Impaired lipoprotein receptor-mediated peripheral binding of plasma amyloid-β is an early biomarker for mild cognitive impairment preceding Alzheimer's disease

Soluble circulating low density lipoprotein receptor-related protein-1 (sLRP) provides key plasma binding activity for Alzheimer's disease (AD) amyloid-β peptide (Aβ). sLRP normally binds 70-90% of plasma Aβ preventing free Aβ access to the brain. In AD, Aβ binding to sLRP is compromised by increased levels of oxidized sLRP which does not bind Aβ. Here, we determined plasma oxidized sLRP and Aβ40/42 sLRP-bound, other proteins-bound and free plasma fractions, cerebrospinal fluid (CSF) tau/Aβ42 ratios, and mini-mental state examination (MMSE) scores in patients with mild cognitive impairment (MCI) who progressed to AD (MCI-AD, n = 14), AD (n = 14) and neurologically healthy controls (n = 14) recruited from the G?teborg MCI study. In MCI-AD patients prior to conversion to AD and AD patients, the respective increases in oxidized sLRP and free plasma Aβ40 and Aβ42 levels were 4.9 and 3.7-fold, 1.8, and 1.7-fold and 4.3 and 3.3-fold (p < 0.05, ANOVA with Tuckey post-hoc test). In MCI-AD and AD patients increases in oxidized sLRP and free plasma Aβ40 and Aβ42 correlated with increases in CSF tau/Aβ42 ratios and reductions in MMSE scores (p < 0.05, Pearson analysis). A heterogeneous group of 'stable' MCI patients that was followed over 2-4 years (n = 24) had normal CSF tau/Aβ42 ratios but increased oxidized sLRP levels (p < 0.05, Student's t test). Data suggests that a deficient sLRP-Aβ binding might precede and correlate later in disease with an increase in the tau/Aβ42 CSF ratio and global cognitive decline in MCI individuals converting into AD, and therefore is an early biomarker for AD-type dementia.     

Evaluation of CSF biomarkers as predictors of Alzheimer's disease: a clinical follow-up study of 4.7 years

In this study, we determined the diagnostic accuracy of cerebrospinal fluid (CSF) biomarkers to predict development of Alzheimer's disease (AD) within five years in patients with mild cognitive impairment (MCI). To do so, the levels of tau, phosphorylated tau, Aβ42, Aβ40, Aβ38, sAβPPα, and sAβPPβ were analyzed in 327 CSF samples obtained at baseline from patients with AD (n = 94), MCI (n = 166), depressive disorder (n = 29), and cognitively healthy controls (n = 38). In the cohort with MCI at baseline, 33% subsequently developed AD and 16% developed other types of dementia; however, 51% were still cognitively stable after a followup of 4.7 years (range 3.0-7.2). Optimal cutoffs for each biomarker or combinations of biomarkers were defined in the AD, control, and depressive disorder groups. Several combinations resulted in sensitivity and specificity levels > 85% for differentiation of AD from controls and depressive disorder. Using the previously established cutoffs, a combination of Aβ42 and tau could predict future development of AD in MCI patients with a sensitivity of 88%, specificity 82%, positive predictive value 71%, and negative predictive value 94%. MCI patients with both low Aβ42 and high tau levels had a substantially increased risk of developing AD (OR 20; 95% CI 6-58), even after adjustment for confounding factors. Ultimately, CSF biomarkers can stratify MCI patients into those with very low or high risk for future development of AD. However, the specificities and positive predictive values are still too low to be able to diagnose AD before the patients fulfill the clinical criteria.     

Cerebrospinal fluid biomarkers and memory present distinct associations along the continuum from healthy subjects to AD patients

The objective was to study the association between cerebrospinal fluid (CSF) levels of amyloid-β (Aβ)(1-42), t-tau, and p-tau and cognitive performance along the Alzheimer's disease (AD) continuum from healthy subjects to AD patients and, specifically, among patients in the pre-dementia stage of the disease. A total of 101 subjects were studied: 19 healthy controls (CTR), 17 subjects with subjective memory complaints (SMC), 47 with mild cognitive impairment (MCI), and 18 AD patients. Only memory performance significantly correlated with CSF levels of Aβ(1-42), t-tau, and p-tau along the AD continuum. Subgroup analyses revealed that in SMC patients Aβ(1-42) levels positively correlated with the total recall score of the Free and Cued Selective Reminding Test (FCRST) (r = 0.666; p < 0.005), Digit Span (r = 0.752; p < 0.005), and CERAD world list learning (r = 0.697; p < 0.005). In MCI patients, a significant inverse correlation was found between the word list recall score from the CERAD and t-tau (r = -0.483; p < 0.005) and p-tau levels (r = -0.495; p < 0.005), as well as between the total recall subtest score from the FCRST and both t-tau (r = -0.420; p < 0.005) and p-tau levels (r = -0.422; p < 0.005). No significant correlations were found between other aspects of cognition and CSF levels in CTR or AD patients. These results indicate that memory performance is related to Aβ(1-42) levels in SMC, while it is associated with tau in the prodromal stage of the disease. This suggests that in the continuum from healthy aging to AD, memory performance is first related with Aβ(1-42) levels and then with t-tau or p-tau, before becoming independent of biomarker levels in the dementia stage.     

Value of CSF beta-amyloid1-42 and tau as predictors of Alzheimer's disease in patients with mild cognitive impairment

Subjects with mild cognitive impairment (MCI) are at a high risk of developing clinical Alzheimer's disease (AD). We asked to what extent the core biomarker candidates cerebro-spinal fluid (CSF) beta-amyloid(1-42) (Abeta(1-42)) and CSF tau protein concentrations predict conversion from MCI to AD. We studied 52 patients with MCI, 93 AD patients, and 10 healthy controls (HC). The MCI group was composed of 29 patients who had converted to AD during follow-up, and of 23 patients who showed no cognitive decline. CSF Abeta(1-42) and tau protein levels were assessed at baseline in all subjects, using enzyme-linked immunosorbent assays. For assessment of sensitivity and specificity, we used independently established reference values for CSF Abeta(1-42) and CSF tau. The levels of CSF tau were increased, whereas levels of Abeta(1-42) were decreased in MCI subjects. Abeta(1-42) predicted AD in converted MCI with a sensitivity of 59% and a specificity of 100% compared to HC. Tau yielded a greater sensitivity of 83% and a specificity of 90%. In a multiple Cox regression analysis within the MCI group, low baseline levels of Abeta(1-42), but not other predictor variables (tau protein, gender, age, apolipoprotein E epsilon4 carrier status, Mini Mental Status Examination score, observation time, antidementia therapy), correlated with conversion status (P<0.05). Our findings support the notion that CSF tau and Abeta(1-42) may be useful biomarkers in the early identification of AD in MCI subjects.     

Blood-cerebrospinal fluid barrier permeability in Alzheimer's disease

The role of blood-cerebrospinal fluid barrier (BCB) dysfunction in Alzheimer's disease (AD) has been addressed but not yet established. We evaluated the BCB integrity in 179 samples of cerebrospinal fluid (CSF) retrospectively collected from AD patients and control cases using both CSF/serum albumin ratio (QAlb) and CSF secretory Ca2+-dependent phospholipase A2 (sPLA2) activity. These analyses were supplemented with the measurement of total tau, amyloid-β1-42 (Aβ1-42), and ubiquitin CSF levels. We found that due to its higher sensitivity, CSF sPLA2 activity could 1) discriminate AD from healthy controls and 2) showed BCB impairment in neurological control cases while QAlb could not. Moreover, the CSF sPLA2 activity measurement showed that around half of the AD patients were characterized by a BCB impairment. The BCB dysfunction observed in AD was independent from Mini-Mental State Examination score as well as CSF levels of total tau, Aβ1-42, and ubiquitin. Finally, the BCB dysfunction was not limited to any of the CSF biomarkers-based previously identified subgroups of AD. These results suggest that the BCB damage occurs independent of and probably precedes both Aβ and tau pathologies in a restricted subgroup of AD patients.     

Interrelations between CSF soluble AβPPβ, amyloid-β 1-42, SORL1, and tau levels in Alzheimer's disease

Recently, light has been shed on possible interrelations between the two most important pathological hallmarks of Alzheimer's disease (AD): the amyloid cascade and axonal degeneration. In this study, we investigated associations between sβAPPβ, a product of the cleavage of the amyloid-β protein precursor (AβPP) by β-secretase, amyloid-β 1-42 (Aβ42), soluble SORL1 (also called LR11 or SORLA), a receptor that is involved in AβPP processing, and the marker of axonal degeneration tau in the cerebrospinal fluid (CSF) of 76 patients with mild cognitive impairment (MCI), 61 patients with AD, and 17 patients with frontotemporal dementia, which neuropathologically is not related to the amyloid pathology. In the AD group, significant associations between sAβPPβ, tau (p < 0.001), and soluble SORL1 (p < 0.001) were detected according to linear regression models. In patients with MCI, sAβPPβ correlated significantly with tau (p < 0.001) and soluble SORL1 (p = 0.003). In the FTD group, only SORL1 (p = 0.011) was associated with sAβPPβ and not tau. Aβ42 was found to be significantly related to tau levels in CSF in the MCI group (p < 0.001) and they tended to be associated in the AD group (p = 0.05). Our results provide further evidence for a link between the two facets of AD pathology, which is likely to be mediated by the binding of Aβ oligomers to specifically targeted neurons, resulting in stimulating tau hyperphosphorylation and neurodegeneration.     

CSF levels of heart fatty acid binding protein are altered during early phases of Alzheimer's disease

Heart fatty acid binding protein (HFABP) has been proposed as a putative marker for dementia disorders. To evaluate the value of this protein as an early marker of Alzheimer's disease (AD), we analyzed HFABP level and the classical biomarkers amyloid-β (Aβ)1-42, total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF) of patients with mild cognitive impairment (MCI) followed up for four years (n=41), AD (n=32), and subjects with other neurological diseases without dementia (OND, n=25). HFABP levels were higher in AD patients and in MCI converting to AD (MCI-AD) with respect to OND and to cognitively stable MCI patients (MCI-MCI). The receiver operator characteristics analysis for HFABP alone showed a sensitivity of 87% and a specificity of 81% for AD versus OND (area under the curve, AUC=0.83); sensitivity and specificity were 46% and 94%, respectively, when comparing MCI-MCI versus MCI-AD. CSF HFABP levels showed a strong positive correlation with both t-tau and p-tau. Interestingly, the ratio between HFABP and Aβ1-42 improved the performance in distinguishing AD from OND (sensitivity: 90%; specificity 82%, AUC=0.89), and gave the best accuracy in discriminating MCI-AD from MCI-MCI (sensitivity: 80%; specificity 100%, AUC=0.90). Survival analysis by means of Kaplan-Meier curve showed a significantly higher proportion of MCI patients converting to AD in the group with higher values of HFABP/Aβ1-42 ratio (cut-off=0.7). A significant correlation between HFABP/Aβ1-42 ratio and MMSE annual decrease rate was also documented (p<0.0001). HFABP /Aβ1-42 ratio might be a useful predictor of conversion in MCI patients.     

Cystatin C and cathepsin B in CSF from patients with inflammatory neurologic diseases

BACKGROUND: In CSF, proteolytic enzymes are believed to have crucial roles in the initiation and progression of inflammatory neurologic diseases (IND). Cystatin C, a major cysteine protease inhibitor in CSF, is tightly bound to cathepsin B and H. OBJECTIVE: To determine if cystatin C is involved in the disease process of IND, the authors measured the cystatin C concentration by ELISA method and cathepsin B and H activities in the CSF of patients with acute IND. METHODS: Cystatin C concentration and cathepsin B and H activities were measured in CSF samples taken from patients during the acute phase of their disease. Subjects studied were 8 patients with Guillain-Barré syndrome (GBS), 5 with chronic inflammatory demyelinating polyneuropathy (CIDP), 12 with MS, 16 with aseptic meningitis, 15 with neurodegenerative diseases as disease controls, and 35 healthy controls. RESULTS: A significant decrease in CSF cystatin C level was seen in the patients with GBS, CIDP, and MS compared to the control subjects. High cathepsin B activity, but not cathepsin H activity, was also observed in the patients with GBS, CIDP, and MS. CONCLUSION: Cystatin C levels in CSF measured by ELISA may help the physician recognize GBS, CIDP, and MS. Decreased levels of cystatin C may be related to the high levels of cathepsin B activity seen in the CSF of patients with GBS, CIDP, and MS.     

The neurofilament heavy chain (NfH) in the cerebrospinal fluid diagnosis of Alzheimer's disease

BACKGROUND/AIMS: Attempting to improve the cerebrospinal fluid (CSF) diagnosis of Alzheimer's disease (AD), the neurofilament heavy chain isoform, NfH(SMI35) was compared to other CSF markers [total tau, phospho-tau, amyloid beta 1-42 (Abeta42), the ratio of amyloid beta fragments Abeta42/Abeta40 (Abeta ratio)]. METHODS: CSF levels were determined in patients with AD (n = 109), mild cognitive impairment (MCI, n = 25), frontotemporal dementia (n = 15), vascular dementia (VD, n = 41), and controls (n = 58). RESULTS: CSF NfH(SMI35) was elevated in AD and VD as compared to controls (p < 0.05). Total tau was higher in AD as compared to controls (p < 0.05). CSF phospho-tau was elevated in AD as compared to controls and VD (p < 0.05 each). CSF Abeta42 and Abeta ratios in AD were lower than in MCI and controls (p < 0.05 each). CONCLUSION: The diagnostic potential of NfH(SMI35) is not superior to that of other CSF markers.     

Intrathecal inflammation precedes development of Alzheimer's disease

OBJECTIVES: To analyse the cerebrospinal fluid (CSF) values of the proinflammatory cytokines, interleukin 1beta (IL1beta), tumour necrosis factor alpha (TNFalpha), GM-CSF, of the anti-inflammatory cytokine TGFbeta, of tau protein, a marker for neurodegeneration, and of beta amyloid (Abeta), a protein involved in the formation of senile plaques, in prospectively followed up patients with mild cognitive impairment (MCI). METHODS: Analyses of CSF levels of TNFalpha, IL1beta, GM-CSF, TGFbeta, betaa, and tau protein were performed using ELISA in 56 patients with MCI who were followed up prospectively and in 25 age matched, healthy controls. RESULTS: Patients with MCI displayed significantly higher levels of TNFalpha and tau protein and significantly lower levels of TGFbeta and Abeta compared with the healthy controls. After nine months of follow up, 25 patients still displayed MCI while the remaining 31 patients had progressed to Alzheimer's disease (AD). Only MCI patients who progressed to AD at follow up, showed significantly higher CSF levels of TNFalpha than controls. In addition, reduced CSF-Abeta42 levels were only found in MCI patients that progressed to AD, further supporting the notion that disturbed metabolism of Abeta is an early finding in AD. CONCLUSIONS: These results demonstrate increased production of the proinflammatory cytokine, TNFalpha and decreased production of the anti-inflammatory cytokine TGFbeta in patients with MCI at risk to develop AD, suggesting a propensity towards inflammation in this patient group and indicating that CNS inflammation is a early hallmark in the pathogenesis of AD.     

Levels of beta-secretase (BACE1) in cerebrospinal fluid as a predictor of risk in mild cognitive impairment

CONTEXT: Elevated beta-secretase (beta-site amyloid precursor protein-cleaving enzyme 1 [BACE1]) activity has been found in the brains of patients with sporadic Alzheimer disease (AD) compared with controls. Now we are particularly interested in whether BACE1 can be identified in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment (MCI), a population at high risk for AD. The possible presence of BACE1 in the CSF of patients with AD and MCI has so far gone unreported. OBJECTIVE: To examine whether BACE1 can be identified in the CSF of patients with MCI. DESIGN: We evaluated CSF BACE1 levels using 2 sandwich enzyme-linked immunosorbent assays, BACE1 enzymatic activities by means of synthetic fluorescence substrate, and total amyloid-beta peptide levels using a sandwich enzyme-linked immunosorbent assay. SETTING: Two independent research centers. PARTICIPANTS: Eighty patients with sporadic AD, 59 patients with MCI, and 69 controls. MAIN OUTCOME MEASURES: BACE1 levels and enzymatic activities and amyloid-beta peptide levels. RESULTS: Increased CSF levels of BACE1 protein were associated with increased risk ratios (RRs) for patients with MCI compared with controls (RR, 2.08; 95% confidence interval [CI], 1.58-2.58) and patients with AD (RR, 1.65; 95% CI, 1.19-2.03). Similarly, patients with MCI showed increased levels of BACE1 activity compared with controls (RR, 2.17; 95% CI, 1.66-2.71) and patients with AD (RR, 3.71; 95% CI, 2.74-4.36). For total amyloid-beta peptide and tau, increased CSF levels were associated with a higher risk of MCI compared with controls. The BACE1 activity was significantly correlated with BACE1 protein level (rho = 0.23; P<.001) and amyloid-beta peptide level (rho = 0.39; P<.001), with amyloid-beta peptide correlated with BACE1 protein level (rho = 0.30; P<.001). CONCLUSION: Significant elevation of BACE1 levels and activity in CSF is an indicator of MCI, which could be an early stage of AD.     

Salivary tau species are potential biomarkers of Alzheimer's disease

Phosphorylation of tau protein is a critical event in the pathogenesis of Alzheimer's disease (AD). Increased phosphorylated tau and total tau levels, combined with reduced concentrations of amyloid-β 1-42 (Aβ42) in cerebrospinal fluid (CSF), but not in plasma or serum, have been generally accepted as sensitive AD diagnostic markers. However, obtaining CSF is a relatively invasive procedure that requires participation of specially trained medical professionals, i.e., CSF is not an ideal sample source for screening or early diagnosis of AD, which is essential to current and future neuroprotective treatments for the disease. Here, we identified tau, but not Aβ species, with mass spectrometry in human saliva, a body fluid that is much more accessible compared to CSF or even blood. Quantitative assessment of salivary levels of total tau, phosphorylated tau, and Aβ42 using highly sensitive Luminex assays revealed that, while Aβ42 was not detectable, the phosphorylated tau/tau ratio significantly increased in patients with AD compared to healthy controls. These results suggest that salivary tau species could be ideal biomarkers for AD diagnosis, especially at early stages of the disease or even screening asymptomatic subjects, allowing for a much larger therapeutic window for AD patients.     

Cerebrospinal fluid biomarkers for Alzheimer’s disease: diagnostic performance in a homogeneous mono-center population

The cerebrospinal fluid (CSF) biomarkers amyloid-β (Aβ)(1-42), T-tau, and P-tau have good diagnostic accuracy for clinically diagnosed Alzheimer’s disease (AD). However, in multi-center studies, the predictive values of the CSF biomarkers have been lower, possibly due to differences in procedures for lumbar puncture and CSF handling and storage, and to differences in patient populations, clinical evaluations, and diagnostic procedures. Here we investigate the diagnostic accuracy of CSF biomarkers in a well defined homogeneous mono-center population. We also evaluate an extended panel of amyloid related biomarkers. Sixty consecutive patients admitted for cognitive impairment to a memory clinic were recruited. The participants included patients with AD or mild cognitive impairment (MCI) diagnosed with AD upon follow-up (n = 32), patients with stable MCI (n = 13), patients with other dementias diagnosed at primary evaluation or upon follow-up (n = 15), and healthy controls(n = 20). CSF was analyzed for Aβ(1-42), T-tau, and P-tau, and PA(X-38), Aβ(X-40), Aβ(X-42), sAβPPα, and sAβPPβ. In multivariate analysis, thecore biomarkers Aβ(1-42), T-tau, and P-tau demonstrated a high ability to diagnose AD versus the combined groups of controls and stable MCI, with an area under the receiver operating characteristic curve (AUROC) of 0.97 (95% CI 0.93–1.00, p < 0.0001). The additional biomarkers only marginally increased AUROC to 0.98 (95% CI 0.95–1.00, p < 0.0001), this increase mainly mediated by Aβ(X-42). In conclusion, CSF biomarkers Aβ(1-42), T-tau, and P-tau have very high diagnostic accuracy in a well defined cohort of untreated patients, demonstrating the excellent potency of CSF biomarkers to identify pathological processes in AD when astringent analytical protocol is used.     

Biomarker profiles and their relation to clinical variables in mild cognitive impairment

The aim of the study was to compare clinical variables between MCI patients at different risk for Alzheimer’s disease (AD) according to their biomarker profile. Fifty-four percent out of 39 MCI patients had a low Aβ42 and high tau in cerebrospinal fluid (CSF) (high-risk), 26% either a low CSF Aβ42 or high CSF tau (intermediate-risk) and 20% a normal CSF Aβ42 and tau (low-risk). Both high- and intermediate-risk subjects differed from the low-risk group in episodic memory, executive functions and the preclinical AD scale (PAS), which combines a set of clinical parameters. Subjects at high risk did not differ from subjects with an intermediate risk. Aβ42 levels correlated with the MTA and PAS scores, tau levels with episodic memory. These correlations suggest that the biomarkers are not independent when compared to the other AD markers. Longitudinal studies are necessary to interpret the correlations between biomarkers, imaging, and neuropsychological markers.     

Performance of aβ1-40, aβ1-42, total tau, and phosphorylated tau as predictors of dementia in a cohort of patients with mild cognitive impairment

Mild cognitive impairment (MCI) is a common condition in the elderly which may remain stable along time (MCI-MCI) or evolve into Alzheimer's disease (MCI-AD) or other dementias. Cerebrospinal fluid (CSF) classical biomarkers, i.e., amyloid-β 1-42 (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) reflect the neuropathological changes taking place in AD brains, thus disclosing the disease in its prodromal phase. With the aim to evaluate the power of each biomarker and/or their combination in predicting AD progression, we have measured CSF Aβ1-40, Aβ1-42, t-tau, and p-tau in patients with AD, MCI-MCI, MCI-AD, and other neurological diseases without dementia (OND) followed up for four years. Aβ1-42 levels were significantly lower in AD and MCI-AD than in MCI-MCI. T-tau and p-tau levels were significantly increased in AD and MCI-AD versus OND and MCI-MCI. The Aβ1-42/Aβ1-40 ratio showed a significant decrease in AD and MCI-AD as compared to MCI-MCI. Both Aβ1-42/t-tau and Aβ1-42/p-tau ratios showed significantly decreased values in AD and MCI-AD with respect to OND and MCI-MCI. Aβ1-42/p-tau ratio was the best parameter for discriminating MCI-AD from MCI-MCI (sensitivity 81%, specificity 95%), being also correlated with the annual change rate in the Mini Mental State Examination annual change rate score (MMSE-ACR, rS = -0.71, p < 0.0001). Survival analysis showed that 81% of MCI with a low Aβ1-42/p-tau ratio (<1372) progressed to AD. The best model of logistic regression analysis retained Aβ1-42 and p-tau (sensitivity 75%, 95%CI: 70-80%; specificity 96%, 95%CI: 94-98%). We can conclude that Aβ1-42 and p-tau reliably predict conversion to AD in MCI patients.     

Combined Plasma Biomarkers for Diagnosing Mild Cognition Impairment and Alzheimer’s Disease

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Longitudinal changes of CSF biomarkers in Alzheimer's disease

Longitudinal changes of cerebrospinal fluid (CSF) biomarkers in Alzheimer's disease (AD) have been studied, but there are few consistent conclusions and even less is known about their variation during the different stages of the disease. We hypothesized that changes in CSF biomarker values would correlate with the progression of the cognitive decline in AD. One hundred and thirty-one memory clinic patients [56 AD, 57 mild cognitive impairment (MCI), 10 other neurological disorders, eight unimpaired subjects] underwent a clinical follow-up with repeated Mini-Mental Status Examination (MMSE) tests and two lumbar punctures with a median interval of 3 years. Levels of CSF amyloid-β (Aβ)(42), tau, and p-tau-181 were measured using commercially available ELISA. Twenty-one of the MCI subjects progressed to AD, whereas 26 subjects remained stable and 56 subjects had AD already at the baseline. The subjects displaying the most rapid MMSE decline rate had the lowest baseline Aβ(42), highest tau, and highest p-tau-181 CSF concentrations. An annual decrease of 2.20 pg/ml/year in the CSF p-tau-181 concentration was seen in AD-AD patients (p = 0.001). The difference was significant compared to stable MCI-MCI (increase of 1.24 pg/ml/year, p = 0.001) and cognitively healthy (increase of 0.84 pg/ml/year, p = 0.013) subjects (p for group difference 0.004). The decrease rate of p-tau-181 correlated with the MMSE decrease rate in AD subjects (r = 0.579, p < 0.001). The CSF Aβ(42) level decreased in the AD-AD group (decrease 11.9 pg/ml/year, p < 0.001). Concentrations of hyperphosphorylated tau decline in the late stages of the AD process. The decrease of p-tau-181 appears to correlate with cognitive functioning and probably reflects neuronal loss. More longitudinal studies of CSF biomarker dynamics are needed, especially in patients during the preclinical stage of the disease.     

Cerebrospinal fluid Aβ42 is the best predictor of clinical progression in patients with subjective complaints

BackgroundThe need to recognize Alzheimer’s disease (AD) as early as possible led us to evaluate the predictive value of amyloid β(1-42) (Aβ42), total tau (tau), and phosphorylated tau (ptau) in cerebrospinal fluid (CSF) for clinical progression in patients with subjective complaints.MethodsWe recruited nondemented patients with subjective complaints (i.e., criteria for mild cognitive impairment [MCI] not fulfilled) from our memory clinic. We assessed the predictive value of CSF Aβ42, tau, and ptau for clinical progression using Cox proportional hazards models adjusted for age, gender, and baseline findings on the Mini-Mental State Examination (MMSE). Clinical progression was defined as progression to MCI or AD.ResultsWe included 127 patients with subjective complaints (age 60 ± 10 years, 61 [48%] females, MMSE 29 ± 1). At baseline, Aβ42 and tau were abnormal in 20 patients (both 16%), and ptau in 32 patients (25%). Thirteen patients (10%) progressed to MCI (n = 11) or AD (n = 2). Aβ42 was the strongest predictor of progression to MCI or AD with an adjusted hazard ratio (HR) of 16.0 (3.8–66.4). The adjusted HR associated with tau was 2.8 (0.9–9.2) and with ptau 2.6 (0.8–8.2). Combinations of biomarkers had a lower predictive value than Aβ42 alone.ConclusionLow Aβ42 was the strongest predictor of clinical progression in patients with subjective complaints. These results are in line with the hypothesis that the cascade of pathologic events starts with deposition of Aβ42, whereas neuronal degeneration and hyperphosphorylation of tau are more downstream events, closer to clinical manifestation of AD.     

Basic and Clinical Studies on the Measurement of β-amyloid(1–42) in Cerebrospinal Fluid as a Diagnostic Marker for Alzheimer's Disease and Related Disorders: Multi Center Study in Japan

Background : The development of diagnostic markers for earlier and more accurate clinical diagnosis of Alzheimer's disease (AD) is essential to identify unequivocally AD patients during life. This study is to investigate the basic performance and clinical significance of β‐amyloid_(1–42) (Aβ₄₂) level measurement in cerebrospinal fluid (CSF) alone or in combination with CSF tau for distinguishing AD from non‐AD disorders. Methods : The basic characteristics of the reagent for measuring Aβ₄₂, which used Sandwich ELISA, was examined. The clinical studies were done at 5 centers in Japan. CSF samples from 353 patients were collected and classified into the following six groups; AD (n=189), Mild Cognitive Impairment (MCI: n=25), Neurodegenerative disorders without AD (ND: n=66), Cerebrovascular disturbance (CVD: n=28), Other neurological disorders (OND: n=18) and Neurological control (NC: n=27) group. Results : Mean levels of Aβ₄₂ in CSF were significantly lower in AD (395 pg/mL) than MCI (586 pg/mL;p<0.001), ND (530 pg/mL; p<0.001), CVD (504 pg/mL; p<0.001) and NC (605 pg/mL; p<0.001), respectively. Mean levels of AD unit (tau/Aβ₄₂) were significantly higher in AD (1.63) than MCI (0.79; p<0.001), ND (0.56; p<0.001), CVD (0.34; p<0.001) and NC (0.19; p<0.001), respectively. Discrimination of AD from other related disorders was significantly improved by the combined assessment of Aβ₄₂ and tau. When the cut‐off level of an AD unit was 0.67, the sensitivity for AD was 80% and the specificity for other related disorders was 86%. The positive rate (AD unit>0.67) of MCI patients who had progressed to AD within a few years was 79% (15/19). Conclusion : The combined measurement of CSF Aβ₄₂ and tau is clinically a useful diagnostic marker to discriminate AD at an early stage including MCI from normal aging and other related disorders.     

Factors affecting A�� plasma levels and their utility as biomarkers in ADNI

Previous studies of Aβ plasma as a biomarker for Alzheimer's disease (AD) obtained conflicting results. We here included 715 subjects with baseline Aβ(1-40) and Aβ(1-42) plasma measurement (50% with 4 serial annual measurements): 205 cognitively normal controls (CN), 348 patients mild cognitive impairment (MCI) and 162 with AD. We assessed the factors that modified their concentrations and correlated these values with PIB PET, MRI and tau and Aβ(1-42) measures in cerebrospinal fluid (CSF). Association between Aβ and diagnosis (baseline and prospective) was assessed. A number of health conditions were associated with altered concentrations of plasma Aβ. The effect of age differed according to AD stage. Plasma Aβ(1-42) showed mild correlation with other biomarkers of Aβ pathology and were associated with infarctions in MRI. Longitudinal measurements of Aβ(1-40) and Aβ(1-42) plasma levels showed modest value as a prognostic factor for clinical progression. Our longitudinal study of complementary measures of Aβ pathology (PIB, CSF and plasma Aβ) and other biomarkers in a cohort with an extensive neuropsychological battery is significant because it shows that plasma Aβ measurements have limited value for disease classification and modest value as prognostic factors over the 3-year follow-up. However, with longer follow-up, within subject plasma Aβ measurements could be used as a simple and minimally invasive screen to identify those at increased risk for AD. Our study emphasizes the need for a better understanding of the biology and dynamics of plasma Aβ as well as the need for longer term studies to determine the clinical utility of measuring plasma Aβ.