Alzheimer's disease is a multifactorial dementia disorder characterized by early amyloid-β, tau deposition, glial activation and neurodegeneration, where the interrelationships between the different ...pathophysiological events are not yet well characterized. In this study, longitudinal multitracer positron emission tomography imaging of individuals with autosomal dominant or sporadic Alzheimer's disease was used to quantify the changes in regional distribution of brain astrocytosis (tracer (11)C-deuterium-L-deprenyl), fibrillar amyloid-β plaque deposition ((11)C-Pittsburgh compound B), and glucose metabolism ((18)F-fluorodeoxyglucose) from early presymptomatic stages over an extended period to clinical symptoms. The 52 baseline participants comprised autosomal dominant Alzheimer's disease mutation carriers (n = 11; 49.6 ± 10.3 years old) and non-carriers (n = 16; 51.1 ± 14.2 years old; 10 male), and patients with sporadic mild cognitive impairment (n = 17; 61.9 ± 6.4 years old; nine male) and sporadic Alzheimer's disease (n = 8; 63.0 ± 6.5 years old; five male); for confidentiality reasons, the gender of mutation carriers is not revealed. The autosomal dominant Alzheimer's disease participants belonged to families with known mutations in either presenilin 1 (PSEN1) or amyloid precursor protein (APPswe or APParc) genes. Sporadic mild cognitive impairment patients were further divided into (11)C-Pittsburgh compound B-positive (n = 13; 62.0 ± 6.4; seven male) and (11)C-Pittsburgh compound B-negative (n = 4; 61.8 ± 7.5 years old; two male) groups using a neocortical standardized uptake value ratio cut-off value of 1.41, which was calculated with respect to the cerebellar grey matter. All baseline participants underwent multitracer positron emission tomography scans, cerebrospinal fluid biomarker analysis and neuropsychological assessment. Twenty-six of the participants underwent clinical and imaging follow-up examinations after 2.8 ± 0.6 years. By using linear mixed-effects models, fibrillar amyloid-β plaque deposition was first observed in the striatum of presymptomatic autosomal dominant Alzheimer's disease carriers from 17 years before expected symptom onset; at about the same time, astrocytosis was significantly elevated and then steadily declined. Diverging from the astrocytosis pattern, amyloid-β plaque deposition increased with disease progression. Glucose metabolism steadily declined from 10 years after initial amyloid-β plaque deposition. Patients with sporadic mild cognitive impairment who were (11)C-Pittsburgh compound B-positive at baseline showed increasing amyloid-β plaque deposition and decreasing glucose metabolism but, in contrast to autosomal dominant Alzheimer's disease carriers, there was no significant longitudinal decline in astrocytosis over time. The prominent initially high and then declining astrocytosis in autosomal dominant Alzheimer's disease carriers, contrasting with the increasing amyloid-β plaque load during disease progression, suggests astrocyte activation is implicated in the early stages of Alzheimer's disease pathology.
...a substantial increase in long-term funding for multidisciplinary research programmes is absolutely essential to reduce the burden of individual suffering and the enormous societal cost of AD. In ...2015, almost 47 million people worldwide were estimated to be affected by dementia, and the numbers are expected to reach 75 million by 2030, and 131 million by 2050, with the greatest increase expected in low-income and middle-income countries.2 In 2012 and 2015, the World Health Organization (WHO) presented reports in which it acknowledged this trend--sometimes described in terms of a fast-growing epidemic--and concluded that AD and other dementias should be regarded as a global public health priority.3,4 Similar policy declarations have been made by the European Union5 (EU) and by some individual countries. Care for people with dementia is provided by several sectors in society, with the social-care (long-term care and home services) and informal-care (provided by non-professional caregivers) sectors accounting for the greatest proportion of costs--even greater than the cost of direct medical care.6 In cost-of-illness studies, total societal cost estimates for dementia in Europe in 2010 were between $238·6 billion6 and euro105·6 billion.7 The economic costs of caring for a growing number of people with AD and other dementias are formidable, but the combined economic and societal burden of dementia is more daunting still, corresponding to the aggregate burden of people with dementia and their next of kin.
It is well-established that subcompartments of endoplasmic reticulum (ER) are in physical contact with the mitochondria. These lipid raft-like regions of ER are referred to as mitochondria-associated ...ER membranes (MAMs), and they play an important role in, for example, lipid synthesis, calcium homeostasis, and apoptotic signaling. Perturbation of MAM function has previously been suggested in Alzheimer’s disease (AD) as shown in fibroblasts from AD patients and a neuroblastoma cell line containing familial presenilin-2 AD mutation. The effect of AD pathogenesis on the ER–mitochondria interplay in the brain has so far remained unknown. Here, we studied ER–mitochondria contacts in human AD brain and related AD mouse and neuronal cell models. We found uniform distribution of MAM in neurons. Phosphofurin acidic cluster sorting protein-2 and σ1 receptor, two MAM-associated proteins, were shown to be essential for neuronal survival, because siRNA knockdown resulted in degeneration. Up-regulated MAM-associated proteins were found in the AD brain and amyloid precursor protein (APP) Swₑ/Lₒₙ mouse model, in which up-regulation was observed before the appearance of plaques. By studying an ER–mitochondria bridging complex, inositol-1,4,5-triphosphate receptor–voltage-dependent anion channel, we revealed that nanomolar concentrations of amyloid β-peptide increased inositol-1,4,5-triphosphate receptor and voltage-dependent anion channel protein expression and elevated the number of ER–mitochondria contact points and mitochondrial calcium concentrations. Our data suggest an important role of ER–mitochondria contacts and cross-talk in AD pathology.
Practice effects (PEs) defined as an improvement of performance in cognition due to repeated assessments between sessions are well known in unimpaired individuals, while less is known about impaired ...cognition and particularly in latent brain disease as autosomal-dominant Alzheimer's disease. The purpose was to evaluate the general (across tests/domains) and domain-specific PE calculated as the annual rate of change (ARC) in relation to years to the estimated disease onset (YECO) and in four groups of AD: asymptomatic mutation carriers (aAD,
n
= 19), prodromal, i.e., symptomatic mutation carriers, criteria for AD diagnosis not fulfilled (pAD,
n
= 4) and mutation carriers diagnosed with AD (dAD,
n
= 6) as well as mutation non-carriers from the AD families serving as a healthy comparison group (HC,
n
= 35). Cognition was assessed at baseline and follow-up about 3 years later by 12 tests covering six domains. The aAD and HC groups were comparable at baseline in demographic characteristics (age, gender, and education), when they were in their early forties, while the pAD and dAD groups were older and cognitively impaired. The results on mean ARC for the four groups were significantly different, small, positive, and age-insensitive in the HC group, while ARC was negative and declined with time/disease advancement in AD. The differences between HC and aAD groups in mean ARC and domain-specific ARC were not significant, indicating a subtle PE in aAD in the early preclinical stage of AD. In the symptomatic stages of AD, there was no PE probably due to cognitive disease-related progression. PEs were the largest in the verbal domain in both the HC and aAD groups, indicating a relationship with cognitive vulnerability. The group-related difference in mean ARC was predominant in timekeeping tests. To conclude, the practice effect in over 3 years was suggested to be linked to procedural learning and memory.
Studying autosomal dominant Alzheimer's disease (ADAD), caused by gene mutations yielding nearly complete penetrance and a distinct age of symptom onset, allows investigation of presymptomatic ...pathological processes that can identify a therapeutic window for disease-modifying therapies. Astrocyte activation may occur in presymptomatic Alzheimer's disease (AD) because reactive astrocytes surround β-amyloid (Aβ) plaques in autopsy brain tissue. Positron emission tomography was performed to investigate fibrillar Aβ, astrocytosis and cerebral glucose metabolism with the radiotracers (11)C-Pittsburgh compound-B (PIB), (11)C-deuterium-L-deprenyl (DED) and (18)F-fluorodeoxyglucose (FDG) respectively in presymptomatic and symptomatic ADAD participants (n = 21), patients with mild cognitive impairment (n = 11) and sporadic AD (n = 7). Multivariate analysis using the combined data from all radiotracers clearly separated the different groups along the first and second principal components according to increased PIB retention/decreased FDG uptake (component 1) and increased DED binding (component 2). Presymptomatic ADAD mutation carriers showed significantly higher PIB retention than non-carriers in all brain regions except the hippocampus. DED binding was highest in presymptomatic ADAD mutation carriers. This suggests that non-fibrillar Aβ or early stage plaque depostion might interact with inflammatory responses indicating astrocytosis as an early contributory driving force in AD pathology. The novelty of this finding will be investigated in longitudinal follow-up studies.
Abstract Background Resolution is the final stage of the inflammatory response, when restoration of tissue occurs. Failure may lead to chronic inflammation, which is known as part of the pathology in ...the brain of individuals with Alzheimer's disease (AD). Methods Specialized pro-resolving mediators (SPMs), receptors, biosynthetic enzyme, and downstream effectors involved in resolution were analyzed in postmortem hippocampal tissue from AD patients and non-AD subjects. SPMs were analyzed in cerebrospinal fluid (CSF). Results SPMs and SPM receptors were detected in the human brain. Levels of the SPM lipoxin A4 (LXA4 ) were reduced in AD, both in the CSF and hippocampus. An enzyme involved in LXA4 synthesis and two SPM receptors were elevated in AD brains. LXA4 and RvD1 levels in CSF correlated with Mini-Mental State Examination (MMSE) scores. Conclusions A resolution pathway exists in the brain and the alterations described herein strongly suggest a dysfunction of this pathway in AD. MMSE correlations suggest a connection with cognitive function in AD.
Mounting evidence shows that the
ε4 allele interferes with cognition in sporadic Alzheimer's disease. Less is known about
in autosomal-dominant Alzheimer's disease (adAD). The present study explored ...the effects on cognition associated with the gene-gene interactions between the
gene and the
and
genes in adAD. This study includes mutation carriers (MC) and non-carriers (NC) from adAD families with mutations in
(
= 28 and
= 25; MC and NC, respectively) and
(
= 12 and
= 15; MC and NC, respectively) that represent the complete spectrum of disease: AD dementia (
= 8) and mild cognitive impairment (MCI,
= 15 and presymptomatic AD,
= 17). NC represented unimpaired normal aging. There was no significant difference in the distribution of
ε4 (absence vs. presence) between the
vs.
adAD genes and mutation status (MC vs. NC). However, episodic memory was significantly affected by the interaction between
and the
vs.
genes in MC. This was explained by favorable performance in the absence of
ε4 in
compared to
MC. Similar trends were seen in other cognitive functions. No significant associations between
ε4 and cognitive performance were obtained in NC. In conclusion, cognitive effects of
-adAD gene interaction were differentiated between the
and
mutation carriers, indicating epistasis.
Abstract
Background
Plasma assays for the detection of Alzheimer’s disease neuropathological changes are receiving ever increasing interest. The concentration of plasma glial fibrillary acidic ...protein (GFAP) has been suggested as a potential marker of astrocytes or recently, amyloid-β burden, although this hypothesis remains unproven. We compared plasma GFAP levels with the astrocyte tracer
11
C-Deuterium-L-Deprenyl (
11
C-DED) in a multi-modal PET design in participants with sporadic and Autosomal Dominant Alzheimer’s disease.
Methods
Twenty-four individuals from families with known Autosomal Dominant Alzheimer’s Disease mutations (mutation carriers = 10; non-carriers = 14) and fifteen patients with sporadic Alzheimer’s disease were included. The individuals underwent PET imaging with
11
C-DED,
11
C-PIB and
18
F-FDG, as markers of reactive astrogliosis, amyloid-β deposition, and glucose metabolism, respectively, and plasma sampling for measuring GFAP concentrations. Twenty-one participants from the Autosomal Dominant Alzheimer’s Disease group underwent follow-up plasma sampling and ten of these participants underwent follow-up PET imaging.
Results
In mutation carriers, plasma GFAP levels and
11
C-PIB binding increased, while
11
C-DED binding and
18
F-FDG uptake significantly decreased across the estimated years to symptom onset. Cross-sectionally, plasma GFAP demonstrated a negative correlation with
11
C-DED binding in both mutation carriers and patients with sporadic disease. Plasma GFAP indicated cross-sectionally a significant positive correlation with
11
C-PIB binding and a significant negative correlation with
18
F-FDG in the whole sample. The longitudinal levels of
11
C-DED binding showed a significant negative correlation with longitudinal plasma GFAP concentrations over the follow-up interval.
Conclusions
Plasma GFAP concentration and astrocyte
11
C-DED brain binding levels followed divergent trajectories and may reflect different underlying processes. The strong negative association between plasma GFAP and
11
C-DED binding in Autosomal Dominant and sporadic Alzheimer’s disease brains may indicate that if both are markers of reactive astrogliosis, they may detect different states or subtypes of astrogliosis. Increased
11
C-DED brain binding seems to be an earlier phenomenon in Alzheimer’s disease progression than increased plasma GFAP concentration.
Direct conversion of human fibroblasts into mature and functional neurons, termed induced neurons (iNs), was achieved for the first time 6 years ago. This technology offers a promising shortcut for ...obtaining patient‐ and disease‐specific neurons for disease modeling, drug screening, and other biomedical applications. However, fibroblasts from adult donors do not reprogram as easily as fetal donors, and no current reprogramming approach is sufficiently efficient to allow the use of this technology using patient‐derived material for large‐scale applications. Here, we investigate the difference in reprogramming requirements between fetal and adult human fibroblasts and identify REST as a major reprogramming barrier in adult fibroblasts. Via functional experiments where we overexpress and knockdown the REST‐controlled neuron‐specific microRNAs miR‐9 and miR‐124, we show that the effect of REST inhibition is only partially mediated via microRNA up‐regulation. Transcriptional analysis confirmed that REST knockdown activates an overlapping subset of neuronal genes as microRNA overexpression and also a distinct set of neuronal genes that are not activated via microRNA overexpression. Based on this, we developed an optimized one‐step method to efficiently reprogram dermal fibroblasts from elderly individuals using a single‐vector system and demonstrate that it is possible to obtain iNs of high yield and purity from aged individuals with a range of familial and sporadic neurodegenerative disorders including Parkinson's, Huntington's, as well as Alzheimer's disease.
Synopsis
REST inhibition removes neuronal reprogramming barrier in adult dermal fibroblasts. The resulting high number of induced neurons from elderly patients allows for large scale biomedical applications such as disease modeling, drug screening and early and/or differential diagnostics.
The most commonly used neural conversion genes Ascl1 and Brn2 elicit largely distinct transcriptional responses between fetal and adult fibroblasts.
REST inhibition removes reprogramming barrier of adult fibroblasts.
The effect of RESTi is only partially mediated via the neuron specific microRNAs miR‐9 and miR‐124 up‐regulation.
In addition to activate a similar subset of neuronal genes as miR‐9 and miR‐124 overexpression, RESTi activates a distinct set of neuronal genes.
An all‐in‐one conversion vector overexpressing Ascl1 and Brn2 and knocking down REST improves the reprogramming process and renders it suitable for biomedical applications.
REST inhibition removes neuronal reprogramming barrier in adult dermal fibroblasts. The resulting high number of induced neurons from elderly patients allows for large scale biomedical applications such as disease modeling, drug screening and early and/or differential diagnostics.
The suprachiasmatic nuclei (SCN) of the hypothalamus contain the master mammalian circadian clock, which is mainly reset by light. Temporal restricted feeding, a potent synchronizer of peripheral ...oscillators, has only weak influence on light-entrained rhythms via the SCN, unless restricted feeding is coupled with calorie restriction, thereby altering phase angle of photic synchronization. Effects of daytime restricted feeding were investigated on the mouse circadian system. Normocaloric feeding at midday led to a predominantly diurnal (60%) food intake and decreased blood glucose in the afternoon, but it did not affect the phase of locomotor activity rhythm or vasopressin expression in the SCN. In contrast, hypocaloric feeding at midday led to 2-4 h phase advances of three circadian outputs, locomotor activity rhythm, pineal melatonin, and vasopressin mRNA cycle in the SCN, and it decreased daily levels of blood glucose. Furthermore, Per1 and Cry2 oscillations in the SCN were phase advanced by 1 and 3 h, respectively, in hypocalorie- but not in normocalorie-fed mice. The phase of Per2 and Bmal1 expression remained unchanged regardless of feeding condition. Moreover, the shape of behavioral phase-response curve to light and light-induced expression of Per1 in the SCN were markedly modified in hypocalorie-fed mice compared with animals fed ad libitum. The present study shows that diurnal hypocaloric feeding affects not only the temporal organization of the SCN clockwork and circadian outputs in mice under light/dark cycle but also photic responses of the circadian system, thus indicating that energy metabolism modulates circadian rhythmicity and gating of photic inputs in mammals.
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