The purpose of this study was to use serial imaging to gain insight into the sequence of pathologic events in Alzheimers disease, and the clinical features associated with this sequence. We measured change in amyloid deposition over time using serial 11C Pittsburgh compound B (PIB) positron emission tomography and progression of neurodegeneration using serial structural magnetic resonance imaging. We studied 21 healthy cognitively normal subjects, 32 with amnestic mild cognitive impairment and 8 with Alzheimers disease. Subjects were drawn from two sourcesongoing longitudinal registries at Mayo Clinic, and the Alzheimers disease Neuroimaging Initiative (ADNI). All subjects underwent clinical assessments, MRI and PIB studies at two time points, approximately one year apart. PIB retention was quantified in global cortical to cerebellar ratio units and brain atrophy in units of cm3 by measuring ventricular expansion. The annual change in global PIB retention did not differ by clinical group (P 0.90), and although small (median 0.042 ratio units/year overall) was greater than zero among all subjects (P < 0.001). Ventricular expansion rates differed by clinical group (P < 0.001) and increased in the following order: cognitively normal (1.3 cm3/year) < amnestic mild cognitive impairment (2.5 cm3/year) < Alzheimers disease (7.7 cm3/year). Among all subjects there was no correlation between PIB change and concurrent change on CDR-SB (r -0.01, P 0.97) but some evidence of a weak correlation with MMSE (r -0.22, P 0.09). In contrast, greater rates of ventricular expansion were clearly correlated with worsening concurrent change on CDR-SB (r 0.42, P < 0.01) and MMSE (r -0.52, P < 0.01). Our data are consistent with a model of typical late onset Alzheimers disease that has two main features: (i) dissociation between the rate of amyloid deposition and the rate of neurodegeneration late in life, with amyloid deposition proceeding at a constant slow rate while neurodegeneration accelerates and (ii) clinical symptoms are coupled to neurodegeneration not amyloid deposition. Significant plaque deposition occurs prior to clinical decline. The presence of brain amyloidosis alone is not sufficient to produce cognitive decline, rather, the neurodegenerative component of Alzheimers disease pathology is the direct substrate of cognitive impairment and the rate of cognitive decline is driven by the rate of neurodegeneration. Neurodegeneration (atrophy on MRI) both precedes and parallels cognitive decline. This model implies a complimentary role for MRI and PIB imaging in Alzheimers disease, with each reflecting one of the major pathologies, amyloid dysmetabolism and neurodegeneration. © 2009 The Author(s)2009This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2009 Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.

© 2017 American Academy of Neurology. Objective: To assess the efficacy of [ 18 F]AV1451 PET in visualizing tau pathology in vivo in a patient with frontotemporal dementia (FTD) associated with the V337M microtubule-associated protein tau (MAPT) mutation. Methods: MAPT mutations are associated with the deposition of hyperphosphorylated tau protein in neurons and glia. The PET tracer [ 18 F]AV1451 binds with high affinity to paired helical filaments tau that comprises neurofibrillary tangles in Alzheimer disease (AD), while postmortem studies suggest lower or absent binding to the tau filaments of the majority of non-AD tauopathies. We describe clinical, structural MRI, and [ 18 F]AV1451 PET findings in a V337M MAPT mutation carrier affected by FTD and pathologic findings in his affected mother and in an unrelated V337M MAPT carrier also affected with FTD. The biochemical similarity between paired helical filament tau in AD and MAPT V337M predicts that the tau pathology associated with this mutation constitutes a compelling target for [ 18 F]AV1451 imaging. Results: We found a strong association between topography and degree of [ 18 F]AV1451 tracer retention in the proband and distribution of tau pathology in the brain of the proband's mother and the unrelated V337M mutation carrier. We also found a significant correlation between the degree of regional MRI brain atrophy and the extent of [ 18 F]AV1451 binding in the proband and a strong association between the proband's clinical presentation and the extent of regional brain atrophy and tau accumulation as assessed by structural brain MRI and [ 18 F]AV1451PET. Conclusion: Our study supports the usefulness of [ 18 F]AV1451 to characterize tau pathology in at least a subset of pathogenic MAPT mutations.

Background: The clinical diagnosis of dementing diseases largely depends on the subjective interpretation of patient symptoms. Consensus panels are frequently used in research to determine diagnoses when definitive pathologic findings are unavailable. Nevertheless, research on group decision making indicates that many factors can adversely affect panel performance. Objective: To determine conditions that improve consensus panel diagnosis. Design: Comparison of neuropathologic diagnoses with individual and consensus panel diagnoses based on clinical scenarios only, fludeoxyglucose F 18 positron emission tomography images only, and scenarios plus images. Setting: Expert and trainee individual and consensus panel deliberations using a modified Delphi method in a pilot research study of the diagnostic utility of fludeoxyglucose F 18 positron emission tomography. Patients: Forty-five patients with pathologically confirmed Alzheimer disease or frontotemporal dementia. Main Outcome Measures: Statistical measures of diagnostic accuracy, agreement, and confidence for individual raters and panelists before and after consensus deliberations. Results: The consensus protocol using trainees and experts surpassed the accuracy of individual expert diagnoses when clinical information elicited diverse judgments. In these situations, consensus was 3.5 times more likely to produce positive rather than negative changes in the accuracy and diagnostic certainty of individual panelists. A rule that forced group consensus was at least as accurate as majority and unanimity rules. Conclusions: Using a modified Delphi protocol to arrive at a consensus diagnosis is a reasonable substitute for pathologic information. This protocol improves diagnostic accuracy and certainty when panelist judgments differ and is easily adapted to other research and clinical settings while avoiding the potential pitfalls of group decision making. ©2010 American Medical Association. All rights reserved.

Objective: To evaluate the cause of diagnostic errors in the visual interpretation of positron emission tomographic scans with fludeoxyglucose F 18 (FDG-PET) in patients with frontotemporal lobar degeneration (FTLD) and patients with Alzheimer disease (AD). Design: Twelve trained raters unaware of clinical and autopsy information independently reviewed FDG-PET scans and provided their diagnostic impression and confidence of either FTLD or AD. Six of these raters also recorded whether metabolism appeared normal or abnormal in 5 predefined brain regions in each hemisphere - frontal cortex, anterior cingulate cortex, anterior temporal cortex, temporoparietal cortex, and posterior cingulate cortex. Results were compared with neuropathological diagnoses. Setting: Academic medical centers. Patients: Forty-five patients with pathologically confirmed FTLD (n=14) or AD (n=31). Results: Raters had a high degree of diagnostic accuracy in the interpretation of FDG-PET scans; however, raters consistently found some scans more difficult to interpret than others. Unanimity of diagnosis among the raters was more frequent in patients with AD (27 of 31 patients [87%]) than in patients with FTLD (7 of 14 patients [50%]) (P=.02). Disagreements in interpretation of scans in patients with FTLD largely occurred when there was temporoparietal hypometabolism, which was present in 7 of the 14 FTLD scans and 6 of the 7 scans lacking unanimity. Hypometabolism of anterior cingulate and anterior temporal regions had higher specificities and positive likelihood ratios for FTLD than temporoparietal hypometabolism had for AD. Conclusions: Temporoparietal hypometabolism in FTLD is common and may cause inaccurate interpretation of FDG-PET scans. An interpretation paradigm that focuses on the absence of hypometabolism in regions typically affected in AD before considering FTLD is likely to misclassify a significant portion of FTLD scans. Anterior cingulate and/or anterior temporal hypometabolism indicates a high likelihood of FTLD, even when temporoparietal hypometabolism is present. Ultimately, the accurate interpretation of FDG-PET scans in patients with dementia cannot rest on the presence or absence of a single region of hypometabolism but rather must take into account the relative hypometabolism of all brain regions. ©2011 American Medical Association. All rights reserved.

© 2016 2016 International Parkinson and Movement Disorder Society Background: Despite the widespread use of the Progressive Supranuclear Palsy Rating Scale (PSPRS), it is not known what change in this scale is meaningful for patients. Methods: We analyzed data from a large clinical trial in PSP-Richardson's syndrome (AL-108-231) to calculate minimal clinically important worsening. This was defined as the difference in mean change of PSPRS in subjects rated “a little worse” and those rated “unchanged” on the Clinicians' Global Impression of Change Scale. A multivariate analysis using logistic regression assessed the relationship between clinical worsening, PSPRS, depression, and activities of daily living. Results: The minimal clinically important worsening on the PSPRS was 5.7 points, corresponding to the mean decline over 6 months in the trial. Changes in activities of daily living and PSPRS were significantly associated with clinical worsening. Conclusions: Clinically meaningful change is measurable on the PSPRS over 6 months. © 2016 International Parkinson and Movement Disorder Society.

Our understanding of the molecular mechanisms of many neurological disorders has been greatly enhanced by the discovery of mutations in genes linked to familial forms of these diseases. These have facilitated the generation of cell and animal models that can be used to understand the underlying molecular pathology. Recently, there has been a surge of interest in the use of patient-derived cells, due to the development of induced pluripotent stem cells and their subsequent differentiation into neurons and glia. Access to patient cell lines carrying the relevant mutations is a limiting factor for many centres wishing to pursue this research. We have therefore generated an open-access collection of fibroblast lines from patients carrying mutations linked to neurological disease. These cell lines have been deposited in the National Institute for Neurological Disorders and Stroke (NINDS) Repository at the Coriell Institute for Medical Research and can be requested by any research group for use in in vitro disease modelling. There are currently 71 mutation-defined cell lines available for request from a wide range of neurological disorders and this collection will be continually expanded. This represents a significant resource that will advance the use of patient cells as disease models by the scientific community.