTau > 362.62, Aß1-42/Aß1-40 < 0.069. For a single biomarker, pTau showed the highest accuracy (AUC 0.926). New PET-driven cut-offs classified patients similarly to manufacturer cut-offs (only two patients changed). However, 20 patients (18%) changed when data-driven cut-offs were used. Conclusions: We established our sample's best CSF biomarkers cut-offs using a-PET as the gold standard. These cut-offs categorize better symptomatic subjects than data-driven in ATN classification, but they are very similar to the manufacturer's.

Association between ATN profiles and mortality in a clinical cohort of patients with cognitive disorders.

BACKGROUND: Alzheimer's disease (AD) is the 5th leading cause of death in people 65 years and older. The ATN classification reflects a biological definition of AD pathology with markers of Aß deposition (A), pathologic tau (T), and neurodegeneration (N). Little is known about the relationship between ATN status and the risk of mortality, leading us to examine this association in a relatively large population of patients seen at a memory clinic for cognitive disorders. METHODS: Data were drawn from the BioCogBank Study, including patients seen for cognitive disorders in Lariboisiere Hospital (Paris, France), followed up to 15 years. All participants underwent a lumbar puncture for an assessment of the levels of CSF tau (tau), phosphorylated tau (p-tau181), and ß-amyloid 42 peptide (Aß42). Vital status on July 1, 2020, was recorded for each participant using the national mortality register. Individuals were categorized according to their ATN profiles based on CSF Aß42 or Aß42/40 ratio, p-tau181, and tau. Kaplan-Meier and multivariate Cox analyses were performed with A-T-N - participants as the reference using a short (5 years) and long follow-up (15 years). RESULTS: Of the 1353 patients in the study (mean age: 68 years old, 53% of women, mean MMSE score: 22.6), 262 died during the follow-up. At 5 years of follow-up, A-T-N + individuals had the highest risk of mortality in Kaplan-Meier and adjusted Cox analyses [HR (95% CI) = 2.93 (1.31-6.56)]. At 15 years of follow-up, patients in the AD spectrum had a higher mortality risk with a gradient effect for biomarker positivity: A-T + [HR = 1.63 (1.04-2.55)], A + T - [HR = 2.17 (1.44-3.26)], and A + T + individuals [HR = 2.38 (1.66-3.39)], compared to A-T-N - patients. Adjustments on potential confounders had little impact on these associations. CONCLUSION: This study shows ATN profiles to be associated with mortality in a relatively large patient cohort based on a memory clinic. Patients with isolated evidence of neurodegeneration had a higher mortality rate in the short follow-up, and patients with the AD profile had the highest mortality rate in the long follow-up.

Surgical Outcomes of Myopic Foveoschisis According to the ATN Classification System.

INTRODUCTION: This study compared the surgical outcomes in eyes with myopic foveoschisis (MF) according to the recently developed ATN classification system. METHODS: This was an observational case series of 64 consecutive eyes that underwent vitrectomy for MF. Eyes were classified into severe myopic maculopathy (MM) (n = 43) and non-severe MM (n = 21) groups according to the ATN classification system. The primary outcome measures constituted best-corrected visual acuity (BCVA) and anatomical changes. RESULTS: In total, BCVA improved from 0.97 to 0.53 (P < 0.001) after surgery. The ATN score was significantly lower in the eyes with vision improvement than those without vision improvement (P < 0.001). In the subgroup, BCVA improved from 0.79 to 0.28 in the non-severe MM group (P < 0.001), and improved from 1.05 to 0.65 in the severe MM group (P = 0.001) after surgery. The non-severe MM group achieved better postoperative BCVA (P = 0.001) and were more likely to gain vision improvement (P < 0.001) after surgery compared with the severe MM group. Anatomical success was achieved in 62 of the 64 eyes (96.88%). Two eyes with anatomical failure developed full-thickness macular holes postoperatively; both were in the severe MM group. CONCLUSIONS: For patients with MF, different severity of MM based on ATN classification could lead to a significantly different prognosis after surgery. For patients with high ATN scores, the operative decision should be made cautiously for the worse anatomical and visual prognosis. ATN system is instructive in making operative proposals for MF.

On the basis of the newly developed ATN classification system, we found significant differences in postoperative visual acuity, the rate of vision improvement, and the rate of primary retinal reattachment after vitrectomy between the severe and non-severe myopic maculopathy groups in patients with myopic foveoschisis.

PASSED: Brain atrophy in non-demented individuals in a long-term longitudinal study from two independent cohorts.

Introduction: Alzheimer's disease (AD) is indicated by a decrease in amyloid beta 42 (Aß42) level or the Aß42/Aß40 ratio, and by increased levels of Tau with phosphorylated threonine at position 181 (pTau181) in cerebrospinal fluid (CSF) years before the onset of clinical symptoms. However, once only pTau181 is increased, cognitive decline in individuals with subjective or mild cognitive impairment is slowed compared to individuals with AD. Instead of a decrease in Aß42 levels, an increase in Aß42 was observed in these individuals, leading to the proposal to refer to them as nondemented subjects with increased pTau-levels and Aß surge with subtle cognitive deterioration (PASSED). In this study, we determined the longitudinal atrophy rates of AD, PASSED, and Biomarker-negative nondemented individuals of two independent cohorts to determine whether these groups can be distinguished by their longitudinal atrophy patterns or rates. Methods: Depending on their CSF-levels of pTau 181 (T), total Tau (tTau, N), Aß42 or ratio of Aß42/Aß40 (A), 185 non-demented subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and 62 non-demented subjects from Erlangen AD cohort were assigned to an ATN group (A-T-N-, A-T+N±, A+T-N±and A+T+N±) and underwent T1-weighted structural magnetic resonance imaging (sMRI). Longitudinal grey matter (GM) atrophy patterns were assessed with voxel-based morphometry (VBM) using the cat12 toolbox on spm12 (statistical parametric mapping) of MRI scans from individuals in the ADNI cohort with a mean follow-up of 2 and 5 years, respectively. The annualized atrophy rate for individuals in the Erlangen cohort was determined using region of interest analysis (ROI) in terms of a confirmatory analysis. Results: In the A-T+N± group, VBM did not identify any brain region that showed greater longitudinal atrophy than the A+T+N±, A+T+N± or biomarker negative control group. In contrast, marked longitudinal atrophy in the temporal lobe was evident in the A+T-N± group compared with A+T-N± and biomarker-negative subjects. The ROI in the angular gyrus identified by VBM analysis of the ADNI cohort did not discriminate better than the hippocampal volume and atrophy rate between AD and PASSED in the confirmatory analysis. Discussion: In this study, nondemented subjects with PASSED did not show a unique longitudinal atrophy pattern in comparison to nondemented subjects with AD. The nonsignificant atrophy rate compared with controls suggests that increased pTau181-levels without concomitant amyloidopathy did not indicate a neurodegenerative disorder.

Development of a deep learning algorithm for myopic maculopathy classification based on OCT images using transfer learning.

Purpose: To apply deep learning (DL) techniques to develop an automatic intelligent classification system identifying the specific types of myopic maculopathy (MM) based on macular optical coherence tomography (OCT) images using transfer learning (TL). Method: In this retrospective study, a total of 3,945 macular OCT images from 2,866 myopic patients were recruited from the ophthalmic outpatients of three hospitals. After culling out 545 images with poor quality, a dataset containing 3,400 macular OCT images was manually classified according to the ATN system, containing four types of MM with high OCT diagnostic values. Two DL classification algorithms were trained to identify the targeted lesion categories: Algorithm A was trained from scratch, and algorithm B using the TL approach initiated from the classification algorithm developed in our previous study. After comparing the training process, the algorithm with better performance was tested and validated. The performance of the classification algorithm in the test and validation sets was evaluated using metrics including sensitivity, specificity, accuracy, quadratic-weighted kappa score, and the area under the receiver operating characteristic curve (AUC). Moreover, the human-machine comparison was conducted. To better evaluate the algorithm and clarify the optimization direction, the dimensionality reduction analysis and heat map analysis were also used to visually analyze the algorithm. Results: Algorithm B showed better performance in the training process. In the test set, the algorithm B achieved relatively robust performance with macro AUC, accuracy, and quadratic-weighted kappa of 0.986, 96.04% (95% CI: 0.951, 0.969), and 0.940 (95% CI: 0.909-0.971), respectively. In the external validation set, the performance of algorithm B was slightly inferior to that in the test set. In human-machine comparison test, the algorithm indicators were inferior to the retinal specialists but were the same as the ordinary ophthalmologists. In addition, dimensionality reduction visualization and heatmap visualization analysis showed excellent performance of the algorithm. Conclusion: Our macular OCT image classification algorithm developed using the TL approach exhibited excellent performance. The automatic diagnosis system for macular OCT images of MM based on DL showed potential application prospects.

Prognostic value of amyloid/tau/neurodegeneration (ATN) classification based on diagnostic cerebrospinal fluid samples for Alzheimer's disease.

OBJECTIVE: The primary study objective of this retrospective academic memory clinic-based observational longitudinal study was to investigate the prognostic value of a cerebrospinal fluid (CSF)-based ATN classification for subsequent cognitive decline during the 3 years following lumbar puncture in a clinical, real-life setting. The secondary objective was to investigate the prognostic value of CSF biomarkers as continuous variables. METHODS: Data from 228 patients (median age 67 (47-85) years), who presented at the Neurology Memory Clinic UZ/KU Leuven between September 2011 and December 2016, were included with a follow-up period of up to 36 months. Patients underwent a CSF AD biomarker test for amyloid-beta 1-42 (Aß42), hyperphosphorylated tau (p181-tau) and total tau (t-tau) in the clinical work-up for diagnostic reasons. Patients were divided into ATN classes based on CSF biomarkers: Aß42 for amyloid (A), p181-tau for tau (T), and t-tau as a measure for neurodegeneration (N). Based on retrospective data analysis, cognitive performance was evaluated by Mini Mental State Examination (MMSE) scores every 6 months over a period up to 36 months following the lumbar puncture. The statistical analysis was based on linear mixed-effects modeling (LME). RESULTS: The distribution in the current clinical sample was as follows: A-/T-/N- 32.02%, A+/T-/N- 33.33%, A+/T+/N+ 17.11%, A+/T-/N+ 11.84%, A-/T-/N+ 4.39%, A-/T+/N+ 1.32% (3 cases), with no cases in the A-/T+/N- and A+/T+/N- class. Hence, the latter 3 classes were excluded from further analyses. The change of MMSE relative to A-/T-/N- over a 36-month period was significant in all four ATN classes: A+/T+/N+ = - 4.78 points on the MMSE; A-/T-/N+ = - 4.76; A+/T-/N+ = - 2.83; A+/T-/N- = - 1.96. The earliest significant difference was seen in the A+/T+/N+ class at 12 months after baseline. The effect of ATN class on future cognitive decline was confirmed for a different set of CSF thresholds. All individual baseline CSF biomarkers including the Aß42/t-tau ratio showed a significant correlation with subsequent cognitive decline, with the highest correlation seen for Aß42/t-tau. CONCLUSION: ATN classification based on CSF biomarkers has a statistically significant and clinically relevant prognostic value for the course of cognitive decline in a 3-year period in a clinical practice setting.

Visuospatial memory impairment as a potential neurocognitive marker to predict tau pathology in Alzheimer's continuum.

BACKGROUND: Given that tau accumulation, not amyloid-ß (Aß) burden, is more closely connected with cognitive impairment in Alzheimer's disease (AD), a detailed understanding of the tau-related characteristics of cognitive function is critical in both clinical and research settings. We investigated the association between phosphorylated tau (p-Tau) level and cognitive impairment across the AD continuum and the mediating role of medial temporal lobe (MTL) atrophy. We also developed a prediction model for abnormal tau accumulation. METHODS: We included participants from the Gwangju Alzheimer's Disease and Related Dementia Cohort in Korea, who completed cerebrospinal fluid analysis and clinical evaluation, and corresponded to one of three groups according to the biomarkers of A and T profiles based on the National Institute on Aging and Alzheimer's Association research framework. Multiple linear and logistic regression analyses were performed to examine the association between p-Tau and cognition and to develop prediction models. Receiver operating characteristic curve analysis was performed to examine the discrimination ability of the models. RESULTS: Among 185 participants, 93 were classified as A-T-, 23 as A+T-, and 69 as A+T+. There was an association between decreased visuospatial delayed memory performance and p-Tau level (B = - 0.754, ß = - 0.363, p < 0.001), independent of other relevant variables (e.g., Aß). MTL neurodegeneration was found to mediate the association between the two. Prediction models with visuospatial delayed memory alone (area under the curve [AUC] = 0.872) and visuospatial delayed memory and entorhinal thickness (AUC = 0.921) for abnormal tau accumulation were suggested and they were validated in an independent sample (AUC = 0.879 and 0.891, respectively). CONCLUSION: It is crucial to identify sensitive cognitive measures that capture subtle cognitive impairment associated with underlying pathological changes. Preliminary findings from the current study might suggest that abnormal tau accumulation underlies episodic memory impairment, particularly visuospatial modality, in the AD continuum. Suggested models are potentially useful in predicting tau pathology, and might be utilized practically in the field.

Risk of dementia in APOE ε4 carriers is mitigated by a polygenic risk score.

INTRODUCTION: We investigated relationships among genetic determinants of Alzheimer's disease (AD), amyloid/tau/neurodegenaration (ATN) biomarkers, and risk of dementia. METHODS: We studied cognitively normal individuals with subjective cognitive decline (SCD) from the Amsterdam Dementia Cohort and SCIENCe project. We examined associations between genetic variants and ATN biomarkers, and evaluated their predictive value for incident dementia. A polygenic risk score (PRS) was calculated based on 39 genetic variants. The APOE gene was not included in the PRS and was analyzed separately. RESULTS: The PRS and APOE ε4 were associated with amyloid-positive ATN profiles, and APOE ε4 additionally with isolated increased tau (A-T+N-). A high PRS and APOE ε4 separately predicted AD dementia. Combined, a high PRS increased while a low PRS attenuated the risk associated with ε4 carriers. DISCUSSION: Genetic variants beyond APOE are clinically relevant and contribute to the pathophysiology of AD. In the future, a PRS might be used in individualized risk profiling.

Temporal Ordering of Inflammatory Analytes sTNFR2 and sTREM2 in Relation to Alzheimer's Disease Biomarkers and Clinical Outcomes.

Inflammatory changes are among the key markers of Alzheimer's disease (AD) related pathological changes. Pro-inflammatory analytes have been related to cognitive decline while others have been related to attenuating neuronal death. Among them, changes in cerebrospinal fluid (CSF) levels of soluble triggering receptor expressed on myeloid cells 2 (sTREM2) and soluble tumor necrosis factor receptor 2 (sTNFR2) have been described as impacting favorable clinical outcomes in AD. We therefore evaluate the effect of CSF sTREM2 and sTNFR2 when taken together on AD biomarkers and longitudinal clinical decline to understand their relative role on impacting AD clinical biomarkers and subsequent clinical outcomes. This longitudinal observational cohort study included 168 amyloid-positive (A+) and p-tau-positive (T+) participants with mild cognitive impairment (MCI) or AD dementia from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with 109 of them having concomitant CSF sTREM2 and sTNFR2 data and 48 A+ T+ participants with MCI from a tertiary memory clinic cohort. An exploratory analysis was performed using data from 86 cognitively normal (CN) participants from ADNI with 72 of them having concomitant CSF AD biomarkers and CSF sTREM2 and sTNFR2 data. General linear models were used to evaluate the effect of sTREM2 and sTNFR2 levels on baseline CSF Aß42, t-tau, and p-tau, and a linear mixed-effects model was used to assess longitudinal cognitive change after controlling for well-known covariates. Among ADNI A+ T+ MCI and AD dementia participants, CSF sTNFR2 had a stronger association, than CSF sTREM2, with CSF t-tau and p-tau. This was replicated among A+ T+ MCI participants from the memory clinic cohort. On the contrary, among A+ T+ CN participants, CSF sTREM2 explained significant variance in CSF t-tau and p-tau, while CSF sTNFR2 did not. When the effects of CSF sTNFR2 and t-tau on longitudinal cognitive change were taken into account, higher CSF sTREM2 predicted slower cognitive decline in A+ T+ AD dementia participants and faster decline in A+ T+ CN participants. Our results show that given the dynamic changes in sTREM2 and sTNFR2, the clinical impact of these distinct inflammation related biomarkers in tracking AD temporal progression across disease stages are likely to differ.

Prevalence of the Preclinical Stages of Alzheimer's Disease in Cognitively Intact Older Adults: The CABLE Study.

BACKGROUND: The National Institute on Aging and Alzheimer's Association proposed an ATN classification system which divided Alzheimer's disease biomarkers into three binary classes: amyloid deposition (A), tauopathy (T), and neurodegeneration or neuronal injury (N). OBJECTIVE: To estimate the prevalence of each profile and to describe the demographic characteristics of each group in Chinese cognitively intact older adults. METHODS: In this cross-sectional study, 561 cognitively intact participants from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study were classified into eight groups using cerebrospinal fluid amyloid-ß 42/40 as A, phosphorylated tau as T, and total tau as N. Multinomial models were used to determine the estimated prevalence of the eight groups. RESULTS: The number and proportion of 561 participants in each ATN profile were 254 A-T-N- (45.3%), 28 A-T+N- (5.0%), 21 A-T-N+ (3.7%), 71 A-T+N+ (12.7%), 78 A + T-N- (13.9%), 14 A + T+N- (2.5%), 21 A + T-N+ (3.7%), and 74 A + T+N+ (13.2%). Individuals in N+ groups tend to be older than N- groups. A+ groups included more female individuals. The prevalence of A-T-N- profile declined with age, while that of A + T+N+ increased continuously. CONCLUSION: This is the first work to estimate the prevalence of each ATN profile and describe the demographic characteristics of ATN profiles based on a Chinese cohort. The clinical implications of our findings need to be scrutinized further in longitudinal studies of the ATN classification system.

Myopic maculopathy: Current status and proposal for a new classification and grading system (ATN).

Myopia is a highly frequent ocular disorder worldwide and pathologic myopia is the 4th most common cause of irreversible blindness in developed countries. Pathologic myopia is especially common in East Asian countries. Ocular alterations associated with pathologic myopia, especially those involving the macular area-defined as myopic maculopathy-are the leading causes of vision loss in patients with pathologic myopia. High myopia is defined as the presence of a highly negative refractive error (>-6 to -8 diopters) in the context of eye elongation (26-26.5 mm). Although the terms high myopia and pathologic myopia are often used interchangeably, they do not refer to the same eye disease. The two key factors driving the development of pathologic myopia are: 1) elongation of the axial length and 2) posterior staphyloma. The presence of posterior staphyloma, which is the most common finding in patients with pathologic myopia, is the key differentiating factor between high and pathologic myopia. The occurrence of staphyloma will, in most cases, eventually lead to other conditions such as atrophic, traction, or neovascular maculopathy. Posterior staphyloma is for instance, responsible for the differences between a myopic macular hole (MH)-with and without retinal detachment-and idiopathic MH. Posterior staphyloma typically induces retinal layer splitting, leading to foveoschisis in myopic MH, an important differentiating factor between myopic and emmetropic MH. Myopic maculopathy is a highly complex disease and current classification systems do not fully account for the numerous changes that occur in the macula of these patients. Therefore, a more comprehensive classification system is needed, for several important reasons. First, to more precisely define the disease stage to improve follow-up by enabling clinicians to more accurately monitor changes over time, which is essential given the progressive nature of this condition. Second, unification of the currently-available classification systems would establish standardized classification criteria that could be used to compare the findings from international multicentric studies. Finally, a more comprehensive classification system could help to improve our understanding of the genetic origins of this disease, which is clearly relevant given the interchangeable-but erroneous-use of the terms high and pathologic myopia in genetic research.