Cross-sectional and longitudinal comparisons of biomarkers and cognition among asymptomatic middle-aged individuals with a parental history of either autosomal dominant or late-onset Alzheimer's disease.

BACKGROUND: Comparisons of late-onset Alzheimer's disease (LOAD) and autosomal dominant AD (ADAD) are confounded by age. METHODS: We compared biomarkers from cerebrospinal fluid (CSF), magnetic resonance imaging, and amyloid imaging with Pittsburgh Compound-B (PiB) across four groups of 387 cognitively normal participants, 42 to 65 years of age, in the Dominantly Inherited Alzheimer Network (DIAN) and the Adult Children Study (ACS) of LOAD: DIAN mutation carriers (MCs) and non-carriers (NON-MCs), and ACS participants with a positive (FH+) and negative (FH-) family history of LOAD. RESULTS: At baseline, MCs had the lowest age-adjusted level of CSF Aß42 and the highest levels of total and phosphorylated tau-181, and PiB uptake. Longitudinally, MC had similar increase in PiB uptake to FH+, but drastically faster decline in hippocampal volume than others, and was the only group showing cognitive decline. DISCUSSION: Preclinical ADAD and LOAD share many biomarker signatures, but cross-sectional and longitudinal differences may exist.

Subcortical and Cortical Regions of Amyloid-ß Pathology Measured by 11C-PiB PET Are Differentially Associated with Cognitive Functions and Stages of Disease in Memory Clinic Patients.

BACKGROUND: The effect of regional brain amyloid-ß (Aß) pathology on specific cognitive functions is incompletely known. OBJECTIVE: The relationship between Aß and cognitive functions was investigated in this cross-sectional multicenter study of memory clinic patients. METHODS: The participants were patients diagnosed with Alzheimer's disease (AD, n = 83), mild cognitive impairment (MCI, n = 60), and healthy controls (HC, n = 32), who had been scanned by 11C-PiB PET in 13 brain regions of both hemispheres and who had been assessed by cognitive tests covering seven domains. RESULTS: Hierarchic multiple regression analyses were performed on each cognitive test as dependent variable, controlling for demographic characteristics and APOE status (block 1) and PiB measures in 13 brain regions (block 2) as independent variables. The model was highly significant for each cognitive test and most strongly for tests of episodic memory (learning and retention) versus PiB in putamen, visuospatially demanding tests (processing and retention) versus the occipital lobe, semantic fluency versus the parietal lobe, attention versus posterior gyrus cinguli, and executive function versus nucleus accumbens. In addition, education had a positively and APOE status a negatively significant effect on cognitive tests. CONCLUSION: Five subcortical and cortical regions with Aß pathology are differentially associated with cognitive functions and stages of disease in memory clinic patients.

Modeling autosomal dominant Alzheimer's disease with machine learning.

INTRODUCTION: Machine learning models were used to discover novel disease trajectories for autosomal dominant Alzheimer's disease. METHODS: Longitudinal structural magnetic resonance imaging, amyloid positron emission tomography (PET), and fluorodeoxyglucose PET were acquired in 131 mutation carriers and 74 non-carriers from the Dominantly Inherited Alzheimer Network; the groups were matched for age, education, sex, and apolipoprotein ε4 (APOE ε4). A deep neural network was trained to predict disease progression for each modality. Relief algorithms identified the strongest predictors of mutation status. RESULTS: The Relief algorithm identified the caudate, cingulate, and precuneus as the strongest predictors among all modalities. The model yielded accurate results for predicting future Pittsburgh compound B (R2  = 0.95), fluorodeoxyglucose (R2  = 0.93), and atrophy (R2  = 0.95) in mutation carriers compared to non-carriers. DISCUSSION: Results suggest a sigmoidal trajectory for amyloid, a biphasic response for metabolism, and a gradual decrease in volume, with disease progression primarily in subcortical, middle frontal, and posterior parietal regions.

Voxel-based morphometry focusing on medial temporal lobe structures has a limited capability to detect amyloid ß, an Alzheimer's disease pathology.

Voxel-based morphometry (VBM) analysis of nuclear Magnetic Resonance Imaging (MRI) data allows the identification of medial temporal lobe (MTL) atrophy and is widely used to assist the diagnosis of Alzheimer's disease (AD). However, its reliability in the clinical environment has not yet been confirmed. To determine the credibility of VBM, amyloid positron emission tomography (PET) and VBM studies were compared retrospectively. Patients who underwent Pittsburgh Compound B (PiB) PET were retrospectively recruited. Ninety-seven patients were found to be amyloid negative and 116 were amyloid positive. MTL atrophy in the PiB positive group, as quantified by thin sliced 3D MRI and VBM software, was significantly more severe (p =0.0039) than in the PiB negative group. However, data histogram showed a vast overlap between the two groups. The area under the ROC curve (AUC) was 0.646. MMSE scores of patients in the amyloid negative and positive groups were also significantly different (p = 0.0028), and the AUC was 0.672. Thus, MTL atrophy could not reliably differentiate between amyloid positive and negative patients in a clinical setting, possibly due to the wide array of dementia-type diseases that exist other than AD.

A harmonized longitudinal biomarkers and cognition database for assessing the natural history of preclinical Alzheimer's disease from young adulthood and for designing prevention trials.

INTRODUCTION: Large longitudinal biomarkers database focusing on middle age is needed for Alzheimer's disease (AD) prevention. METHODS: Data for cerebrospinal fluid analytes, molecular imaging of cerebral fibrillar ß-amyloid with positron emission tomography, magnetic resonance imaging-based brain structures, and clinical/cognitive outcomes were harmonized across eight AD biomarker studies. Statistical power was estimated. RESULTS: The harmonized database included 7779 participants with clinical/cognitive data: 3542 were 18∼65 years at the baseline, 5865 had longitudinal cognitive data for a median of 4.7 years, 2473 participated in the cerebrospinal fluid studies (906 had longitudinal data), 2496 participated in the magnetic resonance imaging studies (1283 had longitudinal data), and 1498 participated in the positron emission tomography amyloid studies (849 had longitudinal data). The database provides adequate power for detecting early biomarker changes, and demonstrates the feasibility of AD prevention trials on middle-aged individuals. DISCUSSION: The harmonized database is an optimum resource to design AD prevention trials decades before symptomatic onset.

Neurotrophin Receptor p75 mRNA Level in Peripheral Blood Cells of Patients with Alzheimer's Disease.

The neurotrophin receptor p75 (p75NTR) plays important roles in regulating amyloid-beta (Aß) metabolism in the brain. The expression of p75NTR is altered in the brain of patients with Alzheimer's disease (AD). In this study, we aimed to evaluate whether p75NTR mRNA level in the peripheral blood cells is changed among AD patients and its potential to be a biomarker for AD. The study subjects included 26 patients with AD (PiB-PET positive) and 28 cognitively normal controls (PiB-PET negative). RNA was extracted from peripheral blood cells of fast blood. p75NTR mRNA was measured using quantitative real-time PCR assay. p75NTR mRNA levels in blood cells were comparable between AD patients and controls. p75NTR mRNA levels in blood cells were not correlated with MMSE scores, ApoE genotypes, gender, and age. p75NTR mRNA expression in blood cells is not changed in AD patients and is unlikely to be a biomarker for AD.

Pittsburgh Compound-B (PiB) binds amyloid ß-protein protofibrils.

The neuropathology of Alzheimer's disease (AD) includes amyloid plaque formation by the amyloid ß-protein (Aß) and intracellular paired helical filament formation by tau protein. These neuropathogenetic features correlate with disease progression and have been revealed in brains of AD patients using positron emission tomography (PET). One of the most useful positron emission tomography imaging agents has been Pittsburgh Compound-B (PiB). However, since its introduction in 2002, substantial evidence has accumulated suggesting that Aß oligomerization and protofibril formation, rather than fibril formation per se, may be the more important pathogenetic event in AD. Detecting protofibrils and oligomeric forms of Aß thus may be of value. We report here the results of experiments to determine whether PiB binds to oligomers or protofibrils formed by Aß40 and Aß42. We observed strong binding to Aß42 fibrils, significant binding to protofibrils, and weaker binding to Aß42 oligomers. PiB also binds Aß40 fibrils, but its binding to Aß40 protofibrils and oligomers is substantially lower than for that observed for Aß42.

Detection of cerebral amyloid angiopathy by 3-T magnetic resonance imaging and amyloid positron emission tomography in a patient with subcortical ischaemic vascular dementia.

The patient was an 81-year-old man who had been treated for hypertension for several decades. In 2012, he developed gait disturbance and mild amnesia. One year later, his gait disturbance worsened, and he developed urinary incontinence. Conventional brain magnetic resonance imaging using T 2 -weighted images and fluid-attenuated inversion recovery showed multiple lacunar infarctions. These findings fulfilled the diagnostic criteria for subcortical ischaemic vascular dementia. However, susceptibility weighted imaging showed multiple lobar microbleeds in the bilateral occipitoparietal lobes, and double inversion recovery and 3-D fluid-attenuated inversion recovery images on 3-T magnetic resonance imaging revealed cortical microinfarctions in the left parietal-temporo-occipito region. Pittsburgh compound B-positron emission tomography revealed diffuse uptake in the cerebral cortex. Therefore, we diagnosed the patient with subcortical ischaemic vascular dementia associated with Alzheimer's disease. The use of the double inversion recovery and susceptibility weighted imaging on 3-T magnetic resonance imaging may be a supplemental strategy for diagnosing cerebral amyloid angiopathy, which is closely associated with Alzheimer's disease.

[(11)C]PiB PET in Gerstmann-Sträussler-Scheinker disease.

Gerstmann-Sträussler-Scheinker Disease (GSS) is a familial neurodegenerative disorder characterized clinically by ataxia, parkinsonism, and dementia, and neuropathologically by deposition of diffuse and amyloid plaques composed of prion protein (PrP). The purpose of this study was to evaluate if [(11)C]Pittsburgh Compound B (PiB) positron emission tomography (PET) is capable of detecting PrP-amyloid in PRNP gene carriers. Six individuals at risk for GSS and eight controls underwent [(11)C]PiB PET scans using standard methods. Approximately one year after the initial scan, each of the three asymptomatic carriers (two with PRNP P102L mutation, one with PRNP F198S mutation) underwent a second [(11)C]PiB PET scan. Three P102L carriers, one F198S carrier, and one non-carrier of the F198S mutation were cognitively normal, while one F198S carrier was cognitively impaired during the course of this study. No [(11)C]PiB uptake was observed in any subject at baseline or at follow-up. Neuropathologic study of the symptomatic individual revealed PrP-immunopositive plaques and tau-immunopositive neurofibrillary tangles in cerebral cortex, subcortical nuclei, and brainstem. PrP deposits were also numerous in the cerebellar cortex. This is the first study to investigate the ability of [(11)C]PiB PET to bind to PrP-amyloid in GSS F198S subjects. This finding suggests that [(11)C]PiB PET is not suitable for in vivo assessment of PrP-amyloid plaques in patients with GSS.

Deformation field correction for spatial normalization of PET images.

Spatial normalization of positron emission tomography (PET) images is essential for population studies, yet the current state of the art in PET-to-PET registration is limited to the application of conventional deformable registration methods that were developed for structural images. A method is presented for the spatial normalization of PET images that improves their anatomical alignment over the state of the art. The approach works by correcting the deformable registration result using a model that is learned from training data having both PET and structural images. In particular, viewing the structural registration of training data as ground truth, correction factors are learned by using a generalized ridge regression at each voxel given the PET intensities and voxel locations in a population-based PET template. The trained model can then be used to obtain more accurate registration of PET images to the PET template without the use of a structural image. A cross validation evaluation on 79 subjects shows that the proposed method yields more accurate alignment of the PET images compared to deformable PET-to-PET registration as revealed by 1) a visual examination of the deformed images, 2) a smaller error in the deformation fields, and 3) a greater overlap of the deformed anatomical labels with ground truth segmentations.