7 Tesla MRI in Alzheimer's disease

T2*-weighted (a and b), T2-weighted (c and d), and FLAIR (e and f) images of the medial temporal lobe obtained at 1.5 T (a, c, and e) and 7 T (b, d, and f), illustrating the strikingly improved resolution that high-field MRI offers. Reprinted from Theysohn et al.: The human hippocampus at 7 T-in vivo MRI, Hippocampus 19:1–7, 2009, copyright 2008, Wiley-Liss, Inc.

Five AD hippocampal specimens (A1–A5) and one normal control (N4) are shown. Note the signal voids in AD specimens along the hippocampus compared with the lack of such signal voids in the normal control. The border between field CA1 and the subiculum is indicated by the white line derived from coregistered acetylcholine, myelin, and Nissl staining. The variability in their locations relative to the medial aspect of the hippocampal body illustrates the challenges inherent in in vivo imaging studies of hippocampal subregions. Reprinted from Neurobiology of Aging, vol 36, Zeineh M, Chen Y, Kitzler HH, Hammond R, Vogel H, Rutt BK, “Activated iron-containing microglia in the human hippocampus identified by magnetic resonance imaging in Alzheimer’s disease,” pp 2483–2500, 2015, with permission from Elsevier.

7-T FLAIR MRI in the (left to right) transverse (left), sagittal (center), and coronal (right) views. The arrow is pointing to a microinfarct. Reprinted with permission from van Rooden S, Goos JD, van Opstal AM, Versluis MJ, Webb AG, Blauw GJ, et al: Increased number of microinfarcts in Alzheimer disease at 7-T MR imaging. Radiology 270:205–211, 2014.

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Detailed comparison of amyloid PET and CSF biomarkers for identifying early Alzheimer disease

Objective: To compare the diagnostic accuracy of CSF biomarkers and amyloid PET for diagnosing early-stage Alzheimer disease (AD).

Methods: From the prospective, longitudinal BioFINDER study, we included 122 healthy elderly and 34 patients with mild cognitive impairment who developed AD dementia within 3 years (MCI-AD). β-Amyloid (Aβ) deposition in 9 brain regions was examined with [¹⁸F]-flutemetamol PET. CSF was analyzed with INNOTEST and EUROIMMUN ELISAs. The results were replicated in 146 controls and 64 patients with MCI-AD from the Alzheimer's Disease Neuroimaging Initiative study.

Results: The best CSF measures for identifying MCI-AD were Aβ42/total tau (t-tau) and Aβ42/hyperphosphorylated tau (p-tau) (area under the curve [AUC] 0.93–0.94). The best PET measures performed similarly (AUC 0.92–0.93; anterior cingulate, posterior cingulate/precuneus, and global neocortical uptake). CSF Aβ42/t-tau and Aβ42/p-tau performed better than CSF Aβ42 and Aβ42/40 (AUC difference 0.03–0.12, p < 0.05). Using nonoptimized cutoffs, CSF Aβ42/t-tau had the highest accuracy of all CSF/PET biomarkers (sensitivity 97%, specificity 83%). The combination of CSF and PET was not better than using either biomarker separately.

Conclusions: Amyloid PET and CSF biomarkers can identify early AD with high accuracy. There were no differences between the best CSF and PET measures and no improvement when combining them. Regional PET measures were not better than assessing the global Aβ deposition. The results were replicated in an independent cohort using another CSF assay and PET tracer. The choice between CSF and amyloid PET biomarkers for identifying early AD can be based on availability, costs, and doctor/patient preferences since both have equally high diagnostic accuracy.

Classification of evidence: This study provides Class III evidence that amyloid PET and CSF biomarkers identify early-stage AD equally accurately.

Reference: Neurology 10.1212/WNL.0000000000001991 Full text

Nonlinear Association Between Cerebrospinal Fluid and Florbetapir F-18 β-Amyloid Measures Across the Spectrum of Alzheimer Disease

Cerebrospinal fluid (CSF) and positron emission tomographic (PET) amyloid biomarkers have been proposed for the detection of Alzheimer disease (AD) pathology in living patients and for the tracking of longitudinal changes, but the relation between biomarkers needs further study. Indeed a study aimed at determining the association between CSF and PET amyloid biomarkers (cross-sectional and longitudinal measures) and compare the cutoffs for these measures has just been published:

Design, Setting, and Participants Longitudinal clinical cohort study from 2005 to 2014 including 820 participants with at least 1 florbetapir F-18 (hereafter referred to as simply florbetapir)–PET scan and at least 1 CSF β-amyloid 1-42 (Aβ1-42) sample obtained within 30 days of each other (501 participants had a second PET scan after 2 years, including 150 participants with CSF Aβ1-42 measurements). Data were obtained from the Alzheimer’s Disease Neuroimaging Initiative database.

Main Outcomes and Measures Four different PET scans processing pipelines from 2 different laboratories were compared. The PET cutoff values were established using a mixture-modeling approach, and different mathematical models were applied to define the association between CSF and PET amyloid measures.

Results The values of the CSF Aβ1-42 samples and florbetapir-PET scans showed a nonlinear association (R2 = 0.48-0.66), with the strongest association for values in the middle range. The presence of a larger dynamic range of florbetapir-PET scan values in the higher range compared with the CSF Aβ1-42 plateau explained the differences in correlation with cognition (R2 = 0.36 and R2 = 0.25, respectively). The APOEgenotype significantly modified the association between both biomarkers. The PET cutoff values derived from an unsupervised classifier converged with previous PET cutoff values and the established CSF Aβ1-42 cutoff levels. There was no association between longitudinal Aβ1-42 levels and standardized uptake value ratios during follow-up.

Conclusions and Relevance The association between both biomarkers is limited to a middle range of values, is modified by the APOE genotype, and is absent for longitudinal changes; 4 different approaches in 2 different platforms converge on similar pathological Aβ cutoff levels; and different pipelines to process PET scans showed correlated but not identical results. Our findings suggest that both biomarkers measure different aspects of AD Aβ pathology.

Reference JAMA Neurol. Published online March 30, 2015. doi:10.1001/jamaneurol.2014.4829

Florbetaben PET imaging to detect amyloid plaques in Alzheimer disease: Phase 3 study

Background

Evaluation of brain β-amyloid by positron emission tomography (PET) imaging can assist in the diagnosis of Alzheimer disease (AD) and other dementias.

Methods

Open-label, nonrandomized, multicenter, phase 3 study to validate the 18F-labeled β-amyloid tracer florbetaben by comparing in vivo PET imaging with post-mortem histopathology.

Results

Brain images and tissue from 74 deceased subjects (of 216 trial participants) were analyzed. Forty-six of 47 neuritic β-amyloid-positive cases were read as PET positive, and 24 of 27 neuritic β-amyloid plaque-negative cases were read as PET negative (sensitivity 97.9% [95% confidence interval or CI 93.8–100%], specificity 88.9% [95% CI 77.0–100%]). In a subgroup, a regional tissue-scan matched analysis was performed. In areas known to strongly accumulate β-amyloid plaques, sensitivity and specificity were 82% to 90%, and 86% to 95%, respectively.

Conclusions

Florbetaben PET shows high sensitivity and specificity for the detection of histopathology-confirmed neuritic β-amyloid plaques and may thus be a valuable adjunct to clinical diagnosis, particularly for the exclusion of AD.

Trial registration

ClinicalTrials.govNCT01020838.

Predicting the risk of mild cognitive impairment

Objective: We sought to develop risk scores for the progression from cognitively normal (CN) to mild cognitive impairment (MCI).

Methods: We recruited into a longitudinal cohort study a randomly selected, population-based sample of Olmsted County, MN, residents, aged 70 to 89 years on October 1, 2004. At baseline and subsequent visits, participants were evaluated for demographic, clinical, and neuropsychological measures, and were classified as CN, MCI, or dementia. Using baseline demographic and clinical variables in proportional hazards models, we derived scores that predicted the risk of progressing from CN to MCI. We evaluated the ability of these risk scores to classify participants for MCI risk.

Results: Of 1,449 CN participants, 401 (27.7%) developed MCI. A basic model had a C statistic of 0.60 (0.58 for women, 0.62 for men); an augmented model resulted in a C statistic of 0.70 (0.69 for women, 0.71 for men). Both men and women in the highest vs lowest sex-specific quartiles of the augmented model's risk scores had an approximately 7-fold higher risk of developing MCI. Adding APOE ε4 carrier status improved the model (p = 0.002).

Conclusions: We have developed MCI risk scores using variables easily assessable in the clinical setting and that may be useful in routine patient care. Because of variability among populations, validation in independent samples is required. These models may be useful in identifying patients who might benefit from more expensive or invasive diagnostic testing, and can inform clinical trial design. Inclusion of biomarkers or other risk factors may further enhance the models.

Reference: Neurology 10.1212/WNL.0000000000001437

Increased CSF APPs-α levels in patients with Alzheimer disease treated with acitretin

Objective: Authors investigated induction of α-secretase A disintegrin and metalloprotease 10 (ADAM10) by the synthetic retinoid acitretin (Neotigason; Actavis, München-Riem, Germany) in patients with mild to moderate Alzheimer disease (AD) via measurement of CSF content of α-secretase–derived amyloid precursor protein (APPs-α).

Methods: Twenty-one patients clinically diagnosed with mild to moderate AD received acitretin (30 mg per day) or placebo in a 4-week double-blind study. Primary endpoint was the difference of CSF APPs-α ratios calculated from the APPs-α levels after treatment and at baseline. We monitored safety and tolerability of the treatment. In addition, we assessed biomarkers such as β-amyloid 42 (Aβ₄₂) under treatment conditions.

Results: The acitretin group showed a significant increase in CSF APPs-α levels compared with the placebo group (difference 0.38, 95% confidence interval 0.03–0.72, p = 0.035) within this rather short treatment period. The synthetic retinoid acitretin was overall safe and well tolerated.

Conclusions: Our pilot study highlights that acitretin is able to enhance the nonamyloidogenic APP processing in human patients. Clinical consequences of this regulation should be investigated in larger and longer trials in patients with AD to evaluate acitretin's potential to serve as a novel therapeutic drug.

Classification of evidence: This study provides Class III evidence that in patients with AD, oral acitretin increases CSF APPs-α levels.

Reference: Neurology 10.1212/WNL.0000000000001017

Anatomical heterogeneity of Alzheimer disease

Objective: Because the signs associated with dementia due to Alzheimer disease (AD) can be heterogeneous, the goal of this study was to use 3-dimensional MRI to examine the various patterns of cortical atrophy that can be associated with dementia of AD type, and to investigate whether AD dementia can be categorized into anatomical subtypes.

Methods: High-resolution T1-weighted volumetric MRIs were taken of 152 patients in their earlier stages of AD dementia. The images were processed to measure cortical thickness, and hierarchical agglomerative cluster analysis was performed using Ward's clustering linkage. The identified clusters of patients were compared with an age- and sex-matched control group using a general linear model.

Results: There were several distinct patterns of cortical atrophy and the number of patterns varied according to the level of cluster analyses. At the 3-cluster level, patients were divided into (1) bilateral medial temporal–dominant atrophy subtype (n = 52, ∼34.2%), (2) parietal-dominant subtype (n = 28, ∼18.4%) in which the bilateral parietal lobes, the precuneus, along with bilateral dorsolateral frontal lobes, were atrophic, and (3) diffuse atrophy subtype (n = 72, ∼47.4%) in which nearly all association cortices revealed atrophy. These 3 subtypes also differed in their demographic and clinical features.

Conclusions: This cluster analysis of cortical thickness of the entire brain showed that AD dementia in the earlier stages can be categorized into various anatomical subtypes, with distinct clinical features.

Reference: Neurology 10.1212/WNL.0000000000001003

The use of biomarkers for the etiologic diagnosis of MCI in Europe: An EADC survey

The most frequently used biomarker is visually rated MTA (75% of the 37 responders reported using it “always/frequently”) followed by CSF markers (22%), FDG-PET (16%), and amyloid-PET (3%). Only 45% of responders perceive MTA as contributing to diagnostic confidence, where the contribution was rated as “moderate”. Seventy-nine percent of responders felt “very/extremely” comfortable delivering a diagnosis of MCI due to AD when both amyloid and neuronal injury biomarkers were abnormal (P < .02 versus any individual biomarker). Responders largely agreed that a combination of amyloidosis and neuronal injury biomarkers was a strongly indicative AD signature.

DOI: http://dx.doi.org/10.1016/j.jalz.2014.06.006

Diagnostic impact of CSF biomarkers for Alzheimer's disease in a tertiary memory clinic

Background

We aimed to assess the impact of cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease on decision making and patient management in a tertiary memory clinic.

Methods

We included all patients, for 1 year, visiting the VUmc Alzheimer Center for cognitive screening. Neurologists completed questionnaires before and after CSF disclosure. We assessed the change of diagnosis, diagnostic confidence, and impact on patient management.

Results

A total of 438 patients (age 63 ± 8 years, 39% women) were included, of whom 351 (80%) underwent lumbar puncture. After the disclosure of CSF 23/351 diagnoses (7%) were changed. Diagnostic confidence increased from 84% to 89% (P < .001). There were consequences for management in 44/351 patients (13%) with CSF, and 13/87 patients (15%) because of unavailable CSF. There was no effect of age on these results.

Conclusions

CSF biomarkers aid clinicians with decision making during diagnostic work-up of cognitive disorders. This study may be useful for developing guidelines for the implementation of CSF biomarkers in daily practice.

DOI: http://dx.doi.org/10.1016/j.jalz.2014.05.1753

FDA Approves Third Amyloid PET Tracer for Alzheimer's

The US Food and Drug Administration (FDA) has approved a third agent for imaging β-amyloid in the setting of Alzheimer's disease (AD), florbetaben F18 injection (Neuraceq, Piramal Imaging).

Florbetaben is indicated for positron emission tomography (PET) of the brain to estimate β-amyloid neuritic plaque density in adults with cognitive impairment who are being evaluated for AD and other causes of cognitive decline. It was recently also approved in Europe.

Two other PET imaging tracers, florbetapir (Amyvid, Eli Lilly and Company) and flutemetamol (Vizamyl, GE Healthcare), were approved previously by the FDA in 2012 and 2013, respectively.

Plasma biomarkers could predict Alzheimer's before it starts

A simple blood test has the potential to predict whether a healthy person will develop symptoms of dementia within two or three years. If larger studies uphold the results, the test could fill a major gap in strategies to combat brain degeneration, which is thought to show symptoms only at a stage when it too late to treat effectively.

About ADNI

Amyloid imaging

Searching for biomarkers

Steps to standardization and validation of hippocampal volumetry as a biomarker in clinical trials and diagnostic criteria for Alzheimer’s disease

Background

The promise of Alzheimer’s disease (AD) biomarkers has led to their incorporation in new diagnostic criteria and in therapeutic trials; however, significant barriers exist to widespread use. Chief among these is the lack of internationally accepted standards for quantitative metrics. Hippocampal volumetry is the most widely studied quantitative magnetic resonance imaging (MRI) measure in AD and thus represents the most rational target for an initial effort at standardization.

Methods and Results

The authors of this position paper propose a path toward this goal. The steps include: 1) Establish and empower an oversight board to manage and assess the effort, 2) Adopt the standardized definition of anatomic hippocampal boundaries on MRI arising from the EADC-ADNI hippocampal harmonization effort as a Reference Standard, 3) Establish a scientifically appropriate, publicly available Reference Standard Dataset based on manual delineation of the hippocampus in an appropriate sample of subjects (ADNI), and 4) Define minimum technical and prognostic performance metrics for validation of new measurement techniques using the Reference Standard Dataset as a benchmark.

Conclusions

Although manual delineation of the hippocampus is the best available reference standard, practical application of hippocampal volumetry will require automated methods. Our intent is to establish a mechanism for credentialing automated software applications to achieve internationally recognized accuracy and prognostic performance standards that lead to the systematic evaluation and then widespread acceptance and use of hippocampal volumetry. The standardization and assay validation process outlined for hippocampal volumetry is envisioned as a template that could be applied to other imaging biomarkers.

Very early brain changes detected in children with genetic predisposition to Alzheimer's

A very interesting study found that infant ε4 carriers had lower MWF and GMV measurements than noncarriers in precuneus, posterior/middle cingulate, lateral temporal, and medial occipitotemporal regions, areas preferentially affected by AD, and greater MWF and GMV measurements in extensive frontal regions and measurements were also significant in the subset of 2- to 6-month-old infants (MWF differences, P<.05, after correction for multiple comparisons; GMV differences, P<.001,uncorrected fo rmultiple comparisons). Infant ε4 carriers also exhibited an attenuated relationship between MWF and age in posterior white matter regions.

This study raises new questions about the role of APOE in normal human brain development, the extent to which these processes are related to subsequent AD pathology, and whether they could be targeted by AD prevention therapies.

Full text

Neuroimaging and Biomarkers: How Early Can We Diagnose Alzheimer's?

Dementia: role of MRI

This review is based on a presentation given by Frederik Barkhof at the Neuroradiology teaching course for the Dutch Radiology Society and was adapted for the Radiology Assistant by Robin Smithuis.
First publication: 1-3-2007.
Updated version: 9-1-2012.

This presentation will focus on the role of MRI in the diagnosis of dementia and related diseases.

We will discuss the following subjects:

• Systematic assessment of MR in dementia
• MR protocol for dementia
• Typical findings in the most common dementia syndromes
  • Alzheimer's disease (AD)
  • Vascular Dementia (VaD)
  • Frontotemporal lobe dementia (FTLD)
• Short overview of neurodegenerative disorders which may be associated with dementia

Going to Biomarker Extremes to Find Rare Alzheimer’s Variants

Researchers have identified potential Alzheimer’s mutations by focusing their attention on people whose biomarkers reach extreme ends of the spectrum. As reported in the August 22 PLoS Genetics, scientists from Washington University in St. Louis, Missouri, found variants both known and novel when they sequenced major AD genes in people with very high or very low amounts of tau and amyloid β in their cerebrospinal fluid (CSF). Led by senior author Carlos Cruchaga, the researchers were surprised to find one of the risk variants was a polymorphism in presenilin 1 (PS1) that had previously been deemed non-pathogenic. When they considered this variant in the context of ApoE4, they found it conferred as much risk as a second copy of that allele. Someone carrying a single copy of both the PS1 variant and ApoE4 has 10 times the risk of someone with wild-type presenilin and no ApoE4, the researchers calculated. As scientists hunt for rare variants, it is important to consider that mutations may still be risk factors even if they exist in people without AD, Cruchaga said.

Biomarkers can predict risk for Alzheimer’s several years before symptoms appear

Brain imaging and spinal-fluid testing can help predict which cognitively normal older people will develop Alzheimer’s disease as many as 7.5 years before symptoms appear, according to a new study supported in part by the NIA. The findings confirm the power of biomarkers as predictors of disease risk in the earliest, symptom-free stages of Alzheimer’s disease. These biomarkers may prove to be valuable tools in testing promising treatments in future studies. While not typically used in clinical practice, investigators worldwide are studying, refining, and standardizing biomarkers aimed at identifying who is at risk for developing Alzheimer’s, the most common form of dementia in older adults. The biomarkers in this study, published May 7 in Neurology, included positron emission tomography (PET) scans of the brain to detect deposits of the telltale protein beta-amyloid, as well as levels of beta-amyloid and another protein, tau, found in cerebrospinal fluid. The research team, at Washington University School of Medicine in St. Louis, tracked the cognition of 201 dementia-free volunteers, ages 45 to 88, at the school’s Alzheimer’s Disease Research Center.
The researchers found that abnormal levels of biomarkers identified in PET scans and lumbar punctures could predict who would develop cognitive impairment among the volunteers who were followed for an average of 3.7 years, but in some cases as long as 7.5 years. Some 28 volunteers (14 percent) of the group developed memory loss and other signs of cognitive impairment. Abnormal levels of all biomarkers predicted the development of Alzheimer’s dementia equally well, the study found. Older participants, men, and African Americans who developed dementia did so faster than those who were younger, female, and white, the researchers report. In a few cases, participants with abnormal biomarker levels remained cognitively normal, perhaps because of “cognitive reserve,” the ability of some brains to cope with or stave off decline.
Reference: Roe CM, et al. Amyloid imaging and CSF biomarkers in predicting cognitive impairment up to 7.5 years later.

Reference: Roe CM, et al. Amyloid imaging and CSF biomarkers in predicting cognitive impairment up to 7.5 years later. Neurology 2013;80(19):1784-91.