Lower Aβ42 Levels Research Articles

Cerebrospinal Fluid Levels of β-Amyloid 40 and β-Amyloid 42 are Proportionately Decreased in Amyloid Positron-Emission Tomography Negative Idiopathic Normal-Pressure Hydrocephalus Patients.

Background and PurposeCerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) could be misleading in idiopathic normal-pressure hydrocephalus (iNPH). We therefore investigated the CSF biomarkers in 18F-florbetaben amyloid-negative positron-emission tomography (PET) [amyloid PET(−)] iNPH, amyloid-positive PET [amyloid PET(+)] AD, and cognitively normal (CN) subjects.MethodsTen amyloid PET(+) AD patients (56.7±5.6 years old, mean±standard deviation), 10 amyloid PET(−) iNPH patients (72.8±4.5 years old), and 8 CN subjects (61.2±6.5 years old) were included. We measured the levels of β-amyloid (Aβ)40, Aβ42, total tau (t-tau) protein, and phosphorylated tau (p-tau) protein in the CSF using enzyme-linked immunosorbent assays.ResultsThe level of Aβ42 and the Aβ42/Aβ40 ratio in the CSF were significantly lower in AD than in iNPH or CN subjects. The Aβ40 level did not differ significantly between AD and iNPH (p=1.000), but it did between AD and CN subjects (p=0.032). The levels of both t-tau and p-tau were higher in AD than in iNPH or CN subjects. The levels of Aβ42, Aβ40, t-tau, and p-tau were lower in iNPH than in CN subjects, but there was no significant difference after controlling for age.ConclusionsOur results suggest that the mechanism underlying low CSF Aβ levels differs between amyloid PET(−) iNPH and amyloid PET(+) AD subjects. The lower levels of all CSF biomarkers in iNPH patients might be due to reduced clearances from extracellular fluid and decreased brain metabolism of the periventricular zone in iNPH resulting from glymphatic dysfunction.

The relationship between CSF biomarkers and cerebral metabolism in early-onset Alzheimer's disease.

One can reasonably suppose that cerebrospinal spinal fluid (CSF) biomarkers can identify distinct subgroups of Alzheimer's disease (AD) patients. In order to better understand differences in CSF biomarker patterns, we used FDG PET to assess cerebral metabolism in CSF-based subgroups of AD patients. Eighty-five patients fulfilling the criteria for probable early-onset AD (EOAD) underwent lumbar puncture, brain 18F-FDG PET and MRI. A cluster analysis was performed, with the CSF biomarkers for AD as variables. Vertex-wise, partial-volume-corrected metabolic maps were computed for the patients and compared between the clusters of patients. Linear correlations between each CSF biomarker and the metabolic maps were assessed. Three clusters emerged. The "Aβ42" cluster contained 32 patients with low levels of Aβ42, while tau and p-tau remained within the normal range. The "Aβ42 + tau" cluster contained 41 patients with low levels of Aβ42 and high levels of tau and p-tau. Lastly, the "tau" cluster contained 12 patients with very high levels of tau and p-tau and low-normal levels of Aβ42. There were no inter-cluster differences in age, sex ratio, educational level, APOE genotype, disease duration or disease severity. The "Aβ42 + tau" and "tau" clusters displayed more marked frontal hypometabolism than the "Aβ42" cluster did, and frontal metabolism was significantly negatively correlated with the CSF tau level. The "Aβ42" and "Aβ42 + tau" clusters displayed more marked hypometabolism in the left occipitotemporal region than the "tau" cluster did, and metabolism in this region was significantly and positively correlated with the CSF Aβ42 level. The CSF biomarkers can be used to identify metabolically distinct subgroups of patients with EOAD. Future research should seek to establish whether these biochemical differences have clinical consequences.

REM behavior disorder predicts motor progression and cognitive decline in Parkinson disease.

To investigate whether REM sleep behavior disorder (RBD) is associated with worse motor and cognitive decline in Parkinson disease (PD) METHODS: Four-hundred twenty-one drug-naive patients with early-stage PD and 196 controls without PD were included in this study. All participants underwent a [123I]FP-CIT SPECT scan, CSF assessment, 3-tesla MRI, and thorough clinical assessments. At cross-sectional analyses, patients with PD and probable RBD (PD-RBD) had lower CSF β-amyloid 1-42 (Aβ42) levels and higher total tau to Aβ42 CSF ratio, higher nonmotor symptoms burden, and worse scores on neuropsychological tests of processing speed, visuospatial functioning, and delayed recognition memory compared to patients with PD without RBD. At longitudinal analyses, the presence of RBD was associated with faster motor progression (hazard ratio [HR] = 1.368, 95% confidence Interval [CI] = 1.036-1.806; p = 0.027) and cognitive decline (HR = 1.794, 95% CI = 1.163-2.768; p = 0.008) over 60-month follow-up. The presence of RBD was a predictor for motor progression only in patients with PD who had both low α-synuclein levels and low [123I]FP-CIT uptake in the striatum (HR = 2.091, 95% CI = 1.116-3.918; p = 0.021) and a predictor for cognitive decline only in patients with PD who had both low Aβ42 and low α-synuclein levels (HR = 2.810, 95% CI = 1.462-5.400; p = 0.002). In the population of controls without PD, the presence of RBD was not associated with cognitive decline or any baseline pathologic changes. The presence of RBD in PD is associated with faster motor progression in patients with greater synuclein and dopaminergic pathology, and with higher risk of cognitive decline in patients with greater synuclein and amyloid pathology. Our findings provide an important direction toward understanding phenotypes and their prognosis in PD.

CSF β-amyloid predicts prognosis in patients with multiple sclerosis

Background: The importance of predicting disease progression in multiple sclerosis (MS) has increasingly been recognized, and hence reliable biomarkers are needed. Objectives: To investigate the prognostic role of cerebrospinal fluid (CSF) amyloid beta1–42 (Aβ) levels by the determination of a cut-off value to classify patients in slow and fast progressors. To evaluate possible association with white matter (WM) and grey matter (GM) damage at early disease stages. Methods: Sixty patients were recruited and followed up for 3–5 years. Patients underwent clinical assessment, brain magnetic resonance imaging (MRI; at baseline and after 1 year), and CSF analysis to determine Aβ levels. T1-weighted volumes were calculated. T2-weighted scans were used to quantify WM lesion loads. Results: Lower CSF Aβ levels were observed in patients with a worse follow-up Expanded Disability Status Scale (EDSS; r = −0.65, p < 0.001). The multiple regression analysis confirmed CSF Aβ concentration as a predictor of patients’ EDSS increase (r = −0.59, p < 0.0001). Generating a receiver operating characteristic curve, a cut-off value of 813 pg/mL was determined as the threshold able to identify patients with worse prognosis (95% confidence interval (CI): 0.690–0.933, p = 0.0001). No differences in CSF tau and neurofilament light chain (NfL) levels were observed (p > 0.05). Conclusion: Low CSF Aβ levels may represent a predictive biomarker of disease progression in MS.

Optimization of 1,4-Oxazine β-Secretase 1 (BACE1) Inhibitors Toward a Clinical Candidate.

In previous studies, the introduction of electron withdrawing groups to 1,4-oxazine BACE1 inhibitors reduced the p Ka of the amidine group, resulting in compound 2 that showed excellent in vivo efficacy, lowering Aβ levels in brain and CSF. However, a suboptimal cardiovascular safety margin, based on QTc prolongation, prevented further progression. Further optimization resulted in the replacement of the 2-fluoro substituent by a CF3-group, which reduced hERG inhibition. This has led to compound 3, with an improved cardiovascular safety margin and sufficiently safe in GLP toxicity studies to progress into clinical trials.

CSF tau and β-amyloid predict cerebral synucleinopathy in autopsied Lewy body disorders

To test the association of antemortem CSF biomarkers with postmortem pathology in Lewy body disorders (LBD). Patients with autopsy-confirmed LBD (n = 24) and autopsy-confirmed Alzheimer disease (AD) (n = 23) and cognitively normal (n = 36) controls were studied. In LBD, neuropathologic criteria defined Lewy body α-synuclein (SYN) stages with medium/high AD copathology (SYN + AD = 10) and low/no AD copathology (SYN - AD = 14). Ordinal pathology scores for tau, β-amyloid (Aβ), and SYN pathology were averaged across 7 cortical regions to obtain a global cerebral score for each pathology. CSF total tau (t-tau), phosphorylated tau at threonine181, and Aβ1-42 levels were compared between LBD and control groups and correlated with global cerebral pathology scores in LBD with linear regression. Diagnostic accuracy for postmortem categorization of LBD into SYN + AD vs SYN - AD or neocortical vs brainstem/limbic SYN stage was tested with receiver operating curves. SYN + AD had higher CSF t-tau (mean difference 27.0 ± 8.6 pg/mL) and lower Aβ1-42 (mean difference -84.0 ± 22.9 g/mL) compared to SYN - AD (p < 0.01, both). Increasing global cerebral tau and plaque scores were associated with higher CSF t-tau (R2 = 0.15-0.16, p < 0.05, both) and lower Aβ1-42 (R2 = 0.43-0.49, p < 0.001, both), while increasing cerebral SYN scores were associated with lower CSF Aβ1-42 (R2 = 0.31, p < 0.001) and higher CSF t-tau/Aβ1-42 ratio (R2 = 0.27, p = 0.01). CSF t-tau/Aβ1-42 ratio had 100% specificity and 90% sensitivity for SYN + AD, and CSF Aβ1-42 had 77% specificity and 82% sensitivity for neocortical SYN stage. Higher antemortem CSF t-tau/Aβ1-42 and lower Aβ1-42 levels are predictive of increasing cerebral AD and SYN pathology. These biomarkers may identify patients with LBD vulnerable to cortical SYN pathology who may benefit from both SYN and AD-targeted disease-modifying therapies.

The nonlinear relationship between cerebrospinal fluid Aβ42 and tau in preclinical Alzheimer's disease.

Cerebrospinal fluid (CSF) studies consistently show that CSF levels of amyloid-beta 1–42 (Aβ42) are reduced and tau levels increased prior to the onset of cognitive decline related to Alzheimer’s disease (AD). However, the preclinical prediction accuracy for low CSF Aβ42 levels, a surrogate for brain Aβ42 deposits, is not high. Moreover, the pathology data suggests a course initiated by tauopathy contradicting the contemporary clinical view of an Aβ initiated cascade. CSF Aβ42 and tau data from 3 normal aging cohorts (45–90 years) were combined to test both cross-sectional (n = 766) and longitudinal (n = 651) hypotheses: 1) that the relationship between CSF levels of Aβ42 and tau are not linear over the adult life-span; and 2) that non-linear models improve the prediction of cognitive decline. Supporting the hypotheses, the results showed that a u-shaped quadratic fit (Aβ2) best describes the relationship for CSF Aβ42 with CSF tau levels. Furthermore we found that the relationship between Aβ42 and tau changes with age—between 45 and 70 years there is a positive linear association, whereas between 71 and 90 years there is a negative linear association between Aβ42 and tau. The quadratic effect appears to be unique to Aβ42, as Aβ38 and Aβ40 showed only positive linear relationships with age and CSF tau. Importantly, we observed the prediction of cognitive decline was improved by considering both high and low levels of Aβ42. Overall, these data suggest an earlier preclinical stage than currently appreciated, marked by CSF elevations in tau and accompanied by either elevations or reductions in Aβ42. Future studies are needed to examine potential mechanisms such as failing CSF clearance as a common factor elevating CSF Aβxx analyte levels prior to Aβ42 deposition in brain.

Amyloid Precursor Protein in Autism Spectrum Disorder

Amyloid precursor protein (APP) gets cleaved by α, β, and γ secretases in both amyloidogenic and nonamyloidogenic processing. In amyloidogenic processing, Aβ40 and Aβ42 peptides result, leading to amyloid plaques in the brain, associated with various dementias, especially Alzheimer’s disease. Amyloid plaques also occur in the brains of children with autism spectrum disorder (ASD), while both elevated and diminished levels of soluble APP have been found in the serum of ASD patients. Treatment with mGluR5 inhibitors has successfully lowered APP and Aβ levels in vitro as well as ASD symptoms in a mouse model. Differences in ASD genotype and phenotype along with similarities to neurodegenerative dementias must be considered when investigating new biomarkers and treatments for ASD.

Alzheimer's Disease Diagnosis: Discrepancy between Clinical, Neuroimaging, and Cerebrospinal Fluid Biomarkers Criteria in an Italian Cohort of Geriatric Outpatients: A Retrospective Cross-sectional Study.

The role of cerebrospinal fluid (CSF) biomarkers, and neuroimaging in the diagnostic process of Alzheimer's disease (AD) is not clear, in particular in the older patients. The aim of this study was to compare the clinical diagnosis of AD with CSF biomarkers and with cerebrovascular damage at neuroimaging in a cohort of geriatric patients. Retrospective analysis of medical records of ≥65-year-old patients with cognitive impairment referred to an Italian geriatric outpatient clinic, for whom the CSF concentration of amyloid-β (Aβ), total Tau (Tau), and phosphorylated Tau (p-Tau) was available. Clinical diagnosis (no dementia, possible and probable AD) was based on the following two sets of criteria: (1) the Diagnostic Statistical Manual of Mental Disorders (DSM-IV) plus the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) and (2) the National Institute on Aging-Alzheimer's Association (NIA-AA). The Fazekas visual scale was applied when a magnetic resonance imaging scan was available. We included 94 patients, mean age 77.7 years, mean Mini Mental State Examination score 23.9. The concordance (kappa coefficient) between the two sets of clinical criteria was 70%. The mean CSF concentration (pg/ml) (±SD) of biomarkers was as follows: Aβ 687 (±318), Tau 492 (±515), and p-Tau 63 (±56). There was a trend for lower Aβ and higher Tau levels from the no dementia to the probable AD group. The percentage of abnormal liquor according to the local cutoffs was still 15 and 21% in patients without AD based on the DSM-IV plus NINCDS-ADRDA or the NIA-AA criteria, respectively. The exclusion of patient in whom normotensive hydrocephalus was suspected did not change these findings. A total of 80% of patients had the neuroimaging report describing chronic cerebrovascular damage, while the Fazekas scale was positive in 45% of patients overall, in 1/2 of no dementia or possible AD patients, and in about 1/3 of probable AD patients, with no difference across ages. We confirmed the expected discrepancy between different approaches to the diagnosis of AD in a geriatric cohort of patients with cognitive impairment. Further research is needed to understand how to interpret this discrepancy and provide clinicians with practical guidelines.

Cognitive impairment in Glucocerebrosidase (GBA)‐associated PD: Not primarily associated with cerebrospinal fluid Abeta and Tau profiles

A proportion of idiopathic Parkinson's disease patients (PDidiopathic ) with dementia show altered CSF profiles of amyloid β (Aβ) and Tau. PD patients with Glucocerebrosidase (GBA) mutations (PDGBA ) present with even more cognitive decline than seen in PDidiopathic . The objective of this study was to evaluate whether CSF profiles of Aβ and tau are associated with the prominent cognitive impairment in PDGBA . CSF levels of Aβ1-42 , t-Tau, p-Tau, and total alpha-synuclein were assessed in 479 participants (50 PDGBA , 308 PDidiopathic , 121 healthy controls). Older age was associated with cognitive impairment in PDGBA and PDidiopathic . Despite prominent cognitive impairment, PDGBA showed similar CSF levels of Aβ1-42 , t-Tau, and p-Tau as seen in healthy controls. In contrast, lower levels of Aβ1-42 and higher levels of t-Tau and p-Tau were associated with worse cognitive performance in PDidiopathic . The prominent cognitive impairment in PDGBA seems not primarily associated with Aβ and Tau profiles in CSF. © 2017 International Parkinson and Movement Disorder Society.

Atrophy of the Posterior Subiculum Is Associated with Memory Impairment, Tau- and Aβ Pathology in Non-demented Individuals

Alzheimer’s disease (AD) is associated with atrophy of the cornu ammonis (CA) 1 and the subiculum subfield of the hippocampus (HC), and with deficits in episodic memory and spatial orientation. These deficits are mainly associated with the functionality of the posterior HC. We therefore hypothesized that key AD pathologies, i.e., β-amyloid and tau pathology would be particularly associated with the volume of the posterior subiculum in non-demented individuals. In our study we included 302 cognitively normal elderly participants (CN), 183 patients with subjective cognitive decline (SCD) and 171 patients with amnestic mild cognitive impairment (MCI), all of whom underwent 3T magnetic resonance images (MRI). The subicular subfield was segmented using Freesurfer 5.3 and divided into 10 volumetric segments moving from the most posterior (segment 1) to the most anterior part along the axis of the hippocampal head and body (segment 10). Cerebrospinal fluid (CSF) Aβ42 and phosphorylated tau (P-tau) were quantified using ELISA and were used as biomarkers for β-amyloid and tau pathology, respectively. In the total sample, tau-pathology and Aβ-pathology and (measured by elevated P-tau and low Aβ42 levels in CSF) and mild memory dysfunction were mostly associated with the volume changes of the posterior subiculum. Both SCD and MCI patients with elevated P-tau or low Aβ42 levels displayed predominantly posterior subicular atrophy in comparisons to control subjects with normal CSF biomarker levels. Finally, there was no main effect of Aβ42 or P-tau when comparing SCD with abnormal P-tau or Aβ42 with SCD with normal levels of these CSF-biomarkers. However, in the left subiculum there was a significant interaction revealing atrophy in the left posterior but not the anterior subiculum in participants with low Aβ42 levels. The same pattern was observed on the contralateral side in participants with elevated P-tau levels. In conclusion, AD pathologies and mild memory dysfunction are mainly associated with atrophy of the posterior parts of the subicular subfields of the HC in non-demented individuals. In light of these findings we suggest that segmentation of the HC subfields may benefit from considering the volume of the different anterior-posterior subsections of each subfield.

Decreased plasma β-amyloid in the Alzheimer's disease APP A673T variant carriers.

We investigated the association of Alzheimer's disease (AD)-related rare variants APP A673T and ABCA7 rs200538373-C with the levels of β-amyloid (Aβ) and parameters of metabolic and cardiovascular health in a population-based cohort of healthy middle-aged and elderly men. Carriers of protective APP A673T variant had, on average, 28% lower levels of Aβ40 and Aβ42 in plasma as compared to the controls and the carriers of ABCA7 rs200538373-C. This is the first report to show decreased Aβ levels in plasma in APP A673T carriers and thus provides evidence that lower Aβ levels throughout life may be protective against AD. Ann Neurol 2017;82:128-132.

TREATING ALZHEIMER’S DISEASE BY TARGETING β-AMYLOID: WHERE DO WE STAND?

A remarkable rise in life expectancy during the past century has made Alzheimer's disease the most common form of progressive mental failure. Patients with AD lose their most human qualities – reasoning, abstraction, judgement, language and memory. Biochemical analyses of classical brain lesions that Alois Alzheimer described – the senile (amyloid) plaques and the neurofibrillary tangles – preceded and guided the search for genetic alterations that underlie AD. In the 1990s, four genes were strongly linked to inheritance of early Alzheimer's disease. Mutations or variations in these four genes all cause accumulation of the amyloid β-protein (Aβ) in the brain, with subsequent alteration of the tau protein into tangles as well as inflammation and neurodegeneration in brain regions serving memory and cognition. Recently, other genes have been found to confer a heightened risk of typical AD, and some have already been shown to increase Aβ levels in various ways. This growing understanding of “genotype-to-phenotype” relationships in familial AD, coupled with innumerable cell culture and animal model studies of the process, have now led to specific strategies to lower brain Aβ levels in order to treat and prevent AD. Although there has been a healthy debate about this ‘amyloid (Aβ) hypothesis', new evidence further supports the idea that an imbalance between production and clearance of Aβ42 may be an initiating factor in AD. For example inheriting the apoE4 gene, which strongly predisposes to AD, impairs clearance of Ab from the brain. “Oligomers” (doublets, quadruplets, etc.) of Aβ isolated from AD brains can decrease synapse numbr and inhibit synapse function in animals, and injecting the oligomers into healthy adult rats impairs their memory. Aβ oligomers modify the tau protein in AD-relevant ways. Human biomarker studies show that low CSF Aβ42 levels and high amyloid plaque levels on PET scans precede other AD features by many years. Recent human trials of an Aβ antibody (aducanumab) led to dose-dependent removal of amyloid plaques from the brain, accompanied by an apparent slowing of cognitive decline. Although many other factors contribute to AD, Aβ accumulation has emerged as the most extensively validated and compelling therapeutic target.

Low normal cerebrospinal fluid Aβ42 levels predict clinical progression in nondemented subjects.

We studied whether continuous lower normal cerebrospinal fluid (CSF) amyloid β1-42 (≥640pg/ml) levels were related with rate of clinical progression in a sample of 393 nondemented memory clinic patients. Lower normal levels were associated with faster clinical progression, and this depended on baseline cognitive status (subjective cognitive decline: hazard ratio [HR] = 0.57, p < 0.05; mild cognitive impairment: HR = 0.19, p < .01), indicating that normal CSF amyloid levels do not exclude incident Alzheimer disease. These findings suggest that research on preclinical markers for Alzheimer disease should take the continuum of CSF amyloid β1-42 levels within the normal range into account. Ann Neurol 2017;81:749-753.

Subjective Cognitive Impairment Is a Predominantly Benign Condition in Memory Clinic Patients Followed for 6 Years: The Gothenburg-Oslo MCI Study

Background/Aims: In the quest for prevention or treatment, there is a need to find early markers for preclinical dementia. This study observed memory clinic patients with subjective cognitive impairment (SCI) and normal cognitive function at baseline. The primary aim was to address SCI as a potential risk factor for cognitive decline. The secondary aim was to address a potential relation between (1) baseline cerebrospinal fluid biomarkers and (2) a decline in memory performance over the first 2 years of follow-up, with a possible cognitive decline after 6 years. Methods: Eighty-one patients (mean age 61 years) were recruited from university memory clinics and followed up for 6 years. Results: Eighty-six percent of the cohort remained cognitively stable or improved, 9% developed mild cognitive impairment, and only 5% (n = 4) developed dementia. Regression analysis revealed that low levels of Aβ₄₂ at baseline and memory decline during the first 2 years predicted dementia. When combined, these variables were associated with a 50% risk of developing dementia. Conclusions: Cognitive stability for 86% of the cohort suggests that SCI is predominantly a benign condition with regard to neuropathology. The low number of individuals who developed dementia limits the generalizability of the results and discussion of progression factors.

Gleevec shifts APP processing from a β-cleavage to a nonamyloidogenic cleavage

Neurotoxic amyloid-β peptides (Aβ) are major drivers of Alzheimer's disease (AD) and are formed by sequential cleavage of the amyloid precursor protein (APP) by β-secretase (BACE) and γ-secretase. Our previous study showed that the anticancer drug Gleevec lowers Aβ levels through indirect inhibition of γ-secretase activity. Here we report that Gleevec also achieves its Aβ-lowering effects through an additional cellular mechanism. It renders APP less susceptible to proteolysis by BACE without inhibiting BACE enzymatic activity or the processing of other BACE substrates. This effect closely mimics the phenotype of APP A673T, a recently discovered mutation that protects carriers against AD and age-related cognitive decline. In addition, Gleevec induces formation of a specific set of APP C-terminal fragments, also observed in cells expressing the APP protective mutation and in cells exposed to a conventional BACE inhibitor. These Gleevec phenotypes require an intracellular acidic pH and are independent of tyrosine kinase inhibition, given that a related compound lacking tyrosine kinase inhibitory activity, DV2-103, exerts similar effects on APP metabolism. In addition, DV2-103 accumulates at high concentrations in the rodent brain, where it rapidly lowers Aβ levels. This study suggests that long-term treatment with drugs that indirectly modulate BACE processing of APP but spare other BACE substrates and achieve therapeutic concentrations in the brain might be effective in preventing or delaying the onset of AD and could be safer than nonselective BACE inhibitor drugs.

Cerebrospinal Fluid Biomarkers of Cognitive Decline in Parkinson's Disease.

Among the nonmotor symptoms in Parkinson's disease (PD), cognitive impairment is one of the most common and devastating. Over recent years, mild cognitive impairment (MCI) has become a recognized feature of PD (PD-MCI). The underlying mechanisms which influence onset, rate of decline, and conversion to dementia (PDD) are largely unknown. Adding to this uncertainty is the heterogeneity of cognitive domains affected. Currently there are no disease-modifying treatments that can slow or reverse this process. Identification of biomarkers that can predict rate and risk of cognitive decline is therefore an unmet need. Cerebrospinal fluid (CSF) is an ideal biomarker candidate as its constituents reflect the metabolic processes underlying the functioning of brain parenchyma. The pathological hallmark of PD is the presence of aggregated α-synuclein (α-Syn) in intracellular Lewy inclusions. In addition, there is concomitant Alzheimer's disease (AD) pathology. In AD, decreased CSF β-amyloid 1-42 (Aβ42) and increased CSF tau levels are predictive of future cognitive decline, setting a precedent for such studies to be carried out in PD. CSF studies in PD have focused on the classical AD biomarkers and α-Syn. Longitudinal studies indicate that low levels of CSF Aβ42 are predictive of cognitive decline; however, results for tau and α-Syn were not consistent. This chapter summarizes recent findings of CSF biomarker studies and cognitive dysfunction in PD.

Label‐free Electrochemical Sensor for Ex‐vivo Monitoring of Alzheimer's Disease Biomarker

AbstractThe beta‐amyloid (Aβ) peptide was used as an important biomarker for Alzheimer's disease (AD) diagnosis. The development of an accurate, selective, rapid, and highly sensitive technique for detecting of Aβ level is an important issue in biology, and medicine to assess human health risks. Here, gold nanoparticles (Au NPs) with different size were electrochemically deposited onto the indium tin oxide (ITO) substrate in the presence of different molecular weights of surfactants. The modified substrates were used as a high sensitive electrochemical sensor of in‐vitro as well as ex‐vivo monitoring of Aβ based on cyclic voltammetry and square wave voltammetry techniques. Our findings revealed that the modification of ITO electrode with Au NPs could enhance its sensor performance with high sensitivity for low concentration levels of Aβ over a wide linear range with a detection limit of about 20.7 ng/g, which is less than the concentration of insoluble Aβ40 (105.4±40.2 μg/g) in brain of AD induced. In addition, Au NPs/ITO modified electrodes have demonstrated ability to monitor Aβ in the brain extracted samples without any potential interference with other components. Raman spectroscopy has been used to confirm the presence of Aβ in the AD‐induced samples. Thus, it is applicable for analyzing ex‐vivo samples.

Performance on the Cogstate Brief Battery Is Related to Amyloid Levels and Hippocampal Volume in Very Mild Dementia.

In a group of older adults with very mild dementia, we aimed to characterize the nature and magnitude of cognitive decline as measured by the Cogstate Brief Battery, in relation to Aβ levels and hippocampal volume. Participants were characterized according to their status on the Clinical Dementia Rating (CDR) scale. A total of 308 individuals who were CDR 0 and had low cerebral Aβ levels (Aβ-), 32 individuals who were Aβ- and CDR 0.5, and 43 individuals who were Aβ+ and CDR 0.5 were included in this study. Participants completed the CogState brief battery at baseline, and at 18-, 36-, 54- and 72-month follow-up. Linear mixed model analyses indicated that relative to the Aβ- CDR 0 group, the Aβ+ CDR 0.5 group showed increased rates of memory decline and hippocampal volume loss. However, compared to the Aβ- CDR 0 group, the Aβ- CDR 0.5 group showed no changes in cognitive function or hippocampal volume over 72months. The results of this study confirm that in individuals with very mild dementia, who also have biomarker confirmation of Aβ+, changes in cognitive function manifest primarily as deterioration in memory processing, and this is associated with hippocampal volume loss. Conversely, the absence of any cognitive decline or loss in hippocampal volume in individuals with very mild dementia but who are Aβ- suggests that some other non-AD disease process may underlie any static impairment in cognitive function.

Cerebral microbleeds topography and cerebrospinal fluid biomarkers in cognitive impairment

Cerebral microbleeds, a marker of small vessel disease, are thought to be of importance in cognitive impairment. We aimed to study topographical distribution of cerebral microbleeds, and their involvement in disease pathophysiology, reflected by cerebrospinal fluid biomarkers; 1039 patients undergoing memory investigation underwent lumbar puncture and a brain magnetic resonance imaging scan. Cerebrospinal fluid samples were analyzed for amyloid β(Aβ)42, total tau(T-tau), tau phosphorylated at threonine 18(P-tau) and cerebrospinal fluid/serum albumin ratios. Magnetic resonance imaging sequences were evaluated for small vessel disease markers, including cerebral microbleeds, white matter hyperintensities and lacunes. Low Aβ42 levels were associated with lobar cerebral microbleeds in the whole cohort and Alzheimer’s disease (P < 0.001). High cerebrospinal fluid/serum albumin ratios were seen with increased number of cerebral microbleeds in the brainstem (P < 0.001). There were tendencies for increased Aβ42 levels and decreased Tau levels with deep and infratentorial cerebral microbleeds (P < 0.05). Lobar cerebral microbleeds were associated with white matter hyperintensities and lacunes (P < 0.001). Probable cerebral amyloid angiopathy-related cerebral microbleeds were associated with low Aβ42 levels and lacunes, whereas probable cerebral amyloid angiopathy-unrelated cerebral microbleeds were associated with white matter hyperintensities (P < 0.001). Our findings show that cerebral microbleed distribution is associated with different patterns of cerebrospinal fluid biomarkers, supporting different pathogenesis of deep/infratentorial and lobar cerebral microbleeds.