Markers Of Alzheimer Research Articles

Implication of Small Vessel Disease MRI Markers in Alzheimer's Disease and Lewy Body Disease.

Small vessel disease (SVD) magnetic resonance imaging (MRI) markers including deep and periventricular white matter hyperintensities (PWMH), lacunes, and microbleeds are frequently observed in Alzheimer's disease (AD) and Lewy body disease (LBD), but their implication has not been clearly elucidated. To investigate the implication of SVD MRI markers in cognitively impaired patients with AD and/or LBD. We consecutively recruited 57 patients with pure AD-related cognitive impairment (ADCI), 49 with pure LBD-related cognitive impairment (LBCI), 45 with mixed ADCI/LBCI, and 34 controls. All participants underwent neuropsychological tests, brain MRI, and amyloid positron emission tomography. SVD MRI markers including the severity of deep and PWMH and the number of lacunes and microbleeds were visually rated. The relationships among vascular risk factors, SVD MRI markers, ADCI, LBCI, and cognitive scores were investigated after controlling for appropriate covariates. LBCI was associated with more severe PWMH, which was conversely associated with an increased risk of LBCI independently of vascular risk factors and ADCI. PWMH was associated with attention and visuospatial dysfunction independently of vascular risk factors, ADCI, and LBCI. Both ADCI and LBCI were associated with more lobar microbleeds, but not with deep microbleeds. Our findings suggest that PWMH could reflect degenerative process related with LBD, and both AD and LBD independently increase lobar microbleeds.

Confusion, cognitive impairment, and spinal cord compression caused by plasmacytoma: a case report

BackgroundPlasmacytomas are rare tumors comprised of neoplastic monoclonal plasma cells and can be found anywhere in the body. Plasmacytomas that involve the nervous system can give rise to diffuse symptoms depending on their location. Patients with confusion or dementia might be difficult to neurologically assess in an acute setting and the subtle symptoms of neurological pathology caused by rare malignancies might go undiagnosed.Case presentationThe patient is an 80 year old man presenting to the ER with walking difficulties, pain, and confusion. He underwent neurological evaluation for dementia and was eventually diagnosed with possible Alzheimer’s disease and a malignant plasmacytoma causing spinal cord compression. His CSF sample showed normal amyloid rate and very low Aβ. Following rehabilitation and oncological treatment, his walking ability and confusion improved.ConclusionThis case is unique as we demonstrate that spinal cord compression by plasmacytoma can lead to abnormal CSF levels of several known pathology markers for Alzheimer’s disease and neuronal damage. We suggest that highly divergent amyloid CSF levels could be indicative of spinal pathologies affecting CSF circulation. We also suggest closer assessment of elderly confusion patients in ER settings by consultants specialized in neurological disorders.

Image segmentation for neuroscience: lymphatics

A recent discovery in neuroscience prompts the need for innovation in image analysis. Neuroscientists have discovered the existence of meningeal lymphatic vessels in the brain and have shown their importance in preventing cognitive decline in mouse models of Alzheimer’s disease. With age, lymphatic vessels narrow and poorly drain cerebrospinal fluid, leading to plaque accumulation, a marker for Alzheimer’s disease. The detection of vessel boundaries and width are performed by hand in current practice and thereby suffer from high error rates and potential observer bias. The existing vessel segmentation methods are dependent on user-defined initialization, which is time-consuming and difficult to achieve in practice due to high amounts of background clutter and noise. This work proposes a level set segmentation method featuring hierarchical matting, LyMPhi, to predetermine foreground and background regions. The level set force field is modulated by the foreground information computed by matting, while also constraining the segmentation contour to be smooth. Segmentation output from this method has a higher overall Dice coefficient and boundary F1-score compared to that of competing algorithms. The algorithms are tested on real and synthetic data generated by our novel shape deformation based approach. LyMPhi is also shown to be more stable under different initial conditions as compared to existing level set segmentation methods. Finally, statistical analysis on manual segmentation is performed to prove the variation and disagreement between three annotators.

The Role of Race in Relations of Social Support to Hippocampal Volumes Among Older Adults.

Evidence suggests social support may buffer brain pathology. However, neither its association with hippocampal volume, a marker of Alzheimer's disease risk, nor the role of race in this association has been fully investigated. Multiple regression analyses examined relations of total social support to magnetic resonance imaging-assessed gray matter (GM) hippocampal volumes in the total sample (n = 165; mean age = 68.48 year), and in race-stratified models of African American and White older adults, adjusting for select covariates. Results showed greater social support was associated with greater GM hippocampal volumes among African American older adults only (p < .01). Our findings suggest greater total social support may play a role in supporting the hippocampus, particularly among African American older adults, who had lower hippocampal volumes than their White counterparts. Further research is needed to test these questions longitudinally and examine which aspects of social support may promote hippocampal integrity, specifically.

Genetic predisposition, A\u03b2 misfolding in blood plasma, and Alzheimer\u2019s disease

Alzheimer’s disease is highly heritable and characterized by amyloid plaques and tau tangles in the brain. The aim of this study was to investigate the association between genetic predisposition, Aβ misfolding in blood plasma, a unique marker of Alzheimer associated neuropathological changes, and Alzheimer’s disease occurrence within 14 years. Within a German community-based cohort, two polygenic risk scores (clinical Alzheimer’s disease and Aβ42 based) were calculated, APOE genotype was determined, and Aβ misfolding in blood plasma was measured by immuno-infrared sensor in 59 participants diagnosed with Alzheimer’s disease during 14 years of follow-up and 581 participants without dementia diagnosis. Associations between each genetic marker and Aβ misfolding were assessed through logistic regression and the ability of each genetic marker and Aβ misfolding to predict Alzheimer’s disease was determined. The Alzheimer’s disease polygenic risk score and APOE ε4 presence were associated to Aβ misfolding (odds ratio, 95% confidence interval: per standard deviation increase of score: 1.25, 1.03–1.51; APOE ε4 presence: 1.61, 1.04–2.49). No association was evident for the Aβ polygenic risk score. All genetic markers were predictive of Alzheimer’s disease diagnosis albeit much less so than Aβ misfolding (areas under the curve: Aβ polygenic risk score: 0.55; AD polygenic risk score: 0.59; APOE ε4: 0.63; Aβ misfolding: 0.84). Clinical Alzheimer’s genetic risk was associated to early pathological changes (Aβ misfolding) measured in blood, however, predicted Alzheimer’s disease less accurately than Aβ misfolding itself. Genetic predisposition may provide information regarding disease initiation, while Aβ misfolding could be important in clinical risk prediction.

Self-reported sleep relates to microstructural hippocampal decline in ß-amyloid positive Adults beyond genetic risk.

Study ObjectivesA critical role linking sleep with memory decay and β-amyloid (Aβ) accumulation, two markers of Alzheimer’s disease (AD) pathology, may be played by hippocampal integrity. We tested the hypotheses that worse self-reported sleep relates to decline in memory and intra-hippocampal microstructure, including in the presence of Aβ.MethodsTwo-hundred and forty-three cognitively healthy participants, aged 19–81 years, completed the Pittsburgh Sleep Quality Index once, and two diffusion tensor imaging sessions, on average 3 years apart, allowing measures of decline in intra-hippocampal microstructure as indexed by increased mean diffusivity. We measured memory decay at each imaging session using verbal delayed recall. One session of positron emission tomography, in 108 participants above 44 years of age, yielded 23 Aβ positive. Genotyping enabled control for APOE ε4 status, and polygenic scores for sleep and AD, respectively.ResultsWorse global sleep quality and sleep efficiency related to more rapid reduction of hippocampal microstructure over time. Focusing on efficiency (the percentage of time in bed at night spent asleep), the relation was stronger in presence of Aβ accumulation, and hippocampal integrity decline mediated the relation with memory decay. The results were not explained by genetic risk for sleep efficiency or AD.ConclusionsWorse sleep efficiency related to decline in hippocampal microstructure, especially in the presence of Aβ accumulation, and Aβ might link poor sleep and memory decay. As genetic risk did not account for the associations, poor sleep efficiency might constitute a risk marker for AD, although the driving causal mechanisms remain unknown.

Cerebrospinal Fluid C18 Ceramide Associates with Markers of Alzheimer's Disease and Inflammation at the Pre- and Early Stages of Dementia.

Background:Understanding how dysregulation in lipid metabolism relates to the severity of Alzheimer‘s disease (AD) pathology might be critical in developing effective treatments.Objective:To identify lipid species in cerebrospinal fluid (CSF) associated with signature AD pathology and to explore their relationships with measures reflecting AD-related processes (neurodegeneration, inflammation, deficits in verbal episodic memory) among subjects at the pre- and early symptomatic stages of dementia.Methods: A total of 60 subjects that had been referred to an Icelandic memory clinic cohort were classified as having CSF AD (n = 34) or non-AD (n = 26) pathology profiles. Untargeted CSF lipidomic analysis was performed using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS) for the detection of mass-to-charge ratio (m/z) features. CSF proteins reflecting neurodegeneration (neurofilament light [NFL]) and inflammation (chitinase-3-like protein 1 [YKL-40], S100 calcium-binding protein B [S100B], glial fibrillary acidic protein [GFAP]) were also measured. Rey Auditory Verbal Learning (RAVLT) and Story tests were used for the assessment of verbal episodic memory.Results: Eight out of 1008 features were identified as best distinguishing between the CSF profile groups. Of those, only the annotation of the m/z feature assigned to lipid species C18 ceramide was confirmed with a high confidence. Multiple regression analyses, adjusted for age, gender, and education, demonstrated significant associations of CSF core AD markers (Aβ42: st.β= –0.36, p = 0.007; T-tau: st.β= 0.41, p = 0.005) and inflammatory marker S100B (st.β= 0.51, p = 0.001) with C18 ceramide levels.Conclusion: Higher levels of C18 ceramide associated with increased AD pathology and inflammation, suggesting its potential value as a therapeutic target.

Fine Particulate Matter and Markers of Alzheimer's Disease Neuropathology at Autopsy in a Community-Based Cohort.

Evidence links fine particulate matter (PM2.5) to Alzheimer's disease (AD), but no community-based prospective cohort studies in older adults have evaluated the association between long-term exposure to PM2.5 and markers of AD neuropathology at autopsy. Using a well-established autopsy cohort and new spatiotemporal predictions of air pollution, we evaluated associations of 10-year PM2.5 exposure prior to death with Braak stage, Consortium to Establish a Registry for AD (CERAD) score, and combined AD neuropathologic change (ABC score). We used autopsy specimens (N = 832) from the Adult Changes in Thought (ACT) study, with enrollment ongoing since 1994. We assigned long-term exposure at residential address based on two-week average concentrations from a newly developed spatiotemporal model. To account for potential selection bias, we conducted inverse probability weighting. Adjusting for covariates with tiered models, we performed ordinal regression for Braak and CERAD and logistic regression for dichotomized ABC score. 10-year average (SD) PM2.5 from death across the autopsy cohort was 8.2 (1.9) μg/m3. Average age (SD) at death was 89 (7) years. Each 1μg/m3 increase in 10-year average PM2.5 prior to death was associated with a suggestive increase in the odds of worse neuropathology as indicated by CERAD score (OR: 1.35 (0.90, 1.90)) but a suggestive decreased odds of neuropathology as defined by the ABC score (OR: 0.79 (0.49, 1.19)). There was no association with Braak stage (OR: 0.99 (0.64, 1.47)). We report inconclusive associations between PM2.5 and AD neuropathology at autopsy among a cohort where 94% of individuals experienced 10-year exposures below the current EPA standard. Prior studies of AD risk factors and AD neuropathology are similarly inconclusive, suggesting alternative mechanistic pathways for disease or residual confounding.

Subtle cognitive impairment as a marker of Alzheimer's pathologies and clinical progression in cognitively normal individuals.

IntroductionSubtle cognitive impairment (SCI) may appear before pathological changes surpass thresholds for abnormality. We aimed to investigate whether SCI could predict Alzheimer's pathologies and advancement.MethodsA total of 816 cognitively normal individuals were enrolled to assess the longitudinal neuropathological and clinical correlates of baseline SCI, via linear mixed‐effects and Cox proportional‐hazard models. Cross‐lagged panel models were used in specific time waves.ResultsSCI individuals had a faster increase in brain amyloid burden and a higher risk of conversion. They also showed greater rates of cerebrospinal fluid (CSF) phosphorylated tau (p‐tau)181 increase and glucose metabolism decrease. In addition, baseline SCI predicted worse clinical progression, whereas multi‐domain SCI advanced faster compared to the single domain group.DiscussionBaseline SCI could be an imperative prediction indicator of clinical and pathological progression. It enables cognitive measures to be informative at a very early stage and provided objective criteria for high‐risk population screening.

Distinct patterns of apolipoprotein C-I, C-II, and C-III isoforms are associated with markers of Alzheimer’s disease

Apolipoproteins C-I, C-II, and C-III interact with ApoE to regulate lipoprotein metabolism and contribute to Alzheimer's disease pathophysiology. In plasma, apoC-I and C-II exist as truncated isoforms, while apoC-III exhibits multiple glycoforms. This study aimed to 1) delineate apoC-I, C-II, and C-III isoform profiles in cerebrospinal fluid (CSF) and plasma in a cohort of nondemented older individuals (n = 61), and 2) examine the effect of APOE4 on these isoforms and their correlation with CSF Aβ42, a surrogate of brain amyloid accumulation. The isoforms of the apoCs were immunoaffinity enriched and measured with MALDI-TOF mass spectrometry, revealing a significantly higher percentage of truncated apoC-I and apoC-II in CSF compared with matched plasma, with positive correlation between CSF and plasma. A greater percentage of monosialylated and disialylated apoC-III isoforms was detected in CSF, accompanied by a lower percentage of the two nonsialylated apoC-III isoforms, with significant linear correlations between CSF and plasma. Furthermore, a greater percentage of truncated apoC-I in CSF and apoC-II in plasma and CSF was observed in individuals carrying at least one APOE Ɛ4 allele. Increased apoC-I and apoC-II truncations were associated with lower CSF Aβ42. Finally, monosialylated apoC-III was lower, and disialylated apoC-III greater in the CSF of Ɛ4 carriers. Together, these results reveal distinct patterns of the apoCs isoforms in CSF, implying CSF-specific apoCs processing. These patterns were accentuated in APOE Ɛ4 allele carriers, suggesting an association between APOE4 genotype and Alzheimer's disease pathology with apoCs processing and function in the brain.

The Alteration of Neurogenesis and Pathological Markers in Alzheimer's Disease After Deep Brain Stimulation.

Alzheimer's disease (AD) is the most common type of dementia that causes disabilities in memory formation and activities of daily living. Unfortunately, pharmacologic treatments have minimal and short-lasting effects on AD. With the increasing aging population, investigations into therapeutic strategies for AD that lead to a delay in disease progression would significantly reduce the global burden of AD. Deep brain stimulation (DBS) is considered therapeutic for several conditions, such as movement disorders and some psychiatric diseases. Preclinical and clinical studies that used DBS as a treatment modality demonstrate the safety of DBS in AD and suggest potential memory improvements after surgery. Nevertheless, more studies are needed to understand the therapeutic mechanism of DBS. In this review, we summarize studies on DBS in various targets for AD and discuss DBS-induced changes in neurogenesis and pathological markers in AD.

Relationship between Amyloid-beta 42 Levels and Y-maze Alternation Values in Sprague Dawley Alzheimer’s Induction Received Medium-Chain Triglycerides Therapy

BACKGROUND: At present, there is no pharmacological therapy that can cure Alzheimer’s disease. Treatment is only limited to preventing progression and controlling risk factors that worsen Alzheimer’s. Medium-chain triglycerides (MCT) are nutritional therapies that are being studied to prevent the progression of Alzheimer’s disease.&#x0D; AIM: This study aims to see the effect of giving MCT to the value of percentage alternation Y-maze test and serum Aβ-42 levels as a marker of Alzheimer’s disease.&#x0D; MATERIALS AND METHODS: This study is an experimental study using postp-test control group design. Samples from this study were 30 Sprague Dawley rats which were divided into positive control groups, negative controls, and three treatment groups. Positive control group and treatment were induced by Alzheimer’s by ovariectomy and d-galactose. After induction, MCT were given to the treatment group for 6 weeks. After treatment, the levels of Aβ-42 serum were examined by ELISA and cognitive function was examined by Y-maze. After that, the data were analyzed by ANOVA. p &lt; 0.05 was said to be statistically significant.&#x0D; RESULTS: The results showed that this study was found a moderate relationship with a positive pattern. This means that the higher the percentage alternation value, the higher the level of Aβ-42 in serum which indicates that the higher the percentage alternation value, the higher the clearance of Aβ-42.&#x0D; CONCLUSION: This study concluded that the group of rats given MCT has a serum Aβ-42 level higher than the group of rats that were not given MCT.

Olfactory response as a marker for Alzheimer's disease: Evidence from perceptual and frontal lobe oscillation coherence deficit.

High-frequency oscillations of the frontal cortex are involved in functions of the brain that fuse processed data from different sensory modules or bind them with elements stored in the memory. These oscillations also provide inhibitory connections to neural circuits that perform lower-level processes. Deficit in the performance of these oscillations has been examined as a marker for Alzheimer’s disease (AD). Additionally, the neurodegenerative processes associated with AD, such as the deposition of amyloid-beta plaques, do not occur in a spatially homogeneous fashion and progress more prominently in the medial temporal lobe in the early stages of the disease. This region of the brain contains neural circuitry involved in olfactory perception. Several studies have suggested that olfactory deficit can be used as a marker for early diagnosis of AD. A quantitative assessment of the performance of the olfactory system can hence serve as a potential biomarker for Alzheimer’s disease, offering a relatively convenient and inexpensive diagnosis method. This study examines the decline in the perception of olfactory stimuli and the deficit in the performance of high-frequency frontal oscillations in response to olfactory stimulation as markers for AD. Two measurement modalities are employed for assessing the olfactory performance: 1) An interactive smell identification test is used to sample the response to a sizable variety of odorants, and 2) Electroencephalography data are collected in an olfactory perception task with a pair of selected odorants in order to assess the connectivity of frontal cortex regions. Statistical analysis methods are used to assess the significance of selected features extracted from the recorded modalities as Alzheimer’s biomarkers. Olfactory decline regressed to age in both healthy and mild AD groups are evaluated, and single- and multi-modal classifiers are also developed. The novel aspects of this study include: 1) Combining EEG response to olfactory stimulation with behavioral assessment of olfactory perception as a marker of AD, 2) Identification of odorants most significantly affected in mild AD patients, 3) Identification of odorants which are still adequately perceived by mild AD patients, 4) Analysis of the decline in the spatial coherence of different oscillatory bands in response to olfactory stimulation, and 5) Being the first study to quantitatively assess the performance of olfactory decline due to aging and AD in the Iranian population.

Plasma Phospho-Tau Identifies Alzheimer's Co-Pathology in Patients with Lewy Body Disease.

ABSTRACTBackgroundAlzheimer's disease co‐pathology is common in dementia with Lewy bodies and Parkinson's disease with dementia (Lewy body disease) and can reliably be detected with positron emission tomography (PET) or cerebrospinal fluid (CSF) biomarkers. Recently developed blood biomarkers are more accessible and less expensive alternatives.ObjectiveTo investigate if plasma phospho‐tau217 and phospho‐tau181 can detect Alzheimer's pathology in Lewy body disease with dementia.MethodsIn this cross‐sectional study we investigated plasma phospho‐tau217 and phospho‐tau181 in 35 patients with Lewy body disease with dementia. Patients underwent tau‐PET imaging (18F‐RO948).ResultsPlasma phospho‐tau217 correlated with plasma phospho‐tau181, CSF phospho‐tau217 (rs = 0.68, P < 0.001), and negatively with CSF β‐amyloid42/40 (rs = −0.52, P = 0.001). Plasma phospho‐tau217 and phospho‐tau181 correlated with tau‐PET signal in the temporal cortex (rs > 0.56, P < 0.001) and predicted abnormal tau‐PET status and β‐amyloid status (area under the curve > 0.78 and > 0.81, respectively).ConclusionPlasma phospho‐tau might be a useful marker for Alzheimer's co‐pathology in Lewy body disease with dementia. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Arterial stiffness acts synergistically with APOE genotype and amyloid status to predict cognitive impairment in non‐demented elderly

AbstractBackgroundVascular disease is a known contributor to cognitive impairment in the elderly, often associated with impairments in Executive Functions. Aortic‐femoral Pulse Wave Velocity (PWV) measures have been proposed as a non‐invasive measure of vascular risk. However, the predictive value for cognitive decline and interactions with amyloid biomarkers have received limited study.MethodsPWV was assessed in 129 non‐demented participants (108 cognitively normal and 21 mild cognitive impairment [MCI]) who underwent comprehensive medical and neuropsychological evaluation at the Shiley‐Marcos UCSD ADRC. PCA‐derived Domain Z‐Scores (relative to robust normal controls) were generated, representing Memory, Language, Visuospatial, Executive Functions, and Attention. Linear models examined if PWV significantly predicted each Domain Score and global cognition (the Mattis Dementia Rating Scale (DRS) total score), adjusting for age, sex, and education. In a subanalysis, history of hypertension, hypercholesterolemia, diabetes, stoke/TIA, CVD, atrial fibrillation, and current smoking status were each added to the model. Next, presence of an APOE ε4 allele was added and allowed to interact with PWV. Amyloid status was determined using CSF AB42/40 ratios in a subset of participants (n = 93), and its interaction with PWV was similarly tested.ResultsAfter adjusting for demographics, PWV predicted DRS scores (B=‐0.47, p=0.01), Memory Domain Scores (B=‐0.11, p=0.02), and Executive Domain Scores (B=‐0.10, p = 0.04, Figure 1). The pattern of results did not change when history of vascular risk factors was added to the models. When restricting to only cognitively normal participants, PWV significantly predicted only Executive Domain Scores (B=‐0.08, p = 0.03). Presence of an APOE e4 allele showed a significant interaction with PWV in predicting Memory (B=‐0.18, p=0.03, Figure 2). In the subsample with CSF data, the Memory Domain Score was predicted by the interaction of PWV with amyloid status (B = ‐0.30, p = 4.2x10‐4, Figure 3).ConclusionsArterial Stiffness measured through aortic‐femoral PWV is a predictor of cognitive impairment, especially in the Memory and Executive Function domains, and interacts with markers of Alzheimer’s disease (APOE and amyloid status), such that a stronger relationship is found in the amyloid/ε4 positive population.

Inflammatory markers in Alzheimer's disease and mild cognitive impairment: A meta‐analysis and systematic review of 170 studies

AbstractBackgroundInflammation plays a crucial role in the pathogenesis of mild cognitive impairment (MCI) and Alzheimer's disease (AD). Our study aimed to analyse previous inconsistent results of inflammatory markers in AD and MCI quantitatively.MethodStudies reporting concentrations of peripheral or cerebrospinal fluid (CSF) markers were included, and eligible data on AD, MCI and control were extracted. Pooled Hedges's g was adopted to illustrate comparisons, and various confounding factors were used to explore sources of heterogeneity.ResultA total of 170 studies were included in the meta‐analysis and systematic review, which demonstrated increased peripheral levels of high‐sensitivity C reactive protein (Hedges's g 0.281, p&lt;0.05), interleukin‐6 (IL‐6) (0.429, p&lt;0.005), soluble tumour necrosis factor receptor 1 (sTNFR1) (0.763, p&lt;0.05), soluble tumour necrosis factor receptor 2 (sTNFR2) (0.354, p&lt;0.005), alpha1‐antichymotrypsin (α1‐ACT) (1.217, p&lt;0.005), IL‐1β (0.615, p&lt;0.05) and soluble CD40 ligand (0.868, p&lt;0.005), and CSF levels of IL‐10 (0.434, p&lt;0.05), monocyte chemoattractant protein‐1 (MCP‐1) (0.798, p&lt;0.005), transforming growth factor‐beta 1 (1.009, p&lt;0.05), soluble triggering receptor expressed on myeloid cells2 (sTREM2) (0.587, p&lt;0.001), YKL‐40 (0.849, p&lt;0.001), α1‐ACT (0.638, p&lt;0.001), nerve growth factor (5.475, p&lt;0.005) and visinin‐like protein‐1 (VILIP‐1) (0.677, p&lt;0.005), in AD compared with the control. Higher levels of sTNFR2 (0.265, p&lt;0.05), IL‐6 (0.129, p&lt;0.05) and MCP‐1 (0.779, p&lt;0.05) and lower levels of IL‐8 (‐1.293, p&lt;0.05) in the periphery, as well as elevated concentrations of YKL‐40 (0.373, p&lt;0.05), VILIP‐1 (0.534, p&lt;0.005) and sTREM2 (0.695, p&lt;0.05) in CSF, were shown in MCI compared with the control. Additionally, increased peripheral sTNFR1 (0.582, p&lt;0.05) and sTNFR2 (0.254, p&lt;0.05) levels were observed in AD compared with MCI.ConclusionSignificantly altered levels of inflammatory markers were verified in comparison between AD, MCI and control, supporting the notion that AD and MCI are accompanied by inflammatory responses in both the periphery and CSF.

Peripapillary retinal nerve fiber layer thickness measured using optical coherence tomography as a marker of Alzheimer's disease

AbstractBackgroundOptical coherence tomography (OCT), is an advanced, noninvasive technology that can provide the images of retinal structure, including peripapillary retinal nerve fiber layer (pRNFL), macular retinal thickness (MRT), as well as macular volume (MV). However, whether the retinal structure varied in Alzheimer's disease (AD) patients was still unclear. This study aims to detect the retinal changes of AD patients and explore their correction with severity of disease and classic biomarker.Method78 AD patients and 188 HC matched with age and sex were enrolled in this study. The pRNFL thickness, MRT and MV were assessed using OCT. In addition, Aβ42, Aβ40 and tau protein in plasma were detected using Simoa technology.ResultThe results showed that the pRNFL thickness of AD patients was significantly thinner than HC (96.76±10.44 vs 101.4±17.74, p=0.023). Compared with HC, MRT and MV were reduced in AD patients, but the differences were not significant(p&gt;0.05). Furthermore, the pRNFL thickness was significantly negatively correlated with MMSE (r=‐0.362, p=0.005) and disease duration (r=‐0.295, p=0.002); In addition, the pRNFL thickness was positively correlated with t‐tau protein in plasma(r=0.409, p=0.002); while negatively correlated with Aβ42/40 in plasma(r=‐0.277, p=0.041). However, there was no significant correction between neither MRT nor MV and MMSE, disease duration, Aβ42, Aβ40 and tau protein in plasma (p&gt;0.05).ConclusionThese results supported that pRNFL thickness measured using OCT may serve as a useful predictor of AD.

Circulating metabolites associated with brain MRI markers of Alzheimer’s disease

AbstractBackgroundPrior research has identified metabolites associated with general cognitive function and Alzheimer’s Disease (AD). However, more research is needed to identify additional metabolites related to AD endophenotypes to better understand the earliest pathological processes. We aimed to identify metabolites associated with brain MRI markers of AD, including total brain volume, lateral ventricular volume, and hippocampal volume in the Framingham Heart Study.MethodAbout 2,145 participants from the Framingham Heart Study Offspring and Third‐Generation cohorts were used in this project. We used linear mixed effect models to assess the association between metabolites and MRI phenotypes. Brain MRI measures were introduced as the percentage of total intracranial volume to correct for head size. Our primary model was adjusted for age, sex, BMI, and use of lipid‐lowering medications. In secondary analyses, we ran the same model stratifying for APOE4 status subgroups (e4 carriers vs. non‐carriers). Multiple testing corrected significance levels was determined as P &lt; 2.09 × 10‐4 after considering inter‐correlation of the metabolites. Finally metabolite set enrichment analysis (MSEA) was carried out to identify biologically meaningful patterns that are significantly enriched in the top associated metabolites.ResultWe found that higher levels of cotinine, fumarate‐malate‐valine and lactate were associated with lower total brain volumes (P &lt; 8.13 × 10‐5). In subgroup analyses, we observed that higher levels of anthranilate were related to lower brain volumes in APOE‐e4 carriers. Further, only in APOE‐e4 non‐carriers, higher phosphatidylcholine (32:1) levels were related to lower brain volumes (P &lt; 1.52 × 10‐4) and higher levels of urate were related to lower hippocampal volume (P &lt; 1.11 × 10‐4). Valine, leucine and isoleucine biosynthesis, and aminoacyl‐tRNA biosynthesis are significantly overrepresented for hippocampal volume in APOE‐e4 non‐carriers.ConclusionSeveral metabolites were associated with total brain and hippocampal volumes. Remarkably, some of these have been previously related to cognitive function and AD, adding to the consistency of our findings and highlighting the power of endophenotype research. Expansion to include additional brain MRI markers and replication in other neuroCHARGE cohorts, a large international consortium, are currently underway.

Correlations of plasma kynurenines with CSF levels, and their relation to markers of Alzheimer’s disease pathology, diagnostic phases and cognitive performance

AbstractBackgroundFinding novel biomarkers for Alzheimer’s disease (AD) for prediction, diagnosis or disease monitoring is a key research area. The kynurenine pathway(KP) consists of different metabolites of the essential amino acid tryptophan that have putative neurotoxic and ‐protective properties such as NMDA‐receptor agonism or potent antioxidation. Small clinical studies have shown altered levels in blood plasma and cerebrospinal fluid(CSF) in AD and other neurodegenerative diseases. However, whether peripheral kynurenine concentrations in plasma resemble those found in CSF is still largely unknown. The present study aims to investigate whether kynurenine concentrations in plasma correlate with those measured in CSF, and to study the role of kynurenines as biomarkers for AD.MethodThis study uses baseline data from 800 participants obtained in the Biobank Alzheimer Centrum Limburg(BBACL) study, an ongoing prospective cohort study in patients of the memory clinic of the Maastricht University Medical Center, the Netherlands. Blood plasma and CSF concentrations (CSF available for 151 participants) of tryptophan, kynurenine, kynurenic acid, 3‐hydroxykynurenine, xanthurenic acid, anthranilic acid, 3‐hydroxy anthranilic acid, quinolinic acid and picolinic acid were determined by means of liquid chromatography‐tandem mass spectrometry. Additionally, Ab1‐42, total‐tau and phosphorylated tau in CSF were determined using commercially available single‐parameter ELISA methods. Correlational and multiple linear regression analyses studied associations between plasma and CSF kynurenine levels, associations of CSF kynurenine concentrations with AD pathological markers, differences in plasma and CSF kynurenine levels in different diagnostic phases (subjective cognitive decline, mild cognitive impairment, dementia) and their associations with cognitive performance.ResultPlasma concentrations of tryptophan (r = .43, p &lt;0.001) and KP metabolites kynurenine (r = .42, p &lt;0.001), 3‐hydroxykynurenine (r = .37, p &lt;0.001), kynurenic acid (r = .32, p &lt;0.001), anthranilic acid (r = .59, p &lt;0.001), quinolinic acid (r = .67, p &lt;0.001) and picolinic acid (r = .76, p &lt;0.001) significantly correlated moderately to high with their corresponding CSF concentrations. Associations with Ab1‐42, t‐tau and p‐tau, disease stages and neuropsychological test scores are currently being analyzed and will be presented.ConclusionFrom a diagnostic viewpoint these results are promising, as the collection of plasma samples is less invasive compared to CSF.

A novel structure associated with aging is augmented in the DPP6-KO mouse brain

In addition to its role as an auxiliary subunit of A-type voltage-gated K+ channels, we have previously reported that the single transmembrane protein Dipeptidyl Peptidase Like 6 (DPP6) impacts neuronal and synaptic development. DPP6-KO mice are impaired in hippocampal-dependent learning and memory and exhibit smaller brain size. Using immunofluorescence and electron microscopy, we report here a novel structure in hippocampal area CA1 that was significantly more prevalent in aging DPP6-KO mice compared to WT mice of the same age and that these structures were observed earlier in development in DPP6-KO mice. These novel structures appeared as clusters of large puncta that colocalized NeuN, synaptophysin, and chromogranin A. They also partially labeled for MAP2, and with synapsin-1 and VGluT1 labeling on their periphery. Electron microscopy revealed that these structures are abnormal, enlarged presynaptic swellings filled with mainly fibrous material with occasional peripheral, presynaptic active zones forming synapses. Immunofluorescence imaging then showed that a number of markers for aging and especially Alzheimer’s disease were found as higher levels in these novel structures in aging DPP6-KO mice compared to WT. Together these results indicate that aging DPP6-KO mice have increased numbers of novel, abnormal presynaptic structures associated with several markers of Alzheimer’s disease.