Association of microplastics in human cerebrospinal fluid with Alzheimer's disease-related changes.

In 1906, Alois Alzheimer described the neuropathology of the disease that was to bear his name. Subsequently, our understanding of Alzheimer disease (AD) has grown significantly. The autosomal dominant mutations to the amyloid precursor protein (APP), presenilin (PS) 1, and PS2 genes that cause early onset AD have been very informative, leading to the articulation of the amyloid cascade hypothesis. This hypothesis has been the basis for several disease-modifying therapeutic approaches for AD. This has been partly because it provided a coherent framework for understanding AD pathogenesis but also because several pharmacological approaches that targeted the amyloid peptide (amyloidocentric) were sufficiently well-founded scientifically to enter clinical development. In the past 5 years, there have been 6 amyloidocentric programs that completed phase 3 clinical testing. None met their primary outcome measures (Table 1), although 1, solanezumab, showed encouraging results in a prespecified secondary outcome measure. This disappointing track record has brought into question the amyloidocentric therapeutic approach. This review will consider these programs from the following perspectives:

Plasminogen activator inhibitor-1 (PAI-1), an inhibitor of fibrinolysis that is associated with adiposity, has been implicated in Alzheimer's disease (AD) pathogenesis. However, whether circulating PAI-1 levels are altered during preclinical AD remains unclear. To measure plasma PAI-1 levels in cognitively normal cerebrospinal fluid (CSF) AD biomarker positive and biomarker negative participants and to examine the association of plasma PAI-1 levels with CSF AD biomarkers and Mini-Mental State Examination (MMSE) scores. In this cross-sectional study, plasma PAI-1 levels were measured in 155 cognitively normal (Clinical Dementia Rating, CDR 0) non-obese older adults. 29 men and 26 women were classified as preclinical AD by previously established CSF tau/Aβ42 criteria. All analyses were sex stratified due to reported sex differences in PAI-1 expression. Plasma PAI-1 levels were associated with body mass index (BMI) but not age in men and women. In men, plasma PAI-1 levels and BMI were lower in preclinical AD compared to control. Plasma PAI-1 levels were positively associated with CSF amyloid-β42 (Aβ42) and CSF Aβ42/Aβ40 and negatively associated with CSF tau/Aβ42, while BMI was positively associated with CSF Aβ42 and negatively associated with CSF p-tau181 and CSF tau/Aβ42. In women, plasma PAI-1 levels and BMI were similar between preclinical AD and control and were not associated with CSF AD biomarkers. For men and women, plasma PAI-1 levels and BMI were not associated with MMSE scores. These findings suggest that there are significant sex differences in the systemic metabolic changes seen in the preclinical stage of AD.

Amyloid β protein 1–40 and 1–42 levels in matched cerebrospinal fluid and plasma from patients with Alzheimer disease

We previously discovered microRNAs (miRNAs) in cerebrospinal fluid (CSF) that differentiate Alzheimer's disease (AD) patients from Controls. Here we examined the performance of 37 candidate AD miRNA biomarkers in a new and independent cohort of CSF from 47 AD patients and 71 Controls on custom TaqMan arrays. We employed a consensus ranking approach to provide an overall priority score for each miRNA, then used multimarker models to assess the relative contributions of the top-ranking miRNAs to differentiate AD from Controls. We assessed classification performance of the top-ranking miRNAs when combined with apolipoprotein E4 (APOE4) genotype status or CSF amyloid-β42 (Aβ42):total tau (T-tau) measures. We also assessed whether miRNAs that ranked higher as AD markers correlate with Mini-Mental State Examination (MMSE) scores. We show that of 37 miRNAs brought forth from the discovery study, 26 miRNAs remained viable as candidate biomarkers for AD in the validation study. We found that combinations of 6-7 miRNAs work better to identify AD than subsets of fewer miRNAs. Of 26 miRNAs that contribute most to the multimarker models, 14 have higher potential than the others to predict AD. Addition of these 14 miRNAs to APOE4 status or CSF Aβ42:T-tau measures significantly improved classification performance for AD. We further show that individual miRNAs that ranked higher as AD markers correlate more strongly with changes in MMSE scores. Our studies validate that a set of CSF miRNAs serve as biomarkers for AD, and support their advancement toward development as biomarkers in the clinical setting.

BackgroundAlzheimer's disease (AD) is characterized by amyloid-β (Aβ) and tau protein accumulation, reflected in cerebrospinal fluid (CSF) analysis. However, the interplay among CSF biomarkers, neuroimaging, and cognition remains elusive.ObjectiveTo explore associations among neuroimaging features, CSF biomarkers, and cognitive performance in AD.MethodsSixty patients with clinically diagnosed AD showing Aβ pathology in CSF underwent neuroimaging assessment of gray matter volume using T1-weighted MRI, cerebral blood flow (CBF) using single-photon emission computed tomography, and white matter hyperintensities (WMHs) using T2-weighted or fluid-attenuated inversion recovery images. Partial least square (PLS) regression identified imaging findings related to CSF biomarkers and Mini-Mental State Examination (MMSE) scores. Structural equation modeling (SEM) explored associations between factors with variable importance in projection (VIP) scores above 1.5 in PLS regression.ResultsLateral temporal and occipital gray matter volumes positively correlated with MMSE scores (VIP = 1.95, 1.53), whereas WMHs in parietal and frontal periventricular regions were negatively associated with CSF Aβ42 (VIP = 1.54, 1.58). Lateral temporal CBF was also associated with MMSE scores (VIP = 2.22). SEM analysis showed that reduced CSF Aβ42 was linked to increased WMHs (p = 0.028), which correlated with each region (p < 0.005) and explained the reduced MMSE score (p = 0.013). Lateral temporal CBF correlated with temporo-occipital gray matter volume (p < 0.001) and influenced the MMSE score (p < 0.001).ConclusionsThis study suggests that amyloid pathology via WMHs and neurodegeneration of the lateral temporal lobe independently contribute to cognitive impairment in patients with AD.

BackgroundThe clinical role and potential mechanisms of the choroid plexus (ChP) in Alzheimer's disease (AD) remains unclear.MethodThis prospective cohort study enrolled 607 participants [110 healthy controls (HCs), 269 mild cognitive impairment (MCI), and 228 AD dementia] from the Chinese Imaging, Biomarkers, and Lifestyle study between January 1, 2021, and December 31, 2022. Relationship between ChP volume and the cerebrospinal fluid (CSF) pathological hallmarks (Aβ42, Aβ40, Aβ42/40, tTau, and pTau), neuropsychological tests [Mini‐Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Neuropsychiatric Inventory (NPI), and Activities of Daily Living (ADL) scores], and multimodal neuroimaging measures were analyzed using partial Spearman’s correlation. The mediating effects of ChP volume were examined on the relationship between CSF hallmarks and neuropsychological tests. The ChP volume performance to differentiate the presence/absence of cerebral Aβ42 deposition was determined using receiver operating characteristic analysis. Generalized linear mixed‐effects models discerned the association between baseline ChP volume and longitudinal changes in neuropsychological tests in patients on AD continuum.ResultThe participants' mean age was 65.99±8.79 years. Patients with AD dementia exhibited a larger baseline ChP volume than the other participants (P&lt;0.001; Figure 1). ChP volume enlargement correlated with decreased Aβ42 and Aβ40 levels; lower MMSE and MoCA and higher NPI and ADL scores; lower volume, cortical thickness, and corrected cerebral blood flow in other cognition‐related regions (all P &lt; 0.05). ChP volume alone mediated and ChP–hippocampal volume combined chain mediated the association of CSF Aβ42 and Aβ40 levels with the MMSE scores (16.91%, 37.15%, 14.25%, and 27.82%, respectively; Figure 2). ChP volume better identified the presence/absence of cerebral Aβ42 deposition than hippocampal volume (AUC: 0.762 vs. 0.724; Figure 3). Baseline ChP volume was associated with subsequent decline and faster worsening in the MMSE, MoCA, and ADL scores with 10.03±4.45 months' follow‐up (all P&lt;0.001).ConclusionChP volume is a novel, candidate, non‐invasive neuroimaging marker associated with neurodegenerative changes in Alzheimer’s continuum. It can detect early cerebral Aβ42 deposition and predict prognosis in clinical practice.

Associations between cerebrospinal fluid biomarkers in individuals with normal cognitive function, mild cognitive impairment, or Alzheimer's disease by amyloid PET status: a cross-sectional survey

Cerebrospinal fluid markers and change in MMSE score over an 8-year follow-up period - the population study of women in Gothenburg, Sweden

Peripheral inflammation has been suggested to influence the development of Alzheimer's disease (AD). Elevated levels of pro-inflammatory markers in the plasma of patients with AD indicate that a systemic pro-inflammatory status occurs concomitantly with inflammatory changes in the brain. To investigate whether allergy influences the levels of immunoglobulins (Ig) and of pro- and anti-inflammatory cytokines in the serum and cerebrospinal fluid (CSF) from patients with AD, mild cognitive impairment (MCI), and subjective cognitive impairment (SCI). IgA, IgG, and its subclasses, IgM, and cytokines were analyzed in CSF and serum from patients with SCI, MCI, and AD, with or without allergy. The relation between allergy and Mini-Mental State Examination (MMSE) scores, and between allergy and CSF biomarkers for AD (phosphorylated (p)-tau, total (t)-tau, amyloid-β 42 (Aβ₄₂), were analyzed. In MCI, the CSF levels of IgG2 were lower in allergic patients, and in AD, the levels of IgA and the IgG1/total IgG ratio were lower in allergic patients, compared to patients without allergy. MCI subjects with allergy had higher serum IgM levels compared to those without allergy. CSF levels of Aβ₄₂ were lower and MMSE scores were higher in AD patients with allergy than in those without allergy. The presence of allergy was associated with seemingly beneficial effects on AD as suggested by higher Aβ₄₂ levels in CSF, and higher MMSE scores. Higher IgM levels and lower other Ig classes suggest that allergy may influence senescence of the immune response.

Background: Low levels of cerebrospinal fluid (CSF) β-amyloid 1–42 (Aβ42) and high total tau (T-tau) are diagnostic for manifest Alzheimer’s disease. It is not known, however, whether these biomarkers may...

No correlation between time-linked plasma and CSF Aβ levels

High Activities of BACE1 in Brains with Mild Cognitive Impairment

Suitability of the Montreal Cognitive Assessment versus the Mini-Mental State Examination in Detecting Vascular Cognitive Impairment

Background: Neurodegeneration plays a major role in determining disability in multiple sclerosis (MS) patients. Hence, there is increasing need to identify reliable biomarkers, which could serve as prognostic measure of disease progression. Objectives: To assess whether cerebrospinal fluid (CSF) tau and β-amyloid (Aβ) levels were altered in newly diagnosed MS patients and correlated with disability. Moreover, we investigated whether these CSF biomarkers associate with macroscopic brain tissue damage measures. Methods: CSF Aβ and tau levels were determined by enzyme-linked immunosorbent assay in CSF samples from 48 newly diagnosed MS patients, followed-up clinically for 3 years by recording their Expanded Disability Status Scale score at 6-month intervals, and 45 controls. All patients underwent magnetic resonance imaging at baseline and at the end of follow-up to quantify their lesion load (LL). Results: CSF Aβ levels were significantly reduced in patients compared to controls (p < 0.001). Lower CSF Aβ levels at baseline were a disability predictor at 3-year follow-up (p = 0.009). CSF tau levels correlated with T2- and T1-LL (p < 0.001). Conclusion: CSF Aβ reduction is a promising biomarker of neurodegeneration and may predict patients’ clinical outcome. Therefore, CSF Aβ should be considered as a potential biomarker of prognostic value.

In this study, an attempt has been made to find the correlation between Diffusion Tensor Imaging (DTI) indices of White Matter (WM) regions and Mini Mental State Examination (MMSE) score of Alzheimer patients. Diffusion weighted images are obtained from the ADNI database. These are preprocessed for eddy current correction and removal of non brain tissue. Fractional Anisotropy (FA), Mean Diffusivity (MD), Radial Diffusivity (RD) and Axial Diffusivity (DA) indices are computed over significant regions (Fornix left, Splenium of corpus callosum left, Splenium of corpus callosum right, Bilateral genu of the corpus callosum) affected by AD pathology. The correlation is computed between diffusion indices of the significant regions and MMSE score using linear fit technique so as to find the relation between clinical parameters and the image features. Binary classification has been employed using SVM, Decision Stumps and Simple Logistic classifiers on the extracted DTI indices along with MMSE score to classify Alzheimer patients from healthy controls. It is observed that distinct values of DTI indices exist for the range of MMSE score. However, there is no strong correlation (r varies from 0.0383 to -0.1924) between the MMSE score and the diffusion indices over the significant regions. Further, the performance evaluation of classifiers shows 94% accuracy using SVM in differentiating AD and Control. In isolation clinical and images features can be used for pre screening and diagnosis of AD but no sub anatomic region correlation exist between these features set. The discussion on the correlation of diffusion indices of WM with MMSE score is presented in this study.