Alzheimer disease (AD) is the most common cause of late-onset dementia. This article describes the epidemiology, genetic and environmental risk factors, clinical diagnosis, biomarkers, and treatment ...of late-onset AD, defined by age of onset of 65 years or older.
An estimated 5.7 million Americans are living with AD dementia, with the number of affected individuals growing rapidly because of an aging population. Vascular risk factors, sleep disorders, and traumatic brain injury are associated with an increased risk of AD, while increased cognitive and physical activity throughout the lifespan reduce the risk of disease. The primary genetic risk factor for late-onset AD is the apolipoprotein E (APOE) ε4 allele. AD typically presents with early and prominent episodic memory loss, although this clinical syndrome is neither sensitive nor specific for underlying AD neuropathology. Emerging CSF and imaging biomarkers can now detect the key neuropathologic features of the disease (amyloid plaques, neurofibrillary tangles, and neurodegeneration) in living people, allowing for characterization of patients based on biological measures. A comprehensive treatment plan for AD includes use of symptomatic medications, optimal treatment of comorbid conditions and neuropsychiatric symptoms, counseling about safety and future planning, and referrals to community resources.
AD is very common in older neurologic patients. Neurologists should set the standard for the diagnosis and care of patients with AD and should be familiar with emerging biomarkers that have transformed AD research and are primed to enter the clinical arena.
The doubly fed induction machine has been traditionally adopted in adjustable-speed ac power generation drives in order to take advantage of the reduced rating for the power electronic interface. ...Aside this well-established application where the doubly fed induction generator (DFIG) is controlled by a back-to-back converter, recent literature records a growing interest toward un-conventional DFIG drives for dc power generation, combining DFIG high control freedom with simplified power electronic interfaces to achieve an overall cheap and fully controllable system. Despite several concepts have been demonstrated on small-scale rigs, there is a lack of systematic comparison among different topologies and control solutions. This paper bridges this gap by providing a review of recent topologies, their control, design and performance, and operation issues. As major novelties, this paper includes off-spec performance comparison of different torque-ripple mitigation strategies, discussion of sizing requirements for generator and power electronics, fundamental aspects of the behavior under voltage dips, and priorities and challenges for future research on the subject.
Tau pathology is a hallmark of Alzheimer’s disease (AD) but also occurs in normal cognitive aging. Using the tau PET agent 18F-AV-1451, we examined retention patterns in cognitively normal older ...people in relation to young controls and AD patients. Age and β-amyloid (measured using PiB PET) were differentially associated with tau tracer retention in healthy aging. Older age was related to increased tracer retention in regions of the medial temporal lobe, which predicted worse episodic memory performance. PET detection of tau in other isocortical regions required the presence of cortical β-amyloid and was associated with decline in global cognition. Furthermore, patterns of tracer retention corresponded well with Braak staging of neurofibrillary tau pathology. The present study defined patterns of tau tracer retention in normal aging in relation to age, cognition, and β-amyloid deposition.
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•AV-1451 PET imaging allows in vivo Braak tau staging based on tracer uptake•Age and β-amyloid are associated with different patterns of tau tracer retention•Medial temporal tau tracer retention relates to episodic memory decline in aging
Schöll, Lockhart, et al. examined tau pathology in vivo using 18F-AV-1451 (tau) PET in healthy aging and found relationships with cognitive function. Confirming neuropathologically established patterns, they also detected different effects of age and β-amyloid on patterns of tau deposition.
The recent development of tau-specific positron emission tomography (PET) tracers enables in vivo quantification of regional tau pathology, one of the key lesions in Alzheimer's disease (AD). Tau PET ...imaging may become a useful biomarker for clinical diagnosis and tracking of disease progression but there is no consensus yet on how tau PET signal is best quantified. The goal of the current study was to evaluate multiple whole-brain and region-specific approaches to detect clinically relevant tau PET signal. Two independent cohorts of cognitively normal adults and amyloid-positive (Aβ+) patients with mild cognitive impairment (MCI) or AD-dementia underwent 18FAV-1451 PET. Methods for tau tracer quantification included: (i) in vivo Braak staging, (ii) regional uptake in Braak composite regions, (iii) several whole-brain measures of tracer uptake, (iv) regional uptake in AD-vulnerable voxels, and (v) uptake in a priori defined regions. Receiver operating curves characterized accuracy in distinguishing Aβ- controls from AD/MCI patients and yielded tau positivity cutoffs. Clinical relevance of tau PET measures was assessed by regressions against cognition and MR imaging measures. Key tracer uptake patterns were identified by a factor analysis and voxel-wise contrasts. Braak staging, global and region-specific tau measures yielded similar diagnostic accuracies, which differed between cohorts. While all tau measures were related to amyloid and global cognition, memory and hippocampal/entorhinal volume/thickness were associated with regional tracer retention in the medial temporal lobe. Key regions of tau accumulation included medial temporal and inferior/middle temporal regions, retrosplenial cortex, and banks of the superior temporal sulcus. Our data indicate that whole-brain tau PET measures might be adequate biomarkers to detect AD-related tau pathology. However, regional measures covering AD-vulnerable regions may increase sensitivity to early tau PET signal, atrophy and memory decline.
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•10 different tau PET measures were evaluated in 2 independent samples.•Global and region-specific tau measures yielded similar diagnostic accuracies.•Correlations to clinical variables were stronger for regional than global measures.•Tau deposition showed typical patterns captured by several different approaches.•Neocortical tau deposition was greater for early- than late-onset AD cases.
Currently, a significant transformation for energy systems has emerged as a result of the trend to develop an energy framework without fossil fuel reliance, the concerns about climate change and air ...quality, and the need to provide electricity to around of 17% of world population who lacks the service. Accordingly, the deployment of power plants located close to end-users and including multiple energy sources and carriers, along with the growing share of renewable energies, have suggested changes in the energy sector. Despite their potential capabilities, the design of distributed energy systems (DES) is a complex problem due to the simultaneous goals and constraints that need to be considered, as well as to the high context dependence of this kind of projects. For these reasons, in this work a systematic literature review of DES including hydrogen as energy vector, was made analyzing 106 research papers published between the years 2000–2018, and extracted from Scopus® and Web of Science databases. The aim was to identify how hydrogen is employed (technologies, uses) and the criteria that are evaluated (economic, technical, social and environmental) when these systems are designed, planned and/or operated. The results constitute a baseline information covering the type of technologies, equipment sizes and hydrogen applications, that could be valuable for the preliminary stages of research or project planning of DES involving hydrogen. Furthermore, other factors have also been identified, such as the focus on techno-economic issues, and the lack of considering socio/political aspects and the uncertainty about input data like weather conditions, energy prices and demands. Additionally, a more integrated approach is needed including all the hydrogen supply chain stages and project stakeholders, to tackle issues like safety of the energy systems that could produce consumer rejections.
•Distributed energy systems including hydrogen as energy carrier were studied.•The identification of hydrogen-related technologies and uses was done.•Different application scales of decentralized energy systems were included.•Baselines to early stage design of distributed energy systems are proposed.•There is a need of multi-dimensional approaches to evaluate this type of systems.
Blood‐based markers (BBMs) have recently shown promise to revolutionize the diagnostic and prognostic work‐up of Alzheimer's disease (AD), as well as to improve the design of interventional trials. ...Here we discuss in detail further research needed to be performed before widespread use of BBMs. We already now recommend use of BBMs as (pre‐)screeners to identify individuals likely to have AD pathological changes for inclusion in trials evaluating disease‐modifying therapies, provided the AD status is confirmed with positron emission tomography (PET) or cerebrospinal fluid (CSF) testing. We also encourage studying longitudinal BBM changes in ongoing as well as future interventional trials. However, BBMs should not yet be used as primary endpoints in pivotal trials. Further, we recommend to cautiously start using BBMs in specialized memory clinics as part of the diagnostic work‐up of patients with cognitive symptoms and the results should be confirmed whenever possible with CSF or PET. Additional data are needed before use of BBMs as stand‐alone diagnostic AD markers, or before considering use in primary care.
The medial temporal lobe (MTL) is an early site of tau accumulation and MTL dysfunction may underlie episodic-memory decline in aging and dementia. Postmortem data indicate that tau pathology in the ...transentorhinal cortex is common by age 60, whereas spread to neocortical regions and worsening of cognition is associated with β-amyloid (Aβ). We used
FAV-1451 and
CPiB positron emission tomography, structural MRI, and neuropsychological assessment to investigate how
tau accumulation in temporal lobe regions, Aβ, and MTL atrophy contribute to episodic memory in cognitively normal older adults (
= 83; age, 77 ± 6 years; 58% female). Stepwise regressions identified tau in MTL regions known to be affected in old age as the best predictor of episodic-memory performance independent of Aβ status. There was no interactive effect of MTL tau with Aβ on memory. Higher MTL tau was related to higher age in the subjects without evidence of Aβ. Among temporal lobe subregions, episodic memory was most strongly related to tau-tracer uptake in the parahippocampal gyrus, particularly the posterior entorhinal cortex, which in our parcellation includes the transentorhinal cortex. In subjects with longitudinal MRI and cognitive data (
= 57), entorhinal atrophy mirrored patterns of tau pathology and their relationship with memory decline. Our data are consistent with neuropathological studies and further suggest that entorhinal tau pathology underlies memory decline in old age even without Aβ.
Tau tangles and β-amyloid (Aβ) plaques are key lesions in Alzheimer's disease (AD) but both pathologies also occur in cognitively normal older people. Neuropathological data indicate that tau tangles in the medial temporal lobe (MTL) underlie episodic-memory impairments in AD dementia. However, it remains unclear whether MTL tau pathology also accounts for memory impairments often seen in elderly people and how Aβ affects this relationship. Using tau-specific and Aβ-specific positron emission tomography tracers, we show that
MTL tau pathology is associated with episodic-memory performance and MTL atrophy in cognitively normal adults, independent of Aβ. Our data point to MTL tau pathology, particularly in the entorhinal cortex, as a substrate of age-related episodic-memory loss.
Imaging of amyloid deposition using PET has been available in research studies for 2 decades and has been approved for clinical use by the U.S. Food and Drug Administration, the European Medicines ...Agency, and other regulatory agencies around the world. Amyloid PET is a crucial tool for the diagnosis of Alzheimer disease, as it allows the noninvasive detection of amyloid plaques, a core neuropathologic feature that defines the disease. The clinical use of amyloid PET is expected to increase with recent accelerated approval in the United States of aducanumab, an antiamyloid monoclonal antibody, for the treatment of mild cognitive impairment and mild dementia due to Alzheimer disease. However, amyloid pathology can also be found in cognitively unimpaired older adults and in patients with other neurodegenerative disorders. The aim of this review is to provide an up-to-date overview of the application of amyloid PET in neurodegenerative diseases. We provide an in-depth analysis of the clinical, pathologic, and imaging correlates; a comparison with other available biomarkers; and a review of the application of amyloid PET in clinical trials and clinical utility studies.
Objective
To determine the rate of tau accumulation in healthy older adults (OA) and patients with Alzheimer disease (AD), as well as the relationship of tau accumulation to cortical atrophy.
Methods
...Two longitudinal flortaucipir (FTP) positron emission tomography (PET) and magnetic resonance imaging (MRI) scans were acquired from 42 OA (21 Pittsburg compound B PiB+, age = 77.6 ± 4.6 years, 25 female F/17 male M) and 19 PiB+ patients with AD (age = 63.1 ± 10.3 years, 12 F/7 M) over 1 to 3 years of follow‐up. FTP change, structural MRI measures of atrophy, and cross‐modal correlations were examined on a voxelwise level. Regional annual percentage change in FTP was also calculated.
Results
Voxelwise FTP change in AD showed the greatest increases in lateral and medial frontal lobes. Atrophy over the same interval was more widespread and included posteromedial cortical areas, where tau accumulation rates were lower. In OA, FTP binding increased in bilateral temporal lobe and retrosplenial cortex, accompanied by atrophy in the same regions. There were no associations between voxelwise change in FTP and sex, PiB, or APOE. Regional FTP significantly increased at follow‐up in OA and patients with AD. Mixed effects models showed greater FTP increases in AD compared to OA, and no differences within OA based on PiB status.
Interpretation
Our findings indicate that tau accumulates even in amyloid‐negative healthy OA and this process can be measured with in vivo tau‐PET. In OA, tau accumulation and atrophy share a similar topography. In AD, tau increases more rapidly and accumulation occurs in frontal regions that are not yet undergoing significant atrophy. Ann Neurol 2019; 1–12 ANN NEUROL 2019;85:229–240.
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