Longitudinal cerebrospinal fluid biomarker trajectories along the Alzheimer's disease continuum in the BIOMARKAPD study

IntroductionWithin-person trajectories of cerebrospinal fluid (CSF) biomarkers in Alzheimer's disease (AD) are not well defined.MethodsWe included 467 subjects from the BIOMARKAPD study with at least two serial CSF samples. Diagnoses were subjective cognitive decline (n = 75), mild cognitive impairment (n = 128), and AD dementia (n = 110), and a group of cognitively unimpaired subjects (n = 154) were also included. We measured baseline and follow-up CSF levels of total tau (t-tau), phosphorylated tau (p-tau), YKL-40, and neurofilament light (NfL). Median CSF sampling interval was 2.1 years.ResultsCSF levels of t-tau, p-tau, NfL, and YKL-40 were 2% higher per each year of baseline age in controls (P <.001). In AD, t-tau levels were 1% lower (P <.001) and p-tau levels did not change per each year of baseline age. Longitudinally, only NfL (P <.001) and YKL-40 (P <.02) increased during the study period.DiscussionAll four CSF biomarkers increase with age, but this effect deviates in AD for t-tau and p-tau.     

Discovery and validation of plasma proteomic biomarkers relating to brain amyloid burden by SOMAscan assay

IntroductionPlasma proteins have been widely studied as candidate biomarkers to predict brain amyloid deposition to increase recruitment efficiency in secondary prevention clinical trials for Alzheimer's disease. Most such biomarker studies are targeted to specific proteins or are biased toward high abundant proteins.Methods4001 plasma proteins were measured in two groups of participants (discovery group = 516, replication group = 365) selected from the European Medical Information Framework for Alzheimer's disease Multimodal Biomarker Discovery study, all of whom had measures of amyloid.ResultsA panel of proteins (n = 44), along with age and apolipoprotein E (APOE) ε4, predicted brain amyloid deposition with good performance in both the discovery group (area under the curve = 0.78) and the replication group (area under the curve = 0.68). Furthermore, a causal relationship between amyloid and tau was confirmed by Mendelian randomization.DiscussionThe results suggest that high-dimensional plasma protein testing could be a useful and reproducible approach for measuring brain amyloid deposition.     

LTP-like cortical plasticity predicts conversion to dementia in patients with memory impairment

BackgroundNew diagnostic criteria consider Alzheimer’s disease (AD) as a clinico-biological entity identifiable in vivo on the presence of specific patterns of CSF biomarkers.ObjectiveHere we used transcranial magnetic stimulation to investigate the mechanisms of cortical plasticity and sensory-motor integration in patients with hippocampal-type memory impairment admitted for the first time in the memory clinic stratified according to CSF biomarkers profile.MethodsSeventy-three patients were recruited and divided in three groups according to the new diagnostic criteria: 1) Mild Cognitive Impaired (MCI) patients (n = 21); Prodromal AD (PROAD) patients (n = 24); AD with manifest dementia (ADD) patients (n = 28). At time of recruitment all patients underwent CSF sampling for diagnostic purposes. Repetitive and paired-pulse transcranial magnetic stimulation protocols were performed to investigate LTP-like and LTD-like cortical plasticity, short intracortical inhibition (SICI) and short afferent inhibition (SAI). Patients were the followed up during three years to monitor the clinical progression or the conversion to dementia.ResultsMCI patients showed a moderate but significant impairment of LTP-like cortical plasticity, while ADD and PROAD groups showed a more severe loss of LTP-like cortical plasticity. No differences were observed for LTD-like cortical plasticity, SICI and SAI protocols. Kaplan-Meyer analyses showed that PROAD and MCI patients converting to dementia had weaker LTP-like plasticity at time of first evaluation.ConclusionLTP-like cortical plasticity could be a novel biomarker to predict the clinical progression to dementia in patients with memory impairment at prodromal stages of AD identifiable with the new diagnostic criteria based on CSF biomarkers.     

Diffusion imaging in dementia with Lewy bodies: Associations with amyloid burden,atrophy, vascular factors and clinical features

IntroductionWhite matter disruption in dementia has been linked to a variety of factors including vascular disease and cortical pathology. We aimed to examine the relationship between white matter changes on diffusion tensor imaging (DTI) in DLB and factors including vascular disease, structural atrophy and amyloid burden.MethodsParticipants with DLB (n = 29), Alzheimer's disease (AD, n = 17) and healthy controls (n = 20) had clinical and neuropsychological assessments followed by structural and diffusion tensor 3T MRI and ¹⁸F-Florbetapir PET-CT imaging. Voxelwise statistical analysis of white matter fractional anisotropy (FA) and mean diffusivity (MD) was carried out using Tract-Based Spatial Statistics with family-wise error correction (p < 0.05).ResultsDLB and AD groups demonstrated widespread increased MD and decreased FA when compared with controls. There were no differences between the DLB and AD groups. In DLB, increased MD and decreased FA correlated with decreased grey matter and hippocampal volumes as well as vascular disease. There was no correlation with cortical florbetapir SUVR. The relationship between DTI changes and grey matter/hippocampal volumes remained after including Cumulative Illness Rating Scale-Geriatric vascular score as a covariate.ConclusionsWidespread disruption of white matter tracts is present in DLB and is associated with vascular disease, reduced hippocampal volume and reduced grey matter volume, but not with cortical amyloid deposition. The mechanism behind the correlation observed between hippocampal volume and white matter tract disruption should be investigated in future cohorts using tau imaging, as hippocampal atrophy has been shown to correlate with tau deposition in DLB.     

Cerebrospinal fluid biomarker profiling in corticobasal degeneration: Application of the AT(N) and other classification systems

IntroductionTotal tau (τT), phosphorylated tau (τP-181) and amyloid beta (Aβ42) are cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD). There is no consensus on the interpretation criteria of these biomarkers. The aim of this study was to apply three different sets of criteria for CSF AD biomarker interpretation in a cohort of corticobasal degeneration (CBD) patients.MethodSForty patients fulfilling diagnostic criteria for “probable CBD” were included. The AT(N), BIOMARKAPD/ABSI and the τP-181/Aβ42 ratio criteria were applied.ResultsThe AT(N) criteria categorized 50% of “probable CBD” patients as AD, and 62.5% as harboring amyloid pathology. The BIOMARKAPD/ABSI and τP- 181/Aβ42 criteria categorized ~40% of “probable CBD” patients as AD.DiscussionUse of different interpretation criteria for CSF AD biomarkers produces diverse results. AD pathology is common in patients fulfilling “probable” CBD criteria. CBD diagnostic criteria may have suboptimal positive predictive value. A consensus regarding interpretation criteria of CSF AD biomarkers is pivotal.     

Neuroimaging correlates with neuropathologic schemes in neurodegenerative disease

IntroductionNeuroimaging biomarkers are important for early diagnosis of Alzheimer's disease, and comparing multimodality neuroimaging to autopsy data is essential.MethodsWe compared the pathologic findings from a prospective autopsy cohort (n = 100) to Pittsburgh compound B PET (PiB-PET), ¹⁸F-fluorodeoxyglucose PET (FDG-PET), and MRI. Correlations between neuroimaging biomarkers and neuropathologic schemes were assessed.ResultsPiB-PET showed strong correlations with Thal amyloid phase and Consortium to Establish a Registry for Alzheimer's Disease score and categorized 44% of Thal phase 1 participants as positive. FDG-PET and MRI correlated modestly with Braak tangle stage in Alzheimer's type pathology. A subset of participants with “none” or “sparse” neuritic plaque scores had elevated PiB-PET signal due to diffuse amyloid plaque. Participants with findings characterized as “suspected non-Alzheimer's pathophysiology” represented 15% of the group.DiscussionPiB-PET is associated with Alzheimer's disease, neuritic plaques, and diffuse plaques. FDG-PET and MRI have modest correlation with neuropathologic schemes. Participants with findings characterized as suspected non-Alzheimer's pathophysiology most commonly had primary age-related tauopathy.     

Identification of candidate cerebrospinal fluid biomarkers in parkinsonism using quantitative proteomics

IntroductionNeurodegenerative parkinsonian syndromes have significant clinical and pathological overlap, making early diagnosis difficult. Cerebrospinal fluid (CSF) biomarkers may aid the differentiation of these disorders, but other than α-synuclein and neurofilament light chain protein, which have limited diagnostic power, specific protein biomarkers remain elusive.ObjectivesTo study disease mechanisms and identify possible CSF diagnostic biomarkers through discovery proteomics, which discriminate parkinsonian syndromes from healthy controls.MethodsCSF was collected consecutively from 134 participants; Parkinson's disease (n = 26), atypical parkinsonian syndromes (n = 78, including progressive supranuclear palsy (n = 36), multiple system atrophy (n = 28), corticobasal syndrome (n = 14)), and elderly healthy controls (n = 30). Participants were divided into a discovery and a validation set for analysis. The samples were subjected to tryptic digestion, followed by liquid chromatography-mass spectrometry analysis for identification and relative quantification by isobaric labelling. Candidate protein biomarkers were identified based on the relative abundances of the identified tryptic peptides. Their predictive performance was evaluated by analysis of the validation set.Results79 tryptic peptides, derived from 26 proteins were found to differ significantly between atypical parkinsonism patients and controls. They included acute phase/inflammatory markers and neuronal/synaptic markers, which were respectively increased or decreased in atypical parkinsonism, while their levels in PD subjects were intermediate between controls and atypical parkinsonism.ConclusionUsing an unbiased proteomic approach, proteins were identified that were able to differentiate atypical parkinsonian syndrome patients from healthy controls. Our study indicates that markers that may reflect neuronal function and/or plasticity, such as the amyloid precursor protein, and inflammatory markers may hold future promise as candidate biomarkers in parkinsonism.     

Cerebrospinal tau,phospho‐tau,and beta‐amyloid and neuropsychological functions in Parkinson's disease

Alzheimer's disease (AD)‐pathology may play a role in Parkinson's disease (PD)‐related dementia (PDD). The aim of this study was to assess cerebrospinal fluid (CSF) levels of tau, phospho‐tau, and beta‐amyloid, proposed AD biomarkers, and their relationship with cognitive function in PD. Forty PD patients [20 nondemented (PDND); 20 PDD] and 30 controls underwent CSF tau, phospho‐tau, and beta‐amyloid analysis using specific ELISA techniques. All PD patients and 15 controls underwent neuropsychological testing of fronto‐subcortical (attention, fluency) and neocortical (memory, naming, visuoperceptive) functions. CSF markers levels were compared between groups, and compared and correlated with neuropsychological measures in PDND and PDD separately and as a continuum (PD). CSF tau and phospho‐tau were higher in PDD than in PDND and controls (P < 0.05). CSF beta‐amyloid ranged from high (controls) to intermediate (PDND) and low (PDD) levels (P < 0.001). In all PD and PDD patients, high CSF tau and phospho‐tau were associated with impaired memory and naming. In PDND, CSF beta‐amyloid was related with phonetic fluency. These findings suggest underlying AD‐pathology in PDD in association with cortical cognitive dysfunction, and that low CSF beta‐amyloid in PDND patients with impaired phonetic fluency can constitute an early marker of cognitive dysfunction. © 2009 Movement Disorder Society     

Pathology and temporal onset of visual hallucinations,misperceptions and family misidentification distinguishes dementia with Lewy bodies from Alzheimer's disease

ObjectiveTo determine whether the temporal onset of visual phenomena distinguishes Lewy body disease (LBD) from Alzheimer's disease (AD), and to characterize the extent Lewy bodies and neurofibrillary tangles are associated with these clinical features.MethodsConsecutive cases of autopsy-confirmed LBD (n = 41), AD (n = 70), and AD with amygdala-predominant Lewy bodies (AD-ALB) (n = 14) with a documented clinical history of dementia were included. We mailed questionnaires to next-of-kin asking about symptoms during life. Lewy pathology and neurofibrillary tangle pathology were assessed.ResultsThe occurrence of visual hallucinations, misperceptions and family misidentification did not distinguish LBD from AD or AD-ALB, but the onset was earlier in LBD compared to AD and AD-ALB. When visual hallucinations developed within the first 5 years of dementia, the odds were 4–5 times greater for autopsy-confirmed LBD (or intermediate/high likelihood dementia with Lewy bodies) and not AD or AD-ALB. In LBD, limbic but not cortical Lewy body pathology was related to an earlier onset of visual hallucinations, while limbic and cortical Lewy body pathology were associated with visual misperceptions and misidentification. Cortical neurofibrillary tangle burden was associated with an earlier onset of misidentification and misperceptions in LBD and AD, but only with earlier visual hallucinations in AD/AD-ALB.ConclusionWhen visual hallucinations occur within the first 5 years of the dementia, a diagnosis of LBD was more likely than AD. Visual hallucinations in LBD were associated with limbic Lewy body pathology. Visual misperceptions and misidentification delusions were related to cortical Lewy body and neurofibrillary tangle burden in LBD and AD/AD-ALB.     

Hypothesis: cerebrospinal fluid protein markers suggest a pathway toward symptomatic resilience to AD pathology

IntroductionWe sought biological pathways that explained discordance between Alzheimer's disease (AD) pathology and symptoms.MethodsIn 306 Alzheimer's Disease Neuroimaging Initiative (ADNI)-1 participants across the AD clinical spectrum, we investigated association between cognitive outcomes and 23 cerebrospinal fluid (CSF) analytes associated with abnormalities in the AD biomarkers amyloid β_1-42 and total-tau. In a 200-person “training” set, Least Absolute Shrinkage and Selection Operator regression estimated model weights for the 23 proteins, and for the AD biomarkers themselves, as predictors of ADAS-Cog₁₁ scores. In the remaining 106 participants (“validation” set), fully adjusted regression models then tested the Least Absolute Shrinkage and Selection Operator–derived models and a related protein marker summary score as predictors of ADAS-Cog₁₁, ADNI diagnostic category, and longitudinal cognitive trajectory.ResultsAD biomarkers alone explained 26% of the variance in validation set cognitive scores. Surprisingly, the 23 AD-related proteins explained 31% of this variance. The biomarkers and protein markers appeared independent in this respect, jointly explaining 42% of test score variance. The composite protein marker score also predicted ADNI diagnosis and subsequent cognitive trajectory. Cognitive outcome prediction redounded principally to ten markers related to lipid or vascular functions or to microglial activation or chemotaxis. In each analysis, apoE protein and four markers in the latter immune-activation group portended better outcomes.DiscussionCSF markers of vascular, lipid-metabolic and immune-related functions may explain much of the disjunction between AD biomarker abnormality and symptom severity. In particular, our results suggest the hypothesis that innate immune activation improves cognitive outcomes in persons with AD pathology. This hypothesis should be tested by further study of cognitive outcomes related to CSF markers of innate immune activation.     

Low soluble amyloid-β 42 is associated with smaller brain volume in Parkinson's disease

IntroductionWe sought to examine whether levels of soluble alpha-synuclein (α‐syn), amyloid-beta (Aβ42), phosphorylated tau (p-tau), and total tau (t-tau), as measured in cerebrospinal fluid (CSF), are associated with changes in brain volume in Parkinson's disease.MethodsWe assessed the 4-year change in total brain volume (n = 99) and baseline CSF α‐syn, Aβ42, p-tau, and t-tau of Parkinson Progression Markers Initiative participants. We used linear mixed models to assess the longitudinal effect of baseline CSF biomarkers on total and regional brain volume and thickness as well as linear regression for cross-sectional analyses at baseline and year 2. All models were adjusted for age and gender; brain volume models also adjusted for baseline intracranial volume. Bonferroni correction was applied.ResultsThe 4-year change in total brain volume was −21.2 mm³ (95% confidence interval, −26.1, −16.3). There were no significant associations between the 4-year change in total brain volume and baseline levels of any CSF biomarker (all p-values > 0.05). On cross-sectional analyses, CSF Aβ42 was linearly associated with total brain volume at baseline (R² = 0.60, p = 0.0004) and at year 2 (R² = 0.66, p < 0.0001), with CSF Aβ42 < 1100 pg/ml, the threshold for brain amyloid pathology, associated with smaller total brain volume at baseline (p = 0.0010) and at year 2 (p = 0.0002). CSF α‐syn was linearly associated with total brain volume at baseline (R² = 0.58, p = 0.0044) but not at year 2 (R² = 0.58, p = 0.1342).ConclusionReduction in soluble Aβ42 is associated with lower total brain volume in Parkinson's disease.     

Idiopathic normal-pressure hydrocephalus,cerebrospinal fluid biomarkers,and the cerebrospinal fluid tap test

Cerebrospinal fluid (CSF) biomarkers, including soluble amyloid β-42 (Aβ-42) and phosphorylated-tau (P-tau), reflect core pathophysiological features of Alzheimer’s disease (AD). AD is frequently a concomitant pathology in older patients with idiopathic normal-pressure hydrocephalus (iNPH), and somewhat similar altered CSF dynamics exist in both AD and iNPH. We therefore investigated relationships between lumbar CSF biomarkers Aβ-42 and P-tau and clinical parameters in iNPH patients, along with differences in these biomarkers between CSF tap test (CSFTT) responders and non-responders. Thirty-one iNPH patients (14 CSFTT responders and 17 CSFTT non-responders) were included in the final analysis. We found lower CSF Aβ-42 correlated with poor cognitive performance (r = 0.687, p < 0.001 for Korean Mini Mental State Examination; r = 0.568, p = 0.001 for Frontal Assessment Battery; r = −0.439, p = 0.014 for iNPH grading scale [iNPHGS] cognitive score; r = −0.588, p = 0.001 for Clinical Dementia Rating Scale), and lower CSF P-tau correlated with gait dysfunction (r = −0.624, p < 0.001 for Timed Up and Go Test; r = −0.652, p < 0.001 for 10 meter walking test; r = −0.578, p = 0.001 for Gait Status Scale; r = −0.543, p = 0.002 for iNPHGS gait score). In subgroup analysis, CSF P-tau/Aβ-42 ratios were significantly higher in CSFTT non-responders compared to responders (p = 0.027). Two conjectures are suggested. One, CSF biomarkers may play different and characteristic roles in relation to different iNPH symptoms such as cognition and gait. Two, comorbid AD pathology in iNPH patients may affect the response to the CSFTT. Larger studies using combinations of other biomarkers associated with AD would be necessary to evaluate these hypotheses.     

Amyloid beta peptides in human plasma and tissues and their significance for Alzheimer's disease

BackgroundWe evaluated the amounts of amyloid beta (Aβ)) peptides in the central nervous system (CNS) and in reservoirs outside the CNS and their potential impact on Aβ plasma levels and Alzheimer's disease (AD) pathology.MethodsAmyloid β levels were measured in (1) the plasma of AD and nondemented (ND) controls in a longitudinal study, (2) the plasma of a cohort of AD patients receiving a cholinesterase inhibitor, and (3) the skeletal muscle, liver, aorta, platelets, leptomeningeal arteries, and in gray and white matter of AD and ND control subjects.ResultsPlasma Aβ levels fluctuated over time and among individuals, suggesting continuous contributions from brain and peripheral tissues and associations with reactive circulating proteins. Arteries with atherosclerosis had larger amounts of Aβ40 than disease-free vessels. Inactivated platelets contained more Aβ peptides than activated ones. Substantially more Aβ was present in liver samples from ND patients. Overall, AD brain and skeletal muscle contained increased levels of Aβ.ConclusionsEfforts to use plasma levels of Aβ peptides as AD biomarkers or disease-staging scales have failed. Peripheral tissues might contribute to both the circulating amyloid pool and AD pathology within the brain and its vasculature. The wide spread of plasma Aβ values is also due in part to the ability of Aβ to bind to a variety of plasma and membrane proteins. Sources outside the CNS must be accounted for because pharmacologic interventions to reduce cerebral amyloid are assessed by monitoring Aβ plasma levels. Furthermore, the long-range impact of Aβ immunotherapy on peripheral Aβ sources should also be considered.     

R47H TREM2 variant increases risk of typical early-onset Alzheimer's disease but not of prion or frontotemporal dementia

BackgroundRare TREM2 variants are significant risk factors for Alzheimer's disease (AD).MethodsWe used next generation sequencing of the whole gene (n = 700), exon 2 Sanger sequencing (n = 2634), p.R47H genotyping (n = 3518), and genome wide association study imputation (n = 13,048) to determine whether TREM2 variants are risk factors or phenotypic modifiers in patients with AD (n = 1002), frontotemporal dementia (n = 358), sporadic (n = 2500), and variant (n = 115) Creutzfeldt-Jakob disease (CJD).ResultsWe confirm only p.R47H as a risk factor for AD (odds ratio or OR = 2.19; 95% confidence interval or CI = 1.04-4.51; P = .03). p.R47H does not significantly alter risk for frontotemporal dementia (OR = 0.81), variant or sporadic CJD (OR = 1.06 95%CI = 0.66-1.69) in our cohorts. Individuals with p.R47H associated AD (n = 12) had significantly earlier symptom onset than individuals with no TREM2 variants (n = 551) (55.2 years vs. 61.7 years, P = .02). We note that heterozygous p.R47H AD is memory led and otherwise indistinguishable from “typical” sporadic AD.ConclusionWe find p.R47H is a risk factor for AD, but not frontotemporal dementia or prion disease.     

Extension and refinement of the predictive value of different classes of markers in ADNI: Four-year follow-up data

BackgroundThis study examined the predictive value of different classes of markers in the progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD) over an extended 4-year follow-up in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database.MethodsMCI patients were assessed for clinical, cognitive, magnetic resonance imaging (MRI), positron emission tomography–fluorodeoxyglucose (PET-FDG), and cerebrospinal fluid (CSF) markers at baseline and were followed on a yearly basis for 4 years to ascertain progression to AD. Logistic regression models were fitted in clusters, including demographics, APOE genotype, cognitive markers, and biomarkers (morphometric, PET-FDG, CSF, amyloid-β, and tau).ResultsThe predictive model at 4 years revealed that two cognitive measures, an episodic memory measure and a Clock Drawing screening test, were the best predictors of conversion (area under the curve = 0.78).ConclusionsThis model of prediction is consistent with the previous model at 2 years, thus highlighting the importance of cognitive measures in progression from MCI to AD. Cognitive markers were more robust predictors than biomarkers.     

Cerebrospinal fluid α-synuclein contributes to the differential diagnosis of Alzheimer's disease

Introduction

The ability of Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers (amyloid β peptide 1–42, total tau, and phosphorylated tau) to discriminate AD from related disorders is limited. Biomarkers for other concomitant pathologies (e.g., CSF α-synuclein [α-syn] for Lewy body pathology) may be needed to further improve the differential diagnosis.

Concordance between the assessment of Aβ42, T-tau,and P-T181-tau in peripheral blood neuronal-derived exosomes and cerebrospinal fluid

IntroductionNeuronal-derived exosomal Aβ42, T-tau, and P-T181-tau have been demonstrated to be biomarkers of Alzheimer's disease (AD). However, no study has assessed the association of Aβ42, T-tau, and P-T181-tau between exosomes and CSF.MethodsThis was a multicenter study with two-stage design. The subjects included 28 AD patients, 25 aMCI patients, and 29 controls in the discovery stage; the results of which were confirmed in the validation stage (73 AD, 71 aMCI, and 72 controls).ResultsThe exosomal concentrations of Aβ42, T-tau, and P-T181-tau in AD group were higher than those in aMCI and control groups (all P < .001). The level of each exosomal biomarker was highly correlated with that in CSF.DiscussionThis study verified the agreement between CSF and blood exosomal biomarkers and confirmed that exosomal Aβ42, T-tau, and P-T181-tau have the same capacity as those in CSF for the diagnosis of AD and aMCI.     

Duration of preclinical,prodromal, and dementia stages of Alzheimer's disease in relation to age,sex, and APOE genotype

IntroductionWe estimated the age-specific duration of the preclinical, prodromal, and dementia stages of Alzheimer's disease (AD) and the influence of sex, setting, apolipoprotein E (APOE) genotype, and cerebrospinal fluid tau on disease duration.MethodsWe performed multistate modeling in a combined sample of 6 cohorts (n = 3268) with death as the end stage and estimated the preclinical, prodromal, and dementia stage duration.ResultsThe overall AD duration varied between 24 years (age 60) and 15 years (age 80). For individuals presenting with preclinical AD, age 70, the estimated preclinical AD duration was 10 years, prodromal AD 4 years, and dementia 6 years. Male sex, clinical setting, APOE ε4 allele carriership, and abnormal cerebrospinal fluid tau were associated with a shorter duration, and these effects depended on disease stage.DiscussionEstimates of AD disease duration become more accurate if age, sex, setting, APOE, and cerebrospinal fluid tau are taken into account. This will be relevant for clinical practice and trial design.     

Cortical phase changes in Alzheimer's disease at 7T MRI: A novel imaging marker

BackgroundPostmortem studies have indicated the potential of high-field magnetic resonance imaging (MRI) to visualize amyloid depositions in the cerebral cortex. The aim of this study is to test this hypothesis in patients with Alzheimer's disease (AD).MethodsT2*-weighted MRI was performed in 16 AD patients and 15 control subjects. All magnetic resonance images were scored qualitatively by visual assessment, and quantitatively by measuring phase shifts in the cortical gray matter and hippocampus. Statistical analysis was performed to assess differences between groups.ResultsPatients with AD demonstrated an increased phase shift in the cortex in the temporoparietal, frontal, and parietal regions (P < .005), and this was associated with individual Mini-Mental State Examination scores (r = −0.54, P < .05).ConclusionIncreased cortical phase shift in AD patients demonstrated on 7-tesla T2*-weighted MRI is a potential new biomarker for AD, which may reflect amyloid pathology in the early stages.