Suspected non-Alzheimer Pathophysiology Research Articles

Atrophy, hypometabolism and implication regarding pathology in late-life major depression with suspected non-alzheimer pathophysiology (SNAP)

BackgroundA substantial proportion of individuals with late-life major depression could be classified as having a suspected non-Alzheimer disease pathophysiology (SNAP), as indicated by a negative test for the biomarker β-amyloid (Aβ-) but a positive test for neurodegeneration (ND+). This study investigated the clinical features, characteristic patterns of brain atrophy and hypometabolism, and implications regarding pathology in this population. MethodsForty-six amyloid-negative patients with late-life major depressive disorder (MDD) patients, including 23 SNAP (Aβ-/ND+) and 23 Aβ-/ND- MDD subjects, and 22 Aβ-/ND-healthy control subjects were included in this study. Voxel-wise group comparisons between the SNAP MDD, Aβ-/ND- MDD and control subjects were performed, adjusting for age, gender and level of education. For exploratory comparisons, 8 Aβ+/ND- and 4 Aβ+/ND + MDD patients were included in the Supplementary Material. ResultsThe SNAP MDD patients had atrophy extending to regions outside the hippocampus, predominately in the medial temporal, dorsomedial and ventromedial prefrontal cortex; hypometabolism involving a large portion of the lateral and medial prefrontal cortex in addition to the bilateral temporal, parietal and precuneus cortex within typical Alzheimer disease regions were observed. Metabolism ratios of the inferior to the medial temporal lobe were significantly elevated in the SNAP MDD patients. We further discussed the implications with regards to underlying pathologies. ConclusionThe present study demonstrated characteristic patterns of atrophy and hypometabolism in patients with late-life major depression with SNAP. Identifying individuals with SNAP MDD may provide insights into currently unspecified neurodegenerative processes. Future refinement of neurodegeneration biomarkers is essential in order to identify potential pathological correlates while in vivo reliable pathological biomarkers are not forthcoming.

Decreased Cerebral Amyloid-β Depositions in Patients With a Lifetime History of Major Depression With Suspected Non-Alzheimer Pathophysiology.

Cerebral amyloid-β (Aβ) depositions in depression in old age are controversial. A substantial proportion of individuals with late-life major depressive disorder (MDD) could be classified as having suspected non-Alzheimer’s disease pathophysiology (SNAP) by a negative test for the biomarker amyloid-β (Aβ−) but positive neurodegeneration (ND+). This study aimed to evaluate subthreshold Aβ loads in amyloid-negative MDD, particularly in SNAP MDD patients. This study included 46 amyloid-negative MDD patients: 23 SNAP (Aβ−/ND+) MDD and 23 Aβ−/ND− MDD, and 22 Aβ−/ND− control subjects. All subjects underwent 18F-florbetapir PET, FDG-PET, and MRI. Regions of interest (ROIs) and voxel-wise group comparisons were performed with adjustment for age, gender, and level of education. The SNAP MDD patients exhibited significantly deceased 18F-florbetapir uptakes in most cortical regions but not the parietal and precuneus cortex, as compared with the Aβ−/ND− MDD and control subjects (FDR correction, p < 0.05). No correlations of neuropsychological tests or depression characteristics with global cortical uptakes, but significant positive correlations between cognitive functions and adjusted hippocampal volumes among different groups were observed. The reduced Aβ depositions in the amyloid-negative MDD patients might be attributed mainly to the SNAP MDD patients. Our results indicated that meaningfully low amounts of subclinical Aβ might contain critical information on the non-amyloid-mediated pathogenesis.

Cerebrovascular disease in suspected non-Alzheimer's pathophysiology and cognitive decline over time.

The underlying cause of cognitive decline in individuals who are positive for biomarkers of neurodegeneration (N) but negative for biomarkers of amyloid-beta (A), designated as Suspected non-Alzheimer's pathophysiology (SNAP), remains unclear. We evaluate whether cerebrovascular disease (CeVD) is more prevalent in those with SNAP compared to A-N- and A+N+ individuals and whether CeVD is associated with cognitive decline over time in SNAP patients. A total of 216 individuals from a prospective memory clinic cohort (mean [SD] age, 72.7 [7.3] years, 100 women [56.5%]) were included and were diagnosed as no cognitive impairment (NCI), cognitive impairment no dementia (CIND), Alzheimer's dementia (AD) or vascular dementia (VaD). All individuals underwent clinical evaluation and neuropsychological assessment annually for up to 5years. Carbon 11-labeled Pittsburgh Compound B ([11 C]-PiB) or [18 F]-flutafuranol-positron emission spectrometry imaging was performed to ascertain amyloid-beta status. Magnetic resonance imaging was performed to assess neurodegeneration as measured by medial temporal atrophy ≥2, as well as significant CeVD (sCeVD) burden, defined by cortical infarct count ≥1, Fazekas score ≥2, lacune count ≥2 or cerebral microbleed count ≥2. Of the 216 individuals, 50 (23.1%) A-N+ were (SNAP), 93 (43.1%) A-N-, 36 (16.7%) A+N- and 37 (17.1%) A+N+. A+N+ individuals were significantly older, while A+N+ and SNAP individuals were more likely to have dementia. The SNAP group had a higher prevalence of sCeVD (90.0%) compared to A-N-. Moreover, SNAP individuals with sCeVD had significantly steeper decline in global cognition compared to A-N- over 5years (p=0.042). These findings suggest that CeVD is a contributing factor to cognitive decline in SNAP. Therefore, SNAP individuals should be carefully assessed and treated for CeVD.

Locus coeruleus signal intensity in progressive amnesia due to suspected non‐Alzheimer pathophysiology (SNAP)

AbstractBackgroundSuspected non‐Alzheimer pathophysiology (SNAP) is underlain by different pathophysiological processes, among which the recently described Limbic‐predominant age‐related TDP‐43 encephalopathy (LATE), which refers to patients with cognitive/memory impairment and limbic‐predominant TDP‐43 proteinopathy, associated or not with hippocampal sclerosis (HS) characterized by severe neuronal loss and gliosis in the CA‐1 and subiculum of the hippocampal formation (Besser and al. J Neuropathol Exp Neurol. 2019), or primary age‐related tauopathy (PART). The locus coeruleus (LC) is the major noradrenergic nucleus in the brain. In AD, the early LC neuronal loss could contribute to cognitive deficits, especially mental flexibility and memory retrieval impairments (Grudzien and al. Neurobiol. Aging, 2007). The involvement of LC alteration in amnestic SNAP patients has not been studied.MethodWe included 10 SNAP subjects defined by episodic memory deficit of the hippocampal type, normal CSF biomarkers profile and negative amyloid‐PET, 26 typical AD patients defined by clinical‐biological criteria (episodic memory deficit of the hippocampal type associated with CSF biomarkers AD profile and positive amyloid PET), and 14 controls with negative amyloid‐PET. All patients had a Clinical Dementia Rating scale ≤ 1. We used the LC signal intensity (LC‐I) on 3T MRI (Neuromelanin‐sensitive T1‐weighted images) as a marker of LC atrophy (Shibata and al. Magn Reson Med Sci. 2006).ResultsSNAP patients were older than AD patients (77.9 years and 70.8 years respectively, p=0.002), with a lower proportion of APOE4 carriers. We found no difference between SNAP and AD groups in neuropsychological scores, especially for MMSE, and verbal or visual episodic memory scores, as well as for hippocampal or entorhinal cortex volumes. We found a significant decrease of the LC‐I in SNAP patients compared with controls (p&lt;0.003) or with AD patients (p&lt;0.009). The episodic memory score was positively correlated with the LC‐I (r=0.33, p=0.034) in SNAP patients.ConclusionOur results suggest a significant LC alteration in patients with amnesia not due to AD. LC involvement could not be specific of AD pathology, and could also be part of the pathophysiological process of non‐AD diseases. Amnestic SNAP patients could thus benefit from innovative therapeutic approaches targeting the noradrenergic system.

Differences in functional connectivity in mild cognitive impairment for amyloid‐positive versus SNAP

AbstractBackgroundThe default mode network (DMN) is a neurofunctional network particularly relevant to Alzheimer's disease (AD) since its structures are vulnerable to the deposition of amyloid (Aβ) and neurofibrillary tangles [1]. Observing the more up‐to‐date classifications, we classified our patients according to AT(N) (alterations in amyloid (A), tau (T) and neurodegeneration (N)) classification: normal AD biomarkers (AD‐) (A‐T‐N‐); suspected non‐Alzheimer pathophysiology (SNAP) (A‐T+N‐, A‐T‐N+, or A‐T+N+) and AD pathophysiologic continuum (AD+) (any A+ combination) [2]. We investigated whether the activity and functional connectivity (FC) can differentiate MCI subgroups according to AD biomarkers classification.MethodWe recruited 58 mild cognitive impairment (MCI) patients who underwent: lumbar puncture to analyze Aβ1‐42, p‐Tau and t‐Tau levels; Magnetic Resonance Imaging in a 3T Philips Achieva scanner; and a broad neuropsychological evaluation. Was considered pathophysiological evidence of AD (AD continuum) low Aβ1‐42 concentrations &lt; 416 pg/m and was considered Tau alteration: p‐Tau &gt; 36.7 pg/mL and t‐Tau &gt; 76.7 pg/mL [3]. To identify the DMN we used the UF2C software and seed‐based analysis using a mask of the posterior cingulate cortex to extract the reference time‐series. We obtained FC values for 8 DMN regions for each patient. We performed a general linear model to compare the groups with FC values of DMN regions.ResultThere was a statistically significant difference between groups SNAP and AD continuum and FC of left hippocampus (p = .017). AD continuum group shows more connectivity than SNAP group.ConclusionCSF protein profiles seem to be related to alterations in resting state activity. In this study we were able to differentiate clinically similar patients through neuroimaging biomarkers. With further refinement, resting‐state connectivity hold promise as non‐invasive neuroimaging markers.

Tau PET imaging, MRI and cognitive progression in subjects with progressive amnesia and suspected non‐Alzheimer pathophysiology (SNAP)

AbstractBackgroundWhile progressive amnesia of the hippocampal type is most often due to Alzheimer’s disease (AD) pathology, other etiologies are not rare during aging, including limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) with or without Hippocampal Sclerosis (HS) and Primary age‐related tauopathy (PART). These pathological conditions differ from AD by the lack of cortical amyloid deposition, but the amnestic syndrome mimicking AD can lead to mis‐diagnosis. By coupling amyloid and tau PET imaging in patients with progressive amnesia, we investigated, in vivo, clinical and biological markers that differentiate suspected non‐AD pathophysiology (SNAP) from AD patients.MethodWe included 41 patients with a progressive episodic memory deficit of the hippocampal type (CDR≤ 1), and 30 controls. All patients underwent both PiB‐PET and AV‐1451‐PET. According to their amyloid PET status, we classified patients in SNAP (negative PiB‐PET defined by a GCI&lt;1.45, n=10) and prodromal‐AD (positive PiB‐PET, n=31). Tau‐PET were analyzed individually vs the control group by using Z‐scores in each ROI. Participants were followed up annually for 2 yearsResultSNAP patients were older than AD (77.9+/‐5 vs 70.0+/‐6.8 years) and the proportion of APOE4 carriers was lower (28% vs 62%). No difference in baseline neuropsychological scores was found between SNAP and AD patients regarding MMSE (22.9+/‐2.6 vs 24.2+/‐3.0), verbal or visual episodic memory, or anxiety/depression scales. Volumes of the hippocampus and entorhinal cortex were lower in SNAP and prodromal‐AD than in controls, without any significant difference between both patient groups. As expected, CSF Ab42/Tau and Ab42/Phospho‐tau ratios were lower in SNAP compared to prodromal AD. Tau‐PET imaging was negative in all SNAP patients except one (fronto‐temporal binding), while tau deposition was observed in all AD patients in the temporal +/‐ parietal cortex. Clinical follow‐up at one and two years showed mild dysexecutive syndrome in SNAP and mild parietal cognitive dysfunction in prodromal‐AD.ConclusionAmnesia of the hippocampal type not due to AD was observed in 24% of our cohort, with similar severity of amnesia and hippocampal/entorhinal atrophy as in prodromal‐AD, but possibly distinct longitudinal clinical trajectories. Molecular PET imaging suggested a non‐tau pathology in 9 patients and a possible non‐AD tauopathy in one.

PREVALENCE AND LONGITUDINAL CLINICAL OUTCOMES OF ALZHEIMER’S ATN BIOMARKER PROFILES: A LONGITUDINAL STUDY

In 2018, the National Institute on Aging and Alzheimer's Association created a research framework to define Alzheimer's Disease (AD) biologically by ATN biomarkers (β-amyloid deposition [A], pathologic tau [T], and neurodegeneration [N]), and treat cognitive impairment as a symptom/sign of the disease. We aimed to estimate the prevalence of each ATN profile in different clinical diagnosis groups and to assess the potential clinical utility of applying the research framework in a large longitudinal cohort. Cognitively normal (CN) participants, mild cognitive impairment (MCI), and AD patients were included from the ADNI, and were assessed at enrolment and every 6 months from August 23, 2005 to March 15, 2017. Longitudinal change in clinical outcomes and conversion risk of ATN profiles are also assessed using linear mixed effects models and multivariate Cox proportional hazard models, respectively. In CN group, the proportions of biomarker profiles were 19.2% A-T-N-, 7.6% A+T-N-, 30.3% A+T+N-, 1% A+T-N+, 2.5% A+T+N+ and 39.4% suspected non-Alzheimer's pathophysiology (SNAP). Among mild cognitive impairment (MCI) patients, the proportions were 26.8% A-T-N-, 3.2% A+T-N-, 32.9% A+T+N-, 2.3% A+T-N+, 30.3% A+T+N+ and 17.4% SNAP. In AD dementia patients, the proportions were 1.5% A-T-N-, 4.4% A+T+N-, 2.9% A+T-N+, 87.6% A+T+N+ and 3.6% SNAP. A+T+N+ showed the fastest clinical progression than the remaining three groups and A+T+N- showed faster clinical progression than A-T-N-, no matter in CN or MCI group. A faster clinical progression was observed in female versus male and APOE ε4 carriers versus APOE ε4 non-carriers in amyloid positive groups. Compared with A-T-N-, participants with A+T+N± had an increased risk of conversion from CN to incident prodromal stage of AD (CDR≥0.5) and from MCI to incident AD dementia. A+T+N+ showed an increased conversion risk when compared with A+T±N-. The Research Framework is valuable to clinical research, and may provide prognostic information of clinical change and progression among non-demented elders which can contribute to clinical care. It may also be useful for targeted recruitment of AD participants into clinical trials, both pharmaceutical and non-pharmaceutical.

Brain metabolic patterns in patients with suspected non-Alzheimer's pathophysiology (SNAP) and Alzheimer's disease (AD): is [18F] FDG a specific biomarker in these patients?

The present study was conducted to compare the pattern of brain [18F] FDG uptake in suspected non-Alzheimer's pathophysiology (SNAP), AD, and healthy controls using 2-deoxy-2-[18F]fluoroglucose ([18F] FDG) positron emission tomography imaging. Cerebrospinal fluid (CSF) biomarkers amyloid-β1-42 peptide (Aβ1-42) and tau were used in order to differentiate AD from SNAP. The study included 43 newly diagnosed AD patients (female = 23; male = 20) according to the NINCDS-ADRDA criteria, 15 SNAP patients (female = 12; male =3), and a group of 34 healthy subjects that served as the control group (CG), who were found to be normal at neurological evaluation (male = 20; female = 14). A battery of neuropsychological tests was administrated in AD and SNAP subjects; cerebrospinal fluid assay was conducted in both AD and SNAP as well. Brain PET/CT acquisition was started 30 ± 5min after [18F] FDG injection in all subjects. SPM12 [statistical parametric mapping] implemented in MATLAB 2018a was used for the analysis of PET scans in this study. As compared to SNAP, AD subjects showed significant hypometabolism in a wide cortical area involving the right frontal, parietal, and temporal lobes. As compared to CG, AD subjects showed a significant reduction in [18F] FDG uptake in the parietal, limbic, and frontal cortex, while a more limited reduction in [18F] FDG uptake in the same areas was found when comparing SNAP to CG. SNAP subjects show milder impairment of brain [18F] FDG uptake as compared to AD. The partial overlap of the metabolic pattern between SNAP and AD limits the use of [18F] FDG PET/CT in effectively discriminating these clinical entities.

Addition of the A\u03b242/40 ratio to the cerebrospinal fluid biomarker profile increases the predictive value for underlying Alzheimer\u2019s disease dementia in mild cognitive impairment

BackgroundCerebrospinal fluid (CSF) biomarkers have been used to increase the evidence of underlying Alzheimer’s disease (AD) pathology in mild cognitive impairment (MCI). However, CSF biomarker-based classification often results in conflicting profiles with controversial prognostic value. Normalization of the CSF Aβ42 concentration to the level of total amyloid beta (Aβ), using the Aβ42/40 ratio, has been shown to improve the distinction between AD and non-AD dementia. Therefore, we evaluated whether the Aβ42/40 ratio would improve MCI categorization and more accurately predict progression to AD.MethodsOur baseline population consisted of 197 MCI patients, of which 144 had a follow-up ≥ 2 years, and comprised the longitudinal study group. To establish our own CSF Aβ42/40 ratio reference value, a group of 168 AD-dementia patients and 66 neurological controls was also included. CSF biomarker-based classification was operationalized according to the framework of the National Institute of Aging–Alzheimer Association criteria for MCI.ResultsWhen using the core CSF biomarkers (Aβ42, total Tau and phosphorylated Tau), 30% of the patients fell into the high-AD-likelihood (HL) group (both amyloid and neurodegeneration markers positive), 30% into the low-AD-likelihood group (all biomarkers negative), 28% into the suspected non-Alzheimer pathophysiology (SNAP) group (only neurodegeneration markers positive) and 12% into the isolated amyloid pathology group (only amyloid-positive). Replacing Aβ42 by the Aβ42/40 ratio resulted in a significant increase in the percentage of patients with amyloidosis (42–59%) and in the proportion of interpretable biological profiles (61–75%), due to a reduction by half in the number of SNAP cases and an increase in the proportion of the HL subgroup. Survival analysis showed that risk of progression to AD was highest in the HL group, and increased when the Aβ42/40 ratio, instead of Aβ42, combined with total Tau and phosphorylated Tau was used for biomarker-based categorization.ConclusionsOur results confirm the usefulness of the CSF Aβ42/40 ratio in the interpretation of CSF biomarker profiles in MCI patients, by increasing the proportion of conclusive profiles and enhancing their predictive value for underlying AD.

Defining SNAP by cross-sectional and longitudinal definitions of neurodegeneration.

IntroductionSuspected non-Alzheimer's pathophysiology (SNAP) is a biomarker driven designation that represents a heterogeneous group in terms of etiology and prognosis. SNAP has only been identified by cross-sectional neurodegeneration measures, whereas longitudinal measures might better reflect “active” neurodegeneration and might be more tightly linked to prognosis. We compare neurodegeneration defined by cross-sectional ‘hippocampal volume’ only (SNAP/L−) versus both cross-sectional and longitudinal ‘hippocampal atrophy rate’ (SNAP/L+) and investigate how these definitions impact prevalence and the clinical and biomarker profile of SNAP in Mild Cognitive Impairment (MCI).Methods276 MCI patients from ADNI-GO/2 were designated amyloid “positive” (A+) or “negative” (A−) based on their florbetapir scan and neurodegeneration ‘positive’ or ‘negative’ based on cross-sectional hippocampal volume and longitudinal hippocampal atrophy rate.Results74.1% of all SNAP participants defined by the cross-sectional definition of neurodegeneration also met the longitudinal definition of neurodegeneration, whereas 25.9% did not. SNAP/L+ displayed larger white matter hyperintensity volume, a higher conversion rate to dementia over 5 years and a steeper decline on cognitive tasks compared to SNAP/L− and the A- CN group. SNAP/L− had more abnormal values on neuroimaging markers and worse performance on cognitive tasks than the A- CN group, but did not show a difference in dementia conversion rate or longitudinal cognition.DiscussionUsing a longitudinal definition of neurodegeneration in addition to a cross-sectional one identifies SNAP participants with significant cognitive decline and a worse clinical prognosis for which cerebrovascular disease may be an important driver.

Amyloid β Deposition and Suspected Non-Alzheimer Pathophysiology and Cognitive Decline Patterns for 12 Years in Oldest Old Participants Without Dementia

ImportanceThe prevalence of pathologic conditions of the brain associated with Alzheimer disease increases strongly with age. Little is known about the distribution and clinical significance of preclinical biomarker staging in the oldest old, when most individuals without dementia are likely to have positive biomarkers.ObjectiveTo compare the patterns of long-term cognitive decline in multiple domains by preclinical biomarker status in the oldest old without dementia.Design, Setting, and ParticipantsA longitudinal observational study with a mean (SD) of 12.2 (2.2) years (range 7.2-15.1 years) of follow-up was conducted in an academic medical center from August 24, 2000, to January 14, 2016, including and extending observations from the Ginkgo Evaluation of Memory study. A total of 197 adults who had completed the Ginkgo Evaluation of Memory study, were free of dementia, and were able to undergo magnetic resonance imaging were eligible for a neuroimaging study in 2009. Of these patients, 175 were included in the present analyses; 140 (80%) were cognitively normal and 35 (20%) had mild cognitive impairment.Main Outcomes and MeasuresBiomarker groups included amyloid β negative (Aβ−)/neurodegeneration negative (ND−), amyloid β positive (Aβ+)/ND−, Aβ−/neurodegeneration positive (ND+), and Aβ+/ND+ based on Pittsburgh Compound B retention and hippocampal volume in 2009. Participants completed baseline neuropsychological testing from 2000 to 2002 and annual testing from 2004 to 2016. Domains included memory, executive function, language, visual-spatial reasoning, and attention and psychomotor speed. Slopes of decline were evaluated with linear mixed models adjusted for age, sex, and years of education.ResultsOf the 175 participants (71 women and 104 men), at imaging, mean (SD) age was 86.0 (2.9) years (range, 82-95 years). A total of 42 participants (24.0%) were Aβ−/ND−, 32 (18.3%) were Aβ+/ND−, 35 (20.0%) were Aβ−/ND+, and 66 (37.7%) were Aβ+/ND+. On all cognitive measures, the Aβ+/ND+ group showed the steepest decline. Compared with the Aβ−/ND− group, the amyloid deposition alone (Aβ+/ND−) group showed faster decline on tests of verbal and visual memory (–0.3513; 95% CI, –0.5269 to –0.1756), executive function (0.0158; 95% CI, 0.0013-0.0303), and language (–0.1934; 95% CI, –0.3520 to –0.0348). The Aβ−/ND+ group showed faster visual memory decline than the Aβ−/ND− reference group (–0.3007; 95% CI, –0.4736 to –0.1279).Conclusions and RelevanceIn the oldest old without dementia, presence of either or both Aβ and hippocampal atrophy is typical (>75%). Isolated hippocampal volume atrophy is associated only with greater decline in memory. However, isolated Aβ is associated with decline in memory plus language and executive functions. These findings suggest different underlying pathophysiologic processes in the Aβ+/ND− and Aβ−/ND+ groups.

SNAP IS PROBABLY NORMAL AGING: FINDINGS FROM BIOMARKERS SIGNATURE

Suspected non-Alzheimer pathophysiology (SNAP) is a biomarker-based entity characterized with neurodegeneration (suggested by high cerebrospinal fluid (CSF) Tau levels, magnetic resonance imaging atrophy in Alzheimer's disease (AD)-vulnerable regions, or positron emission tomography (PET) hypometabolism in AD-vulnerable regions) but lack of amyloidosis (defined by high PET radiotracer binding or low CSF fluid of Aβ levels), regardless of clinical status (clinically normal, mild cognitive impairment or dementia). SNAP is also a complement to the new National Institute on Aging–Alzheimer Association (NIA-AA) research criteria of preclinical AD. We aimed to explore the biomarkers in different clinical status with SNAP. We used the baseline data from Alzheimer's Disease Neuroimaging Initiative 1 (ADNI1) and collected the individuals with SNAP (clinically normal, mild cognitive impairment or dementia). The criteria were decreased CSF Aβ1–42 (<192pg/ml) and elevated CSF Tau (total Tau>93pg/ml, or phosphorylated Tau>23pg/ml). The data of biomarkers from CSF (e.g. Aβ, Tau, α-synuclein, sAPPβ, neurogranin, β-secretase, neurofilament, isoprostane, multiplex proteomics) and plasma (e.g. Aβ, Tau, neurofilament) were extracted. Mann-Whitney U tests were carried out between the groups of different clinical status, and P<0.05 was regarded as statistical significance. A total of 31 SNAP individuals were selected from ADNI1 cohort, with 18 clinically normal, 9 MCI and 4 dementia. APOE4 alleles were only 8%. In comparison with clinically normal, CSF CD40 (Mann-Whitney U test, Z=-2.024, P =0.046) and fibrinogen (Mann-Whitney U test, Z=-2.239, P =0.025) significantly changed in MCI, as well as CSF isoprostane (ISO8PGF2A) was elevated in dementia. In comparison with clinically normal, CSF isoprostane (ISO8PGF2A) (Mann-Whitney U test, Z=-2.315, P=0.020) was elevated in dementia. APOE4 is less common in SNAP. Only elevated ISO8PGF2A is observed in dementia in comparison with clinically normal and MCI, which is not found between clinically normal and MCI. Large-sample is required to confirm our findings and seek better biomarkers to differentiate the clinical status of SNAP. As the previous opinion “SNAP individuals are stable over time”, biomarkers signature suggests SNAP may be normal aging rather than pathological changes, in which brain atrophy and cognitive decline progress slowly.

Age-specific and sex-specific prevalence of cerebral β-amyloidosis, tauopathy, and neurodegeneration in cognitively unimpaired individuals aged 50–95 years: a cross-sectional study

SummaryBackgroundA new descriptive classification scheme for biomarkers used in Alzheimer's and cognitive aging research, labeled ATN, was recently proposed. One implementation of this ATN construct dichotomizes biomarkers of amyloid, tau, and neurodegeneration/neuronal injury as normal or abnormal resulting in 2 × 2× 2=8 possible biomarker profiles. We determined the clinical characteristics and prevalence of each ATN group among clinically normal individuals aged 50 and older from a population based cohort.MethodsAll individuals in this study were participants in the Mayo Clinic Study of Aging, a population-based study of cognitive aging. Potential participants were randomly selected from the Olmsted County, Minnesota population by age- and sex-stratification and invited to participate in cognitive evaluations and undergo multimodality imaging. To be eligible for inclusion in this study, participants must have been judged clinically to have no cognitive impairment and have undergone multi-modality imaging. Imaging studies were obtained from October 11, 2006 to October 5, 2016. All participants were classified as having normal (A−) or abnormal (A+) amyloid using amyloid PET, normal (T−) or abnormal (T+) tau using tau PET, and normal (−) or abnormal (N+) neurodegeneration/neuronal injury using cortical thickness. The cut points used were SUVR 1·42 (centiloid 19) for amyloid PET, 1·23 SUVR for tau PET, and 2·67 mm for MRI cortical thickness. Age- and sex- specific prevalences of the eight ATN biomarker groups were determined using 435 individuals with amyloid PET, tau PET, and MR imaging and 1113 additional clinically normal individuals who underwent amyloid PET and MR imaging, but not tau PET imaging.FindingsThere were 165 A−T−N-, 35 A−T+N-, 63 A−T−N+, 19 A−T+N+, 44 A+T−N−, 25 A+T+N−, 35 A+T−N+, and 49 A+T+N+ individuals. Age differed by ATN group (p<0 001) ranging from a median age of 57 in the A−T−N-−and A−T+N− groups to 80 in the A+T−N+ and A+T+N+ groups. The frequency of APOE ε4 carriers differed by ATN group (p=0·04) with ε4 carriers roughly twice as frequent in A+ versus A−. White matter hyperintensity volume (p<0·0001), and cognitive performance (p<0·0001) also differed by ATN group. Tau PET and neurodegeneration biomarkers were discordant in the majority of individuals who would be labeled stage 2/3 preclinical AD (86% at age 65 and 51% at age 80) or suspected non-Alzheimer's pathophysiology (SNAP) (92% at age 65 and 78% at age 80). From age 50, A−T−N− prevalence declines while A+T+N+ and A−T+N+ increase continuously with age. In both men and women, A−T−N− is the most prevalent group until their late 70s. After about age 80, A+T+N+ is the most prevalent group until their late 70s. After about age 80, A+T+N+ is the most prevalent group. The remaining ATN groups reach individual peaks in the 60–90 age range and then decline in prevalence. By age 85 over 90% of men and women have one or more biomarker abnormalities.InterpretationBiomarkers of fibrillar tau deposition can be included with those of Aβ and neurodegeneration/neuronal injury to more fully characterize the heterogeneous pathological profiles in the population. The prevalence of each ATN group changes substantially with age with progression toward more biomarker abnormalities even among individuals who remain clinically normal. Both abnormal amyloid and normal amyloid pathological profiles can be identified in the clinically normal population.

At the crossroads of preclinical AD and normal brain ageing

At the crossroads of preclinical AD and normal brain ageing