SEE THAL AND VANDENBERGHE DOI101093/BRAIN/AWW057 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Post-mortem Braak staging of neurofibrillary tau tangle topographical distribution is one of the core neuropathological criteria for the diagnosis of Alzheimer's disease. The recent development of positron emission tomography tracers targeting neurofibrillary tangles has enabled the distribution of tau pathology to be imaged in living subjects. Methods for extraction of classic Braak staging from in vivo imaging of neurofibrillary tau tangles have not yet been explored. Standardized uptake value ratio images were calculated from 80-100 minute (18)F-AV-1451 (also known as T807) positron emission tomography scans obtained from n = 14 young reference subjects (age 21-39 years, Mini-Mental State Examination 29-30) and n = 173 older test subjects (age 50-95 years) comprising amyloid negative cognitively normal (n = 42), clinically-diagnosed mild cognitive impairment (amyloid positive, n = 47, and amyloid negative, n = 40) and Alzheimer's disease (amyloid positive, n = 28, and amyloid negative, n = 16). We defined seven regions of interest in anterior temporal lobe and occipital lobe sections corresponding closely to those used as decision points in Braak staging. An algorithm based on the Braak histological staging procedure was applied to estimate Braak stages directly from the region of interest profiles in each subject. Quantitative region-based analysis of (18)F-AV-1451 images yielded region of interest and voxel level profiles that mirrored key features of neuropathological tau progression including profiles consistent with Braak stages 0 through VI. A simple set of decision rules enabled plausible Braak stages corresponding to stereotypical progression patterns to be objectively estimated in 149 (86%) of test subjects. An additional 12 (7%) subjects presented with predefined variant profiles (relative sparing of the hippocampus and/or occipital lobe). The estimated Braak stage was significantly associated with amyloid status, diagnostic category and measures of global cognition. In vivo (18)F-AV-1451 positron emission tomography images across the Alzheimer's disease spectrum could be classified into patterns similar to those prescribed by Braak neuropathological staging of tau pathology.

The corpus callosum (CC) is the major conduit for information transfer between the cerebral hemispheres and plays an integral role in relaying sensory, motor and cognitive information between homologous cortical regions. The majority of fibers that make up the CC arise from large pyramidal neurons in layers III and V, which project contra-laterally. These neurons degenerate in Huntington’s disease (HD) in a topographically and temporally selective way. Since any focus of cortical degeneration could be expected to secondarily de-afferent homologous regions of cortex, we hypothesized that regionally selective cortical degeneration would be reflected in regionally selective degeneration of the CC. We used conventional T1-weighted, diffusion tensor imaging (DTI), and a modified corpus callosum segmentation scheme to examine the CC in healthy controls, huntingtin gene-carriers and symptomatic HD subjects. We measured mid-sagittal callosal cross-sectional thickness and several DTI parameters, including fractional anisotropy (FA), which reflects the degree of white matter organization, radial diffusivity, a suggested index of myelin integrity, and axial diffusivity, a suggested index of axonal damage of the CC. We found a topologically selective pattern of alterations in these measures in pre-manifest subjects that were more extensive in early symptomatic HD subjects and that correlated with performance on distinct cognitive measures, suggesting an important role of for disrupted inter-hemispheric transfer in the clinical symptoms of HD. Our findings provide evidence for early degeneration of commissural pyramidal neurons in the neocortex, loss of cortico-cortical connectivity, and functional compromise of associative cortical processing.

Background The neuroanatomy of agitation and aggression in Alzheimer's disease is not well understood. Methods We analyzed 24 months of Alzheimer's Disease Neuroimaging Initiative data for patients with Alzheimer's disease, mild cognitive impairment-stable, and mild cognitive impairment-converter (n = 462) using the Neuropsychiatric Inventory Questionnaire Agitation and Aggression subscale. Magnetic resonance imaging regions of interest that correlated with Neuropsychiatric Inventory Questionnaire Agitation and Aggression subscale raw scores were included in mixed-model, repeated-measures analyses of agitation and aggression over time with age, sex, apolipoprotein E ε4 status, education, and Mini-Mental State Examination score as covariates. Results Neuropsychiatric Inventory Questionnaire Agitation and Aggression subscale scores worsened in patients with Alzheimer's disease and in mild cognitive impairment-converter (P <.05; trend for mild cognitive impairment, P =.0518). Greater agitation and aggression severity was associated with greater atrophy of frontal, insular, amygdala, cingulate, and hippocampal regions of interest (P < .05). Mini-Mental State Examination score was significant in mixed-effect model repeated measures only in mild cognitive impairment-converters for posterior regions of interest. Demographics and apolipoprotein ε4 were not associated with agitation and aggression. Conclusions Agitation and aggression in Alzheimer's disease and mild cognitive impairment is associated with neurodegeneration affecting the anterior salience network that may reduce capacity to process and regulate behaviors properly.

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We summarize the scientific rationale and the data that supported the first qualification of an imaging biomarker by the European Medicines Agency.

Background Neuropsychiatric symptoms (NPS) are common in Mild Cognitive Impairment (MCI) and Alzheimer's Disease (AD) and often measured using the Neuropsychiatric Inventory (NPI). Development of validated subscales that measure clinically meaningful symptom clusters would improve capacity for individualized treatment and assessment of treatment interventions. We report preliminary validation of three NPI Questionnaire (NPI-Q) subscales derived from examination of the existing exploratory literature and clinical knowledge. Methods The validity of subscales that assess Frontal, Agitation/Aggression, and Mood symptoms (based on NPI-Q-10 item scores) was ascertained by comparison of cross-sectional data from amnestic MCI and AD dementia cases from the National Alzheimer's Coordinating Center (NACC) and Alzheimer's Disease Neuroimaging Initiative (ADNI) databases. The statistical approach was confirmatory unrotated principal component analysis. Results ADNI contributed 103 MCI, 90 MCI-converters and 112 AD dementia cases while NACC had 1042, 763, and 3048. Baseline mean age was higher in NACC (74.6 vs 75.7). Patients in NACC were significantly more impaired at last visit on MMSE (mean scores 19.5 vs 22.4) and NPI-Q-10 (5.0 vs 4.3), as well as for each of the three subscales (NPI-Q-4-Frontal, NPI-Q-4-Agitation/Aggression, and NPI-Q-3-Mood than ADNI (at month 24). Medians were not different for Agitation/Aggression or Mood subscales, however. Each item on all scales contributed variance in PCA Pareto plots. All items in Factor (F) 1 for each scale projected in a positive direction on biplots (coherence), while F2 and F3 items showed more spatial separation (independence). Scale analyses showed remarkable similarities between ADNI and NACC cohorts for factor loadings and spatial patterns of item projections, though factor item identities varied somewhat, especially beyond F1. Conclusions The similar pattern of results across two cohorts of patients support the validity of these constructs. These subscales are worthy of further psychometric evaluation in patients with MCI and AD dementia and preliminary application in clinical settings.

It is generally recognized that more sensitive instruments for the earliest stages of Alzheimer’s disease (AD) are needed. The integrated Alzheimer’s Disease Rating Scale (iADRS) combines scores from 2 widely accepted measures, the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and the Alzheimer’s Disease Cooperative Study – instrumental Activities of Daily Living (ADCS-iADL). Disease progression and treatment differences as measured by the iADRS were analyzed using data from solanezumab EXPEDITION, EXPEDITION2, and EXPEDITION-EXT Studies; semagacestat IDENTITY Study; and donepezil ADCS – mild cognitive impairment (ADCS-MCI) Study. Psychometric properties of the iADRS were established through principal component analysis (PCA) and estimation of contributions of subscores and individual item scores to the iADRS total score. The iADRS performed better than most composites and scales in detecting disease progression and comparably or better than individual scales in detecting treatment differences. PCA demonstrated the iADRS can be divided into two principal components primarily representing cognitive items and instrumental ADLs. Dynamic ranges of the subscales were similar across all studies, reflecting approximately equal contributions from both subscales to the iADRS total score. In item analyses, every item contributed to the total score, with varying strength of contributions by item and across data sets. The iADRS demonstrated acceptable psychometric properties and was effective in capturing disease progression from MCI through moderate AD and treatment effects across the early disease spectrum. These findings suggest the iADRS can be used in studies of mixed populations, ensuring sensitivity to treatment effects as subjects progress during studies of putative disease-modifying agents.

Our results demonstrate imputing Aβ status from MRI scans in mild-AD subjects may be a useful screening tool in global clinical trials if amyloid measurement is not available.