CSF biomarkers for mild cognitive impairment

A correct clinical diagnosis of Alzheimer's disease (AD) early in the course of the disease is of importance to initiate symptomatic treatment with acetylcholine esterase inhibitors, and will be even more important when disease-arresting drugs, such as beta-sheet breakers or gamma-secretase inhibitors, will reach the clinic. However, there is no clinical method to determine if a patient with mild cognitive impairment (MCI) has incipient AD, i.e. will progress to AD with dementia, or have a benign form of MCI without progression. Thus, there is a great clinical need for diagnostic biomarkers to identify incipient AD in MCI cases. Three cerebrospinal fluid (CSF) biomarkers; total-tau (T-tau), phospho-tau (P-tau) and the 42 amino acid form of beta-amyloid (Abeta42) have been evaluated in numerous scientific papers. These CSF markers have high sensitivity to differentiate early and incipient AD from normal ageing, depression, alcohol dementia and Parkinson's disease, but lower specificity against other dementias, such as frontotemporal and Lewy body dementia. However, if the CSF biomarkers are used in the right clinical context, i.e. together with the cumulative information from the clinical examination, standard laboratory tests and brain-imaging techniques [single photon emission tomography (SPECT) and magnetic resonance tomography (MRT) scans], they may have a role in the clinical evaluation of MCI cases.     

Validation of Alzheimer’s disease CSF and plasma biological markers: The multicentre reliability study of the pilot European Alzheimer’s Disease Neuroimaging Initiative (E-ADNI)

Background

Alzheimer’s Disease Neuroimaging Initiatives (“ADNI”) aim to validate neuroimaging and biochemical markers of Alzheimer’s disease (AD). Data of the pilot European-ADNI (E-ADNI) biological marker programme of cerebrospinal fluid (CSF) and plasma candidate biomarkers are reported.

Methods

Six academic EADC centres recruited 49 subjects (healthy controls, subjects with mild cognitive impairment (MCI) and AD). We measured CSF β-amyloid 42 (CSF Aβ42), total tau-protein (t-tau), phosphorylated tau-proteins (P-tau181, P-tau231), plasma β-amyloid 40 and 42 (Aβ40/Aβ42). Immediate fresh shipment was compared to freezing and later shipment on dry ice.

Results

CSF T-tau (fresh samples) was increased in AD versus controls (p = 0.049), CSF Aβ42 (frozen samples) was decreased in MCI and AD (p = 0.02), as well as plasma Aβ40 (fresh and frozen samples) in AD (p = 0.049 and p = 0.016). Pooled values of neurochemical parameters and ratios thereof were different between centres (p < 0.005). Analysis of frozen samples yielded higher diagnostic accuracy than immediate fresh shipment with 100% (fresh: 100%) correctly classified in control subjects, 100% (78%) in MCI, 91% (91%) in AD.

Conclusion

The use of frozen rather than fresh samples renders higher diagnostic accuracy within a multicentre context. We confirmed the feasibility of a multicentre AD biomarker programme for future clinical trials.     

Leukocyte telomere length (LTL) is reduced in stable mild cognitive impairment but low LTL is not associated with conversion to Alzheimer's disease: a pilot study

Leukocyte telomere length (LTL) is associated with the aging process and may be related to cognitive aging. Previous studies have shown conflicting results whether LTL is affected in patients with Alzheimer's disease (AD). In this pilot study, we investigated LTL in a well-defined homogeneous mono-center population. 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). LTL was determined using a quantitative PCR assay. Patients with AD had similar LTL as healthy controls. Patients with stable MCI had reduced LTL both compared to AD patients (p=0.02) and controls (p=0.008). Subanalyses within the AD group showed that patients with MCI that later converted to AD had similar LTL as patients with clinical diagnosis of AD at primary evaluation and healthy controls whereas the LTL was longer compared to the stable MCI group (p=0.02). There were no correlations between LTL and the core AD biomarkers Aβ(1-42), T-tau and P-tau. In conclusion, in this pilot study, patients with AD or MCI that later converted to AD had similar LTL as healthy controls. Patients with stable MCI that did not progress to dementia had reduced LTL compared to controls, which might suggest a more marked biological aging as a cause of the cognitive symptoms in this group.     

Variation in MAPT is associated with cerebrospinal fluid tau levels in the presence of amyloid-beta deposition

There is substantial evidence that cerebrospinal fluid (CSF) levels of both Abeta42 and tau/ptau are promising biomarkers for Alzheimer's disease (AD). We show that both Abeta and tau exhibit more than 10-fold interindividual variation in CSF levels suggesting that these biomarkers may also be effectively used as endophenotypes for genetic studies of AD. To test the role of common variation in the gene encoding microtubule associated protein tau (MAPT) in influencing CSF tau/ptau levels, we genotyped 21 MAPT single nucleotide polymorphisms (SNPs) in 313 individuals and tested for association with CSF tau/ptau levels. We identified alleles of several SNPs that show association with increased CSF tau/ptau levels. When CSF Abeta42 levels were used to stratify the sample into those with and without likely Abeta deposition in the brain the association was only observed in individuals with evidence of Abeta deposition. This association was replicated in an independent CSF series. When these SNPs were evaluated in a late-onset AD case control series the alleles associated with higher CSF tau/ptau were associated with an earlier age at onset but had no effect on risk for AD. In vivo gene expression studies show that these alleles are associated with increased MAPT mRNA levels in individuals with evidence of brain Abeta deposition. This endophenotype-based approach provides evidence for a gene (MAPT SNPs)-physiological environment (Abeta deposition) interaction that places changes in CSF tau after Abeta deposition and suggest that this interaction predisposes for the development of tauopathy and accelerated disease progression.     

Near a biological diagnosis of Alzheimer's disease and related disorders

PURPOSE: To review the current concepts in the biological diagnosis of Alzheimer's disease (AD) and related disorders. CURRENT KNOWLEDGE AND KEY POINTS: As new therapeutics specific of AD may be available soon, early diagnosis of AD in the context of mild cognitive impairment (MCI) or dementia appears to be challenging. The high amount of atypical clinical forms of AD leads to develop new tools allowing in vivo diagnosis. New CerebroSpinal Fluid (CSF) biomarkers seem to reflect specific aspects of deep neuropathological changes observed in AD, i.e. amyloid deposits and neurofibrillary tangles. Amyloid beta-peptide 1-42 (Abeta(1-42)) and hyperphosphorylated tubulin associated unit (tau) isoforms appear to be the most sensitive and specific CSF biomarkers, the combination of these biomarkers depicting the best diagnosis value for AD. These molecules are also efficient in the prediction of the conversion from the MCI state to the dementia state of AD. Combined to clinical and neuro-imaging information, CSF biomarkers appear thus to be highly relevant in improving the early etiological diagnosis of dementia. FUTURE PROSPECTS AND PROJECTS: The current research focalises on the development of new molecules coming from Abeta and tau protein families, in the CSF and in the serum, as well as molecules reflecting other pathological metabolism changes, as alpha-synuclein in Lewy Body Disease. The diagnosis value of CSF biological markers is so promising that they have been recently included in the research diagnosis criteria of AD.     

Cerebrospinal fluid amyloid beta42/phosphorylated tau ratio discriminates between Alzheimer's disease and vascular dementia

BACKGROUND: The differentiation of Alzheimer's disease (AD) from vascular dementia (VaD) is hampered by clinical diagnostic criteria with disappointing sensitivity and specificity. The objective of this study was to investigate whether cerebrospinal fluid (CSF) levels of total tau protein (t-tau), amyloid beta42 protein (Abeta42), and tau phosphorylated at threonine 181 (p-tau181) are useful biomarkers to distinguish AD patients from VaD patients. METHODS: We measured CSF levels of p-tau181, Abeta42, and t-tau in 86 patients with a clinical diagnosis of AD or VaD and in 30 control participants. RESULTS: Optimal differentiation between AD and VaD was achieved by using the ratio of the CSF levels of Abeta42 and p-tau181 (Q Abeta42/p-tau) with sensitivity, specificity, positive and negative predictive values all > or = 85%. CONCLUSIONS: Our results support further efforts to prospectively validate the use of Q Abeta42/p-tau as a biomarker to discriminate between AD and VaD.     

Standardization of measurement of beta-amyloid(1-42) in cerebrospinal fluid and plasma.

The standardization and clinical validation of the measurement of beta-amyloid(1-42) (Abeta42) in cerebrospinal fluid (CSF), plasma and urine is described using a commercially available sandwich-type ELISA with 21F12 and 3D6 as monoclonal antibodies. The INNOTEST beta-amyloid(1-42) allows the specific and reliable measurement of(1-42) amyloid peptides in CSF and plasma. The Abeta42 concentrations in serum and urine were below the detection limit. In plasma, no differences were found in Abeta42 levels between controls and patients with different neurodegenerative disorders (Alzheimer's disease (AD), Lewy body disease (LBD), others). In contrast, CSF-Abeta42 concentrations were lower in AD and LBD patients as compared to controls. No correlation was found in AD patients between CSF and plasma concentrations of Abeta42 or between CSF Abeta42 levels and blood-brain-barrier function. The quantitative outcome of the test is in part dependent on confounding factors such as tube type, freeze/thaw cycles, temperature of incubation, standard preparation protocol, and antibody selection. Notwithstanding these aspects, it emerged that Abeta42 is a useful biochemical marker for the diagnosis of AD patients, but there is a need for an international Abeta standard, a universally accepted protocol for CSF preparation, and a thorough evaluation of assay performance in function of the boundary conditions.     

Early detection of Alzheimer's disease using neuroimaging

Neuroimaging is being increasingly used to complement clinical assessments in the early detection of Alzheimer's disease (AD). Structural magnetic resonance imaging (MRI) and metabolic positron emission tomography (FDG-PET) are the most clinically used and promising modalities to detect brain abnormalities in individuals who might be at risk for AD but who have not yet developed symptoms. The knowledge of established risk factors for AD enabled investigators to develop enrichment strategies for longitudinal imaging studies to reduce the sample sizes and study duration. The present review focuses on the results obtained by MRI and FDG-PET studies that examined the preclinical AD stages in several at risk populations: (1) individuals from families with autosomal dominant early-onset AD (FAD), (2) patients with mild cognitive impairment (MCI), particularly in memory, who are at very high risk for declining to AD with an estimated decline rate of 10-30% per year, (3) normal young and middle-age subjects carriers of known susceptibility genes for late-onset AD such as the Apolipoprotein E (ApoE) E4 allele, and (4) as age is the main risk factor for AD, normal elderly individuals followed to the onset of MCI and AD. Overall, these studies show that the use of imaging for the early detection of AD is successful even in the earlier stages of disease when clinical symptoms are not fully expressed and the regional brain damage may be limited.     

Lipocalin-type prostaglandin D synthase/beta-trace is a major amyloid beta-chaperone in human cerebrospinal fluid

The conformational change in amyloid beta (Abeta) peptide from its monomeric form to aggregates is crucial in the pathogenesis of Alzheimer's disease (AD). In the healthy brain, some unidentified chaperones appear to prevent the aggregation of Abeta. Here we reported that lipocalin-type prostaglandin D synthase (L-PGDS)/beta-trace, the most abundant cerebrospinal fluid (CSF) protein produced in the brain, was localized in amyloid plaques in both AD patients and AD-model Tg2576 mice. Surface plasmon resonance analysis revealed that L-PGDS/beta-trace tightly bound to Abeta monomers and fibrils with high affinity (K(D) = 18-50 nM) and that L-PGDS/beta-trace recognized residues 25-28 in Abeta, which is the key region for its conformational change to a beta-sheet structure. The results of a thioflavin T fluorescence assay to monitor Abeta aggregation disclosed that L-PGDS/beta-trace inhibited the spontaneous aggregation of Abeta (1-40) and Abeta (1-42) within its physiological range (1-5 microM) in CSF. L-PGDS/beta-trace also prevented the seed-dependent aggregation of 50 microM Abeta with K(i) of 0.75 microM. Moreover, the inhibitory activity toward Abeta (1-40) aggregation in human CSF was decreased by 60% when L-PGDS/beta-trace was removed from the CSF by immunoaffinity chromatography. The deposition of Abeta after intraventricular infusion of Abeta (1-42) was 3.5-fold higher in L-PGDS-deficient mice and reduced to 23% in L-PGDS-overexpressing mice as compared with their wild-type levels. These data indicate that L-PGDS/beta-trace is a major endogenous Abeta-chaperone in the brain and suggest that the disturbance of this function may be involved in the onset and progression of AD. Our findings may provide a diagnostic and therapeutic approach for AD.     

Value of neuropsychological tests, neuroimaging, and biomarkers for diagnosing Alzheimer's disease in younger and older age cohorts

OBJECTIVES: To examine the influence of age on the value of four techniques for diagnosing Alzheimer's disease (AD). DESIGN: Observational cohort study. SETTING: Alzheimer's Disease Neuroimaging Initiative. PARTICIPANTS: Individuals with mild cognitive impairment (MCI; n=179), individuals with AD (n=91), and normal controls (n=105). MEASUREMENTS: Neuropsychological tests, structural magnetic resonance imaging (MRI), amyloid‐beta and tau in cerebrospinal fluid (CSF), and [18F]fluorodeoxyglucose positron emission tomography (FDG‐PET) for the diagnosis of MCI or AD. MCI was defined according to subjective memory complaints corroborated by an informant and an abnormal score on the delayed paragraph recall subtest of the Wechsler Memory Scale–Revised, a Mini‐Mental State Examination score greater than 23, and a Clinical Dementia Rating score of 0.5. Participants with AD satisfied National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association criteria of probable AD. RESULTS: Neuropsychological tests and MRI were the most informative techniques, with 84% and 82% correct classifications, respectively, and areas under the receiver operating characteristic curve (AUCs) of 0.93 (90% confidence interval (CI)=0.91–0.95) and 0.88 (90% CI=0.85–0.91). FDG‐PET and CSF assessments had 76% and 73% correct classifications, respectively, (AUC=0.77, 90% CI=0.71–0.83; AUC=0.77, 90% CI=0.73–0.82). These figures increased slightly when the techniques were combined. All analyses were repeated for the younger (<75) and older (≥75) halves of the sample. FDG‐PET and CSF assessment were substantially less informative in the older cohort, and they did not add diagnostic information when all techniques were combined. CONCLUSIONS: Structural MRI and neuropsychological assessment are diagnostic methods of first choice if AD is suspected. CSF and FDG‐PET add little to these diagnostic techniques, especially in older adults.     

Growth factors and cytokines/chemokines as surrogate biomarkers in cerebrospinal fluid and blood for diagnosing Alzheimer’s disease and mild cognitive impairment

Alzheimer’s disease (AD) is a severe chronic neurodegenerative disorder of the brain. A probable diagnosis of AD can be obtained by cerebrospinal fluid levels of 3 biomarkers: beta-amyloid (1–42), total tau and phospho-tau181. Researchers are interested in finding additional biomarkers in CSF to improve the specificity and sensitivity of diagnosis, including also other forms of dementia, such as mild cognitive impairment (MCI). In addition, less invasive diagnostic methods using blood or blood-derived cells are being investigated. This mini-review (in concert with the other reviews of this special issue) summarizes the usefulness of growth factors and cytokines/chemokines as putative surrogate biomarkers for diagnosing AD and MCI in CSF and blood. Briefly, the expression levels of growth factors and cytokines/chemokines are very heterogenous, indicating the pathological diversity of these diseases. At present, no single growth factor or cytokine alone stands out as a useful biomarker for diagnosing AD or MCI. However, the combined “patients profile signature” of several selected growth factors and/or cytokines/chemokines may allow to diagnose AD and MCI with higher selectively and specificity.     

探讨补体受体1基因与脑脊液中相关蛋白的关系

目的探讨补体成分(3b/4b)受体1基因[the complement component (3b/4b) receptor 1gene,CR1]多态性与脑脊液相关蛋白的关系。方法从美国国立老年研究所组织建立的阿尔茨海默病(AD)神经影像学研究数据库中选择812例受试者,其中48例AD患者为AD组,483例轻度认知障碍(MCI)患者为MCI组,281例正常对照(NC)者为NC组。用免疫分析试剂盒和xMAP Luminex试剂盒检测入选者脑脊液中β淀粉样蛋白(Aβ)、总tau(t-tau)蛋白和磷酸化tau(p-tau)蛋白水平。结果 AD组rs61522287位点基因突变后,GA基因型较GG基因型脑脊液Aβ42水平增加[(193.20±79.05)ng/L vs(137.90±37.28)ng/L,P=0.03762]。8个CR1的单核苷酸多态性(SNP)位点可以调节AD患者脑脊液中t-tau蛋白和p-tau蛋白水平。11个CR1的SNP突变位点参与调节MCI组患者tau蛋白水平。3个CR1的SNP位点基因突变增加MCI组脑脊液中Aβ42水平。rs41274776和rs12567945位点突变同时增加NC组脑脊液中p-tau和Aβ42水平。结论本研究率先明确了CR1的SNP位点与脑脊液蛋白(Aβ42,t-tau和p-tau)之间的关系,这对未来寻找AD的早期诊断,早期筛查提供了新思路。     

Elevation of plasma soluble amyloid precursor protein beta in Alzheimer’s disease

IntroductionBeta-amyloid is considered to be a pathophysiological marker in Alzheimer's disease (AD). Soluble amyloid precursor proteins (sAPPs) –α (sAPPα) and –β (sAPPβ), which are the byproducts of non-amyloidogenic and amyloidogenic process of APP, respectively, have been repeatedly observed in the cerebrospinal fluids (CSF) of AD patients. The present study focused on the determination of sAPP levels in peripheral blood.MethodsThe plasma protein levels of sAPPα and sAPPβ were measured with ELISA. Plasma from 52 AD patients, 98 amnestic mild cognitive impairment (MCI) patients, and 114 cognitively normal controls were compared.ResultsThe plasma level of sAPPβ was significantly increased in AD patients than in cognitively healthy controls. However, no significant change in plasma sAPPα was observed among the three groups. Furthermore, the plasma sAPPβ levels significantly correlated with cognitive assessment scales, such as clinical dementia rating (CDR), and mini-mental status examination (MMSE). Interestingly, sAPPα and sAPPβ had a positive correlation with each other in blood plasma, similar to previous studies on CSF sAPP. This correlation was stronger in the MCI and AD groups than in the cognitively healthy controls.ConclusionsThese results suggest that individuals with elevated plasma sAPPβ levels are at an increased risk of AD; elevation in these levels may reflect the progression of disease.     

Genetic susceptibility sets for Alzheimer's disease identified from diverse candidate loci

Alzheimer's disease (AD) has been demonstrated to be associated with gene variants of APOE, but numerous additional candidate loci exist with varying levels of statistical support. We defined susceptibility sets for AD based on information on 18 genetic loci on chromosome 10q (32 loci) and elsewhere (34 loci) and quantitative traits, including CSF tau and Abeta(42) levels. The 938 AD patients and 397 control subjects were enrolled in Scotland and Sweden. A fuzzy latent classification approach -- grade-of-membership analysis (GoM) -- was taken to identify risk sets. Individuals were automatically related to each set via GoM scores. Set I: unaffected + (downward arrow) CSF tau + (upward arrow) CSF Abeta(42) + multiple protective alleles. High intrinsic risk sets II-VI differed in onset age and relevant alleles: close resemblance (i.e., >75% aggregate membership) multiplied risk of AD >100-fold at ages 65 to 84. It is likely that AD has multiple determinants, including APOE polymorphism and gene variants located on chromosome 10q and elsewhere.     

Soluble cell adhesion molecules in monocytes of Alzheimer’s disease and mild cognitive impairment

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with characteristic neuropathological features that are accompanied by inflammatory processes and release of pro-inflammatory cytokines. There is evidence that microglial cells are a key mediator of damage in AD. The microglial compartment may arise to a greater part from activation and transmigration of circulating monocytes. The aim of the present pilot study was to explore, if different cell adhesion molecules (ICAM-1 and -3, PECAM-1, VCAM-1, P-, L- and E-selectins, E-cadherin), RAGE and CD14 are affected in monocytes of healthy subjects compared to patients suffering from AD or mild cognitive impairment (MCI). Monocytes were isolated by negative magnetic selection (MACS) from EDTA blood samples, and extracts were analyzed by Searchlight Multiplex ELISAs. When compared to healthy subjects, the ratio of monocytic ICAM-3/CD14 was significantly decreased in MCI and AD patients and the ratio of the monocytic P-selectin/CD14 was specifically decreased in AD patients. In conclusion, our data show that monocytic cell adhesion molecules are decreased in AD and MCI patients. Further larger longitudinal studies should then clarify whether any of these parameters may be useful as a diagnostic biomarker.     

Diabetes as a risk factor for dementia and mild cognitive impairment: a meta-analysis of longitudinal studies

This study examined the association of diabetes with the onset of dementia (including Alzheimer's disease (AD), vascular dementia (VD) and any dementia) and mild cognitive impairment (MCI) by using a quantitative meta-analysis of longitudinal studies. EMBASE and MEDLINE were searched for articles published up to December 2010. All studies that examined the relationship between diabetes and the onset of dementia or MCI were included. Pooled relative risks were calculated using fixed and random effects models. Nineteen studies met our inclusion criteria for this meta-analysis, and 6184 subjects with diabetes and 38 530 subjects without diabetes were included respectively. All subjects were without dementia or MCI at baseline. The quantitative meta-analysis showed that subjects with diabetes had higher risk for AD (relative risk (RR):1.46, 95% confidence interval (CI): 1.20-1.77), VD (RR: 2.48, 95% CI: 2.08-2.96), any dementia (RR: 1.51, 95% CI: 1.31-1.74) and MCI (RR: 1.21, 95% CI: 1.02-1.45) than those without. The quantitative meta-analysis showed that diabetes was a risk factor for incident dementia (including AD, VD and any dementia) and MCI.     

Total and phosphorylated tau protein as biological markers of Alzheimer’s disease

Advances in our understanding of tau-mediated neurodegeneration in Alzheimer’s disease (AD) are moving this disease pathway to center stage for the development of biomarkers and disease modifying drug discovery efforts. Immunoassays were developed detecting total (t-tau) and tau phosphorylated at specific epitopes (p-tauX) in cerebrospinal fluid (CSF), methods to analyse tau in blood are at the experimental beginning. Clinical research consistently demonstrated CSF t- and p-tau increased in AD compared to controls. Measuring these tau species proved informative for classifying AD from relevant differential diagnoses. Tau phosphorylated at threonine 231 (p-tau231) differentiated between AD and frontotemporal dementia, tau phosphorylated at serine 181 (p-tau181) enhanced classification between AD and dementia with Lewy bodies. T- and p-tau are considered “core” AD biomarkers that have been successfully validated by controlled large-scale multi-center studies. Tau biomarkers are implemented in clinical trials to reflect biological activity, mechanisms of action of compounds, support enrichment of target populations, provide endpoints for proof-of-concept and confirmatory trials on disease modification. World-wide quality control initiatives are underway to set required methodological and protocol standards. Discussions with regulatory authorities gain momentum defining the role of tau biomarkers for trial designs and how they may be further qualified for surrogate marker status.     

Inhaled Sevoflurane May Promote Progression of Amnestic Mild Cognitive Impairment: A Prospective,Randomized Parallel-Group Study

BackgroundAmnestic mild cognitive impairment (aMCI) is thought to be a transitional stage between normal aging and the development of Alzheimer’s disease (AD). Recent studies have suggested that the inhalational anesthetic isoflurane can induce caspase activation and apoptosis, increase aggregates of β-amyloid (Aβ) levels, and enhance Aβ aggregation. The aim of this study was to investigate whether previous exposure to different anesthetics induced progression of aMCI.MethodsA prospective, randomized parallel-group study was completed with 180 patients with aMCI who were randomly assigned to a sevoflurane, propofol or lidocaine epidural anesthesia group (n = 60 per group) during an L3 to L4 or an L4 to L5 spinal surgery. Sixty additional outpatients with aMCI served as a control group. Before surgery, all subjects underwent a neuropsychological assessment. Cerebrospinal fluid (CSF) was obtained by lumbar puncture, and neuropsychological assessments were completed in the clinic. CSF Aβ₄₂, total tau and phosphorylated tau181 were quantitatively assayed. The neuropsychological assessments were repeated after 2 years.ResultsTwo years after anesthesia, the number of AD cases that emerged did not differ significantly between the groups. However, the number of cases of progressive MCI was greater in the sevoflurane group than in the control group. Age correlated linearly with aMCI progression, whereas sex did not. Both patients with AD and progressive MCI had decreased CSF Aβ₄₂, increased total tau and increased phosphorylated tau levels compared with those with stable MCI and the controls.ConclusionsInhaled sevoflurane accelerated the progression of aMCI to progressive MCI in this selected Chinese population.     

Subregional neuroanatomical change as a biomarker for Alzheimer's disease

Regions of the temporal and parietal lobes are particularly damaged in Alzheimer''s disease (AD), and this leads to a predictable pattern of brain atrophy. In vivo quantification of subregional atrophy, such as changes in cortical thickness or structure volume, could lead to improved diagnosis and better assessment of the neuroprotective effects of a therapy. Toward this end, we have developed a fast and robust method for accurately quantifying cerebral structural changes in several cortical and subcortical regions using serial MRI scans. In 169 healthy controls, 299 subjects with mild cognitive impairment (MCI), and 129 subjects with AD, we measured rates of subregional cerebral volume change for each cohort and performed power calculations to identify regions that would provide the most sensitive outcome measures in clinical trials of disease-modifying agents. Consistent with regional specificity of AD, temporal-lobe cortical regions showed the greatest disease-related changes and significantly outperformed any of the clinical or cognitive measures examined for both AD and MCI. Global measures of change in brain structure, including whole-brain and ventricular volumes, were also elevated in AD and MCI, but were less salient when compared to changes in normal subjects. Therefore, these biomarkers are less powerful for quantifying disease-modifying effects of compounds that target AD pathology. The findings indicate that regional temporal lobe cortical changes would have great utility as outcome measures in clinical trials and may also have utility in clinical practice for aiding early diagnosis of neurodegenerative disease.