Evaluation of plasma Abeta(40) and Abeta(42) as predictors of conversion to Alzheimer's disease in patients with mild cognitive impairment

Numerous studies have shown a marked decrease of beta-amyloid(42) (Abeta(42)) in the cerebrospinal fluid (CSF) of patients with incipient Alzheimer's disease (AD). However, studies on Abeta in plasma are contradictory, and show very marginal differences between patients and controls. Here, we analyzed plasma samples using a new multiplex immunoassay for simultaneous analysis of Abeta(1-40), Abeta(n-40), Abeta(1-42), and Abeta(n-42). The plasma samples were obtained at baseline from two independent cohorts of patients with mild cognitive impairment (MCI) and age-matched controls. In the first cohort, 41% of the 117 MCI cases converted to AD during a clinical follow-up period of 4-7 years. In the second cohort, 14% of the 110 MCI subjects developed AD during a clinical follow-up period of 2-4 years. None of the plasma Abeta isoforms differed between MCI patients that subsequently developed AD and healthy controls or stable MCI patients. The Cox proportional hazards model did not reveal any differences in the probability of progression from MCI to AD related to plasma Abeta levels. In contrast, low levels of Abeta(1-42) in CSF were strongly associated with increased risk of future AD. The absence of a change in plasma Abeta in incipient AD, despite the marked change in CSF, may be explained by the lack of a correlation between the levels of Abeta(1-42) in CSF and plasma. In conclusion, the results show that CSF biomarkers are better predictors of progression to AD than plasma Abeta isoforms.     

Plasma levels of beta-amyloid (1-42) in Alzheimer's disease and mild cognitive impairment

We compared plasma levels of beta-amyloid 1-42 (pg/ml) found for 146 sporadic Alzheimer (AD) patients, 89 subjects with mild cognitive impairment (MCI) and 89 age-matched controls (CT). AD patients had significantly lower levels (38, 54, 52; p<0.01), unrelated to severity of the disease as assessed by MMSE score, age, sex or APOE4 status. Twenty cases investigated at two time points 18 months apart did not demonstrate further decreases. Thus, the reduction in beta-amyloid 1-42 may be a marker for AD status, specifically, a transition from normal status or MCI to AD, rather than a marker for neurodegenerative processes occurring in the disease.     

The normal equilibrium between CSF and plasma amyloid beta levels is disrupted in Alzheimer's disease

Amyloid-beta (Abeta) with 40 (Abeta40) and 42 (Abeta42) amino acids, the main components of amyloid plaques in the Alzheimer's disease (AD) brain, can be measured in human cerebrospinal fluid (CSF) and plasma. Whereas CSF Abeta42 is decreased in AD, some studies have reported changed plasma Abeta levels in AD and in subjects with mild cognitive impairment (MCI). To this date it is unclear if and how CSF and plasma levels of Abeta correlate with each other in healthy individuals, albeit earlier studies on AD patients found no correlation between CSF and plasma Abeta. We have measured Abeta40 and Abeta42 in paired CSF and plasma samples from patients with AD (n=39), MCI (n=29) and healthy control subjects (n=18). We observed a clear correlation between CSF and plasma levels for both Abeta40 and Abeta42 in healthy individuals, whereas no such correlation could be seen for AD or MCI cases. Similarly to other studies we also found low levels of Abeta42 in AD CSF, whereas there were no significant differences in plasma Abeta levels between the diagnostic groups. Our findings suggest that the normal equilibrium between CSF and plasma Abeta may be disrupted with the initiation of amyloid deposition in the brain.     

Elevated plasma levels of soluble CD40 in incipient Alzheimer's disease

CD40 is a member of the tumor necrosis factor receptor super-family and has been suggested to play a role in the metabolism of beta-amyloid (Abeta) in Alzheimer's disease (AD). However, the role of CD40-signalling in incipient AD has not yet been studied. We investigated the plasma levels of soluble CD40 (sCD40) and the soluble CD40 ligand (sCD40L) at baseline in 136 subjects with mild cognitive impairment (MCI) and 30 age-matched controls. Sixty of the 136 MCI cases converted to AD (MCI-AD) during a clinical follow-up period of 4-7 years. The baseline levels of sCD40, but not sCD40L, were elevated in MCI-AD cases when compared to age-matched controls (Mann-Whitney U-test, p=0.02). However, MCI patients who were cognitively stable or developed vascular dementia during follow-up did not have significantly increased levels of sCD40 or sCD40L when compared to controls. The levels of sCD40 correlated to decreased baseline performance on mini-mental state examination (MMSE) in both controls (r(s)=-0.37, p<0.05) and MCI-AD cases (r(s)=-0.29, p<0.05). Finally, the plasma levels of sCD40 correlated with the levels of soluble amyloid precursor protein-alpha (sAPP-alpha) (r(s)=0.28, p<0.01) and sAPP-beta (r(s)=0.23, p<0.05) in cerebrospinal fluid. In conclusion, CD40-signalling might play a role in the pathogenesis of early AD.     

Increased levels of CSF phosphorylated tau in apolipoprotein E epsilon4 carriers with mild cognitive impairment

We investigated the correlation between the apolipoprotein E varepsilon4 allele (apoE epsilon4) carrier status, a major risk factor of Alzheimer's disease (AD), and levels of tau protein phosphorylated at threonine 231 (P-tau(231P)) in cerebrospinal fluid (CSF) in predementia and clinical stages of AD and healthy controls (HC). Thirty-one subjects with mild cognitive impairment (MCI) who had converted to AD during follow-up were included, as well as 71 AD patients, and 29 HC subjects. In MCI, but not in AD and HC, CSF P-tau(231P) levels were significantly higher in apoE epsilon4 carriers compared to non-carriers (p<0.001). Controlling for disease duration, the apoE epsilon4 effect on P-tau(231P) remained significant. Our study indicates that the apoE epsilon4 carrier status should be considered when CSF P-tau(231P) is evaluated as biomarker candidate of AD in MCI subjects.     

Quantitative electroencephalography in mild cognitive impairment: longitudinal changes and possible prediction of Alzheimer's disease

The present study evaluated the clinical course of patients with mild cognitive impairment (MCI), the pattern of electroencephalography (EEG) changes following cognitive deterioration, as well as the potential of neurophysiological measures in predicting dementia. Twenty-seven subjects with MCI were followed for a mean follow up period of 21 months. Fourteen subjects (52%) progressed (P MCI) to clinically manifest Alzheimer's disease (AD), and 13 (48%) remained stable (S MCI). The two MCI subgroups did not differ in baseline EEG measures between each other and the healthy controls (n = 16), but had significantly lower theta relative power at left temporal, temporo-occipital, centro-parietal, and right temporo-occipital derivation when compared to the reference AD group (n = 15). The P MCI baseline alpha band temporo-parietal coherence, alpha relative power values at left temporal and temporo-occipital derivations, theta relative power values at frontal derivations, and the mean frequency at centro-parietal and temporo-occipital derivations overlapped with those for AD and control groups. After the follow-up, the P MCI patients had significantly higher theta relative power and lower beta relative power and mean frequency at the temporal and temporo-occipital derivations. A logistic regression model of baseline EEG values adjusted for baseline Mini-Mental Test Examination showed that the important predictors were alpha and theta relative power and mean frequency from left temporo-occipital derivation (T5-O1), which classified 85% of MCI subjects correctly.     

Combination of plasma biomarkers and clinical data for the detection of sporadic Alzheimer's disease

Amyloid β and alpha 1-antichymotrypsin (ACT) play an important role in the pathogenesis of sporadic Alzheimer's disease (AD). The present study was to investigate whether a combination of plasma biomarkers and clinical data would discriminate AD from vascular dementia, other neurodegenerative dementia and non-demented controls. The study included 112 patients with AD, 85 patients with vascular dementia, 30 patients with other neurodegenerative dementia and 116 age-matched, non-demented controls. Although ACT, Aβ42 and the ratio of Aβ42/Aβ40 had significant differences between AD, vascular dementia, other neurodegenerative dementia and non-demented controls (P<0.001), none of them reached the sensitivity and specificity required for AD biomarkers. The combination of biomarkers and clinical data had higher discriminating power than either alone. Our results indicated that plasma biomarkers of ACT and the ratio of Aβ42/Aβ40 could discriminate AD from non-demented controls, vascular dementia, or other neurodegenerative dementias with higher diagnostic accuracy than clinical data and that if plasma biomarkers were combined with clinical data, the discriminating power was enhanced.     

Homocysteine and electroencephalographic rhythms in Alzheimer disease: a multicentric study

High plasma concentration of homocysteine is an independent risk factor for Alzheimer’s disease (AD), due to microvascular impairment and consequent neural loss [Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D’Agostino RB, Wilson PW, Wolf PA (2002) Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med 346(7):476–483]. Is high plasma homocysteine level related to slow electroencephalographic (EEG) rhythms in awake resting AD subjects, as a reflection of known relationships between cortical neural loss and these rhythms? To test this hypothesis, we enrolled 34 mild AD patients and 34 subjects with mild cognitive impairment (MCI). Enrolled people were then subdivided into four sub-groups of 17 persons: MCI and AD subjects with low homocysteine level (MCI− and AD−, homocysteine level <11 μmol/l); MCI and AD subjects with high homocysteine level (MCI+ and AD+, homocysteine level ≥11 μmol/l). Resting eyes-closed EEG data were recorded. EEG rhythms of interest were delta (2–4 Hz), theta (4–8 Hz), alpha 1 (8–10.5 Hz), alpha 2 (10.5–13 Hz), beta 1 (13–20 Hz), and beta 2 (20–30 Hz). EEG cortical sources were estimated by low-resolution brain electromagnetic tomography (LORETA). Results showed that delta (frontal and temporal), theta (central, frontal, parietal, occipital, and temporal), alpha 1 (parietal, occipital, and temporal), and alpha 2 (parietal and occipital) sources were stronger in magnitude in AD+ than AD− group. Instead, no difference was found between MCI− and MCI+ groups. In conclusion, high plasma homocysteine level is related to unselective increment of cortical delta, theta, and alpha rhythms in mild AD, thus unveiling possible relationships among that level, microvascular concomitants of advanced neurodegenerative processes, and synchronization mechanisms generating EEG rhythms.     

Reduced hippocampal glutamate in Alzheimer disease

Altered neurometabolic profiles have been detected in Alzheimer disease (AD) using ¹H magnetic resonance spectroscopy (MRS), but no definitive biomarker of mild cognitive impairment (MCI) or AD has been established. This study used MRS to compare hippocampal metabolite levels between normal elderly controls (NEC) and subjects with MCI and AD. Short echo-time (TE = 46 ms) ¹H spectra were acquired at 4 T from the right hippocampus of 23 subjects with AD, 12 subjects with MCI and 15 NEC. Absolute metabolite levels and metabolite ratios were compared between groups using a multivariate analysis of covariance (covariates: age, sex) followed by post hoc Tukey's test (p < 0.05 significant). Subjects with AD had decreased glutamate (Glu) as well as decreased Glu/creatine (Cr), Glu/myo-inositol (mI), Glu/N-acetylaspartate (NAA), and NAA/Cr ratios compared to NEC. Subjects with AD also had decreased Glu/mI ratio compared to MCI. There were no differences between subjects with MCI and NEC. Therefore, in addition to NAA/Cr, decreased hippocampal Glu may be an indicator of AD.     

Plasma antioxidants are similarly depleted in mild cognitive impairment and in Alzheimer's disease

In order to assess peripheral levels and activities of a broad spectrum of non-enzymatic and enzymatic antioxidants in elderly subjects with mild cognitive impairment (MCI) and Alzheimer's disease (AD), plasma levels of water-soluble (Vitamin C and uric acid) and of lipophilic (Vitamin A, Vitamin E and carotenoids including lutein, zeaxanthin, beta-cryptoxanthin, lycopene, alpha- and beta-carotene) antioxidant micronutrients as well as activities of plasma and red blood cell (RBC) superoxide dismutase (SOD) and of plasma glutathione peroxidase (GPx) were measured in 25 patients with MCI, 63 AD patients and 53 controls. Peripheral levels and activities of antioxidants were similarly lower in MCI and AD patients as compared to controls. As MCI may represent a prodromal stage of AD, and oxidative damage appears to occur as one of the earliest pathophysiological events in AD, an increased intake of antioxidants in patients with MCI could be helpful in lowering the risk of conversion to dementia.     

CSF cortisol in Alzheimer's disease and mild cognitive impairment

Hypercortisolaemia occurs in Alzheimer's disease (AD) and may be involved in the AD related neurodegenerative process. In order to determine whether brain structures are exposed to high cortisol concentrations early in AD, we measured cerebrospinal fluid (CSF) cortisol in 66 subjects with AD, 33 subjects with mild cognitive impairment (MCI) and 34 control subjects. CSF cortisol concentrations were higher in AD subjects compared to controls (p<0.001) and to MCI subjects (p=0.002). There was no significant increase of cortisol in MCI subjects compared with controls suggesting that the increase of CSF cortisol is not an early event in the course of AD.     

Conversion from cognitive health to mild cognitive impairment and Alzheimer's disease: prediction by plasma amyloid beta 42, medial temporal lobe atrophy and homocysteine

The changes of plasma amyloid beta (Abeta42) protein, homocysteine and medial temporal lobe atrophy (MTA) were studied by the transition from cognitive health to mild cognitive impairment (MCI) and to Alzheimer's disease (AD) in a prospective cohort of individuals aged 75 years. MTA but not plasma Abeta42 measured at baseline predicted which persons remained cognitively healthy (CH) and who developed AD 2.5 years later. The increase of plasma Abeta42 over time significantly distinguished between persons who remained CH on the one hand and MCI converters and AD converters out of cognitive health on the other (CH-to-MCI and CH-to-AD converters). Although both groups showed similar increase of Abeta42 levels, CH-to-AD converters had a higher increase of homocysteine compared to CH-to-MCI converters or to persons remaining CH. In comparison to all cognitive subgroups, the AD converters from MCI at baseline showed the smallest increase of Abeta42 levels and rather no increase of homocysteine. In logistic regression analysis, the increase of plasma Abeta42 but not change of MTA significantly predicted the conversion from CH to MCI, and changes of MTA and homocysteine but not of plasma Abeta42 predicted the conversion from CH to AD. The increase of plasma Abeta42 correctly allocated CH-to-MCI and CH-to-AD converters with low (63%) specificity (for both) and low (60%) sensitivity (54% for AD group). These results indicate that (1) plasma Abeta42 alone is not suitable as a biomarker for AD, (2) in the course of cognitive deterioration of the AD-type the increase of plasma Abeta42 seems to be an initial event, (3) similar to cerebrospinal fluid, changes of plasma Abeta42 may reflect the transition from cognitive health to AD, and (4) whether persons with MCI develop AD may depend on an accumulation of further toxic metabolites such as homocysteine.     

Changes in the levels of plasma soluble fractalkine in patients with mild cognitive impairment and Alzheimer's disease

Soluble fractalkine plays a distinctive role in the inflammatory processes of the nervous system; however, the role of soluble fractalkine in Alzheimer's disease (AD) has not yet been investigated. In the present study, we evaluated the levels of plasma soluble fractalkine in patients with mild cognitive impairment (MCI), patients with AD and healthy controls. We also investigated the changes in the levels of plasma soluble fractalkine in patients with AD. A total of 102 patients with cognitive impairment, including 51 patients with MCI, 51 patients with AD, and 57 healthy control subjects, were enrolled in this study. The Mini-Mental Status Examination (MMSE) was used to evaluate the severity of cognitive impairment in patients with MCI and AD. The levels of plasma soluble fractalkine were measured using a specific enzyme-linked immunosorbent assay. There were significant group differences in the levels of plasma soluble fractalkine between the MCI, AD, and control groups. Post hoc analyses revealed significant differences between the MCI and control groups, the AD and control groups, and the MCI and AD groups. The level of plasma soluble fractalkine was significantly greater in the patients with mild to moderate AD than in the patients with severe AD. In addition, there was a positive correlation between MMSE score and plasma soluble fractalkine level in the patients with AD. This study provides preliminary evidence that soluble fractalkine is involved in the pathogenesis of AD.     

Directionality of EEG synchronization in Alzheimer's disease subjects

Is directionality of electroencephalographic (EEG) synchronization abnormal in amnesic mild cognitive impairment (MCI) and Alzheimer's disease (AD)? EEG data were recorded in 64 normal elderly (Nold), 69 amnesic MCI, and 73 mild AD subjects at rest condition (closed eyes). Direction of information flux within EEG functional coupling at electrode pairs was performed by directed transfer function (DTF) at delta (2-4 Hz), theta (4-8 Hz), alpha 1 (8-10 Hz), alpha 2 (10-12 Hz), beta 1 (13-20 Hz), beta 2 (20-30 Hz), and gamma (30-40 Hz). Parietal to frontal direction of the information flux within EEG functional coupling was stronger in Nold than in MCI and/or AD subjects, namely for alpha and beta rhythms. In contrast, the directional flow within inter-hemispheric EEG functional coupling did not discriminate among the three groups. These results suggest that directionality of parieto-to-frontal EEG synchronization is abnormal not only in AD but also in amnesic MCI.     

Kinesin gene variability may affect tau phosphorylation in early Alzheimer's disease

Kinesin is a microtubule-associated motor protein that transports Alzheimer-associated amyloid precursor protein (APP) in neurons. In animal models, impaired kinesin-mediated APP transport seems to enhance formation of the neurotoxic 42 amino acid fragment of beta-amyloid (A beta 42). In man, one study suggests that a polymorphism (rs8702, 56,836G>C) in the kinesin light chain 1 gene (KNS2) may affect the risk of Alzheimer's disease (AD). To further assess KNS2 as a susceptibility gene for AD we analyzed 802 patients with sporadic AD and 286 controls, 134 longitudinally followed patients with mild cognitive impairment (MCI) and 39 cognitively stable controls for the rs8702 polymorphism. The rs8702 polymorphism did not influence risk of AD (p=0.46). However, rs8702 interacted with APOE epsilon 4 carrier status in AD (p=0.006) and influenced cerebrospinal fluid levels of hyperphosphorylated tau in MCI patients who converted to AD during follow-up (p=0.018). These findings support earlier indications that genetic variability in the KNS2 gene may play a role during early stages of AD pathogenesis.     

血浆β淀粉样蛋白在阿尔茨海默病早期诊断中的临床价值

目的 探究血浆Aβ42、Aβ40和Aβ42/Aβ40比值作为生物标志物在阿尔茨海默病和轻度认知障碍早期诊断中的价值.方法 入选受试者113例,其中44例阿尔茨海默病患者,33例轻度认知障碍患者和36例正常老年人,取静脉血测定其血浆Aβ42和Aβ40蛋白水平.结果 NC组、MCI组和AD组Aβ42水平和Aβ42/Aβ40比值逐渐下降.Aβ40水平逐渐升高,但差异无统计学意义.Aβ42水平可以区分NC组和AD组,但无法区分MCI组.Aβ40水平在各组之间比较差异无统计学意义.Aβ42/Aβ40比值在各组之间差异均具有统计学意义.结论 血浆Aβ42和Aβ40不能独立作为阿尔茨海默病早期诊断标志物,而它们的比值或许可以作为潜在的MCI和AD的诊断生物标志物,作为脑脊液检查和影像学检查的补充作用.     

Resistance to Alzheimer's pathology is associated with nuclear hypertrophy in neurons

This study focuses on the morphometric changes of neurons in asymptomatic Alzheimer's disease (AD), a state characterized by the presence of AD lesions in subjects without cognitive impairment. In autopsy brains, we used stereological methods to compare the cell body and nuclear volumes of anterior cingulate gyrus (ACG) and CA1 hippocampal neurons in asymptomatic AD subjects (n=9), subjects with AD dementia (AD, n=8), mild cognitive impairment (MCI, n=9), and age-matched controls (controls, n=9). In ACG, we observed a significant decrease in the neuronal volume of MCI and AD compared to controls; by contrast, no atrophy was present in asymptomatic AD. Moreover, we found a significant increase in nuclear volume in asymptomatic AD compared to controls (P<0.001), MCI (P<0.01) and AD (P<0.001) brains. Similar results were found in the CA1 region of the hippocampus. This nuclear hypertrophy may represent an early neuronal reaction to Abeta or Tau, or a compensatory mechanism which forestalls the progression of AD and allows the brain to resist the development of dementia.     

Blood fatty acids in Alzheimer’s disease and mild cognitive impairment: A meta-analysis and systematic review

Plasma fatty acids have been reported to be dysregulated in mild cognitive impairment (MCI) and Alzheimer’s disease (AD), though outcomes are not always consistent, and subject numbers often small. Our aim was to use a meta-analysis and systematic review approach to identify if plasma fatty acid dysregulation would be observed in case control studies of AD and MCI. Six databases were searched for studies reporting quantified levels of fatty acids in MCI and/or AD individuals, relative to cognitively normal controls. Docosahexaenoic (DHA) and vaccenic acids were significantly lower and higher respectively in MCI relative to controls. Total fatty acids were 27.2% lower in AD relative to controls, and this was reflected almost uniformly in all specific fatty acids in AD. Changes to plasma/serum fatty acids were identified in both MCI and AD relative to age and gender matched controls. Differences were greatest in AD, in both total number of fatty acids significantly altered, and the degree of change. Docosahexaenoic acid was lower in both MCI and AD, suggesting that it may be a driver of pathology.     

Both plasma retinol-binding protein and haptoglobin precursor allele 1 in CSF: Candidate biomarkers for the progression of normal to mild cognitive impairment to Alzheimer's disease

Cerebrospinal fluid (CSF) may be of valuable for exploring protein markers for the diagnosis of Alzheimer's disease (AD). The prospect of early detection and treatment, to slow progression, holds hope for aging populations with increased average lifespan. The aim of the present study was to investigate candidate CSF biological markers in patients with mild cognitive impairment (MCI) and AD and compare them with age-matched normal control subjects. In this report, we applied proteomics approaches to analyze 60 CSF samples derived from patients with neurodegenerative diseases such as MCI and AD. We classified patients by three groups: normal controls without cognitive dysfunction, MCI and AD. The AD group was subdivided into three groups by clinical severity according to clinical dementia rating (CDR), a well known clinical scale for dementia. We demonstrated a gradual decrease or absent of plasma retinol-binding protein (RBP) and haptoglobin precursor allele 1 in CSF from patients with MCI and AD compared to the age-matched normal subjects. Moreover, expression levels of both RBP and haptoglobin precursor allele 1 were observed to be very high in age-matched normal subjects. In contrast, the RBP and haptoglobin precursor allele 1 were much decreased in the MCI group; those expressions were more weak or absent in AD group, and correlated with disease severity and progression. These findings suggest that the CSF levels of both RBP and haptoglobin precursor allele 1 may be candidate biomarkers for the progression of normal to MCI to AD.     

Both plasma retinol-binding protein and haptoglobin precursor allele 1 in CSF: candidate biomarkers for the progression of normal to mild cognitive impairment to Alzheimer's disease

Cerebrospinal fluid (CSF) may be of valuable for exploring protein markers for the diagnosis of Alzheimer's disease (AD). The prospect of early detection and treatment, to slow progression, holds hope for aging populations with increased average lifespan. The aim of the present study was to investigate candidate CSF biological markers in patients with mild cognitive impairment (MCI) and AD and compare them with age-matched normal control subjects. In this report, we applied proteomics approaches to analyze 60 CSF samples derived from patients with neurodegenerative diseases such as MCI and AD. We classified patients by three groups: normal controls without cognitive dysfunction, MCI and AD. The AD group was subdivided into three groups by clinical severity according to clinical dementia rating (CDR), a well known clinical scale for dementia. We demonstrated a gradual decrease or absent of plasma retinol-binding protein (RBP) and haptoglobin precursor allele 1 in CSF from patients with MCI and AD compared to the age-matched normal subjects. Moreover, expression levels of both RBP and haptoglobin precursor allele 1 were observed to be very high in age-matched normal subjects. In contrast, the RBP and haptoglobin precursor allele 1 were much decreased in the MCI group; those expressions were more weak or absent in AD group, and correlated with disease severity and progression. These findings suggest that the CSF levels of both RBP and haptoglobin precursor allele 1 may be candidate biomarkers for the progression of normal to MCI to AD.