Alzheimer's Disease-related Pathology Research Articles

Top-Down Projections Direct the Gradual Progression of Alzheimer-Related Tau Pathology Throughout the Neocortex.

In sporadic Alzheimer's disease (sAD), tau pathology gradually but relentlessly progresses from the transentorhinal region of the temporal lobe into both the allocortex and temporal high order association areas of the neocortex. From there, it ultimately reaches the primary sensory and motor fields of the neocortex. The brunt of the changes seen during neurofibrillary stages (NFT) I-VI is borne by top-down projection neurons that contribute to cortico-cortical connectivities between different neocortical fields. Very early changes develop in isolated pyramidal cells in layers III and V, and these cells are targets of top-down projections terminating in association areas of the first temporal gyrus or in peristriate regions of the occipital lobe. Neurofibrillary pathology in these regions is routinely associated with late NFT stages. Sequential changes occur in different cell compartments (dendritic, somatic, axonal) of these early-involved neurons. Tau pathology first develops in distal segments of basal dendrites, then in proximal dendrites, the soma, and, finally, in the axon of affected pyramidal neurons. This sequence of abnormal changes supports the concept that axons of cortico-cortical top-down neurons may carry and spread abnormal tau seeds in a focused manner (transsynaptically) into the distal dendritic segments of nerve cells directly following in the neuronal chain, thereby sustaining tau-seeded templating in sAD.

A multiomic approach to characterize the temporal sequence in Alzheimer's disease-related pathology

No single-omic approach completely elucidates the multitude of alterations taking place in Alzheimer's disease (AD). Here, we coupled transcriptomic and phosphoproteomic approaches to determine the temporal sequence of changes in mRNA, protein, and phosphopeptide expression levels from human temporal cortical samples, with varying degree of AD-related pathology. This approach highlighted fluctuation in synaptic and mitochondrial function as the earliest pathological events in brain samples with AD-related pathology. Subsequently, increased expression of inflammation and extracellular matrix-associated gene products was observed. Interaction network assembly for the associated gene products, emphasized the complex interplay between these processes and the role of addressing post-translational modifications in the identification of key regulators. Additionally, we evaluate the use of decision trees and random forests in identifying potential biomarkers differentiating individuals with different degree of AD-related pathology. This multiomic and temporal sequence-based approach provides a better understanding of the sequence of events leading to AD.

A methodological approach to studying resilience mechanisms: demonstration of utility in age and Alzheimer's disease-related brain pathology.

The present work aims at providing a methodological approach for the investigation of resilience factors and mechanisms in normal aging, Alzheimer's disease (AD) and other neurodegenerative disorders. By expanding and re-conceptualizing traditional regression approaches, we propose an approach that not only aims at identifying potential resilience factors but also allows for a differentiation between general and dynamic resilience factors in terms of their association with pathology. Dynamic resilience factors are characterized by an increasing relevance with increasing levels of pathology, while the relevance of general resilience factors is independent of the amount of pathology. Utility of the approach is demonstrated in age and AD-related brain pathology by investigating widely accepted resilience factors, including education and brain volume. Moreover, the approach is used to test hippocampal volume as potential resilience factor. Education and brain volume could be identified as general resilience factors against age and AD-related pathology. Beyond that, analyses highlighted that hippocampal volume may not only be disease target but also serve as a potential resilience factor in age and AD-related pathology, particularly at higher levels of tau-pathology (i.e. dynamic resilience factor). Given its unspecific and superordinate nature the approach is suitable for the investigation of a wide range of potential resilience factors in normal aging, AD and other neurodegenerative disorders. Consequently, it may find a wide application and thereby promote the comparability between studies.

Tau Imaging in Parkinsonism: What Have We Learned So Far?

Positron emission tomography ligands are now available that bind to tau proteins in the brain, providing the exciting opportunity to assess the presence and distribution of tau in vivo in living patients. This manuscript performed a systematic review of studies that have performed tau PET imaging in patients with parkinsonian disorders. Pubmed was searched up to November 2017, and the review included case reports and patient-control studies. Most tau-PET studies have utilized the [18F]AV-1451 ligand, with a few using the [11C]PBB3 and [18F]THK-5351 ligands. Elevated cortical tau-PET uptake has been observed in Parkinson's disease dementia and dementia with Lewy bodies, presumed to be related to Alzheimer's disease-related pathology. Mild patterns of tau-PET uptake have been observed in subcortical structures in progressive supranuclear palsy and subcortical structures and motor cortex in corticobasal syndrome, although discrepancy with autoradiographic studies that show lack of binding to 4-repeat tau and "off-target" binding observed in subcortical structures limits interpretation of these findings. Findings in frontotemporal dementia with tau mutations are variable, but elevated signal is most pronounced in mutations with deposition of both 3 and 4-repeat tau. Elevated tau-PET uptake has also been observed in multiple system atrophy, a synucleinopathy. The value of the current generation of tau-PET ligands varies across Parkinsonian syndromes depending upon underlying variability in tau pathology and "off-target" binding. More work is needed to understand the biological basis of binding and more specific tau PET ligands are needed to study parkinsonian disorders.

Brain comorbidities in normal pressure hydrocephalus.

This cross-sectional study aims to compare gait changes after the cerebrospinal fluid (CSF) tap test between normal pressure hydrocephalus patients with and without brain comorbidities (NPH+ and NPH- respectively) and then to identify significant contributors to a poor CSF tap test amongst individuals with NPH+. Gait changes (during the single task and the dual task of backward counting) were quantified before and 24 h after the CSF tap test with an optoelectronic system in 52 NPH patients (77.4 ± 6.0 years; 34.6% women). Changes after the CSF tap test in stride time variability (STV, %) were our main outcome. CSF Alzheimer's disease biomarkers, cerebrovascular white matter changes assessed with brain imaging and neurodegenerative diseases with parkinsonian syndrome represented the three individual brain comorbidities. Brain comorbidities were frequently identified, NPH+ patients representing 40 patients of our sample (76.9%). NPH- patients improved their STV better in the single task (delta of STV = -58.6% ± 54.3% vs. -14.1% ± 62.0%; P = 0.031) and in the dual task (delta of STV =-32.2% ± 33.7% vs. 6.3% ± 58.4%; P = 0.028) after the CSF tap test than NPH+ patients. Amongst NPH+ individuals, only comorbid Alzheimer's disease was associated with STV increase (i.e. deterioration of gait) in the dual task [β 38.4; 95% confidence interval (5.64; 71.24); P = 0.023] after the CSF tap test, whilst it was borderline in the single task [β 35.0; 95% confidence interval (-1.97; 71.90); P = 0.063]. Brain comorbidities affect gait improvement after the CSF tap test in NPH patients; this influence is driven by Alzheimer's disease-related pathology.

Networks of tau distribution in Alzheimer's disease.

See Whitwell (doi:10.1093/brain/awy001) for a scientific commentary on this article.A stereotypical anatomical propagation of tau pathology has been described in Alzheimer's disease. According to recent concepts (network degeneration hypothesis), this propagation is thought to be indicative of misfolded tau proteins possibly spreading along functional networks. If true, tau pathology accumulation should correlate in functionally connected brain regions. Therefore, we examined whether independent components could be identified in the distribution pattern of in vivo tau pathology and whether these components correspond with specific functional connectivity networks. Twenty-two 18F-AV-1451 PET scans of patients with amnestic Alzheimer's disease (mean age = 66.00 ± 7.22 years, 14 males/eight females) were spatially normalized, intensity standardized to the cerebellum, and z-transformed using the mean and deviation image of a healthy control sample to assess Alzheimer's disease-related tau pathology. First, to detect distinct tau pathology networks, the deviation maps were subjected to an independent component analysis. Second, to investigate if regions of high tau burden are associated with functional connectivity networks, we extracted the region with the maximum z-value in each of the generated tau pathology networks and used them as seeds in a subsequent resting-state functional MRI analysis, conducted in a group of healthy adults (n = 26) who were part of the 1000 Functional Connectomes Project. Third, to examine if tau pathology co-localizes with functional connectivity networks, we quantified the spatial overlap between the seed-based networks and the corresponding tau pathology network by calculating the Dice similarity coefficient. Additionally, we assessed if the tau-dependent seed-based networks correspond with known functional resting-state networks. Finally, we examined the relevance of the identified components in regard to the neuropathological Braak stages. We identified 10 independently coherent tau pathology networks with the majority showing a symmetrical bi-hemispheric expansion and coinciding with highly functionally connected brain regions such as the precuneus and cingulate cortex. A fair-to-moderate overlap was observed between the tau pathology networks and corresponding seed-based networks (Dice range: 0.13-0.57), which in turn resembled known resting-state networks, particularly the default mode network (Dice range: 0.42-0.56). Moreover, greater tau burden in the tau pathology networks was associated with more advanced Braak stages. Using the data-driven approach of an independent component analysis, we observed a set of independently coherent tau pathology networks in Alzheimer's disease, which were associated with disease progression and coincided with functional networks previously reported to be impaired in Alzheimer's disease. Together, our results provide novel information regarding the impact of tau pathology networks on the mechanistic pathway of Alzheimer's disease.

The release and transmission of amyloid precursor protein via exosomes

Amyloid precursor protein (APP) processing is central in Alzheimer's disease (AD) pathogenesis. The healthy unaffected neurons suffer the transmission of amyloid protein from pathologically affected neurons, which may play an important role in the anatomical spread of the disease. Exosomes are appropriate candidates for transmission of amyloid species, because of their potential role as “intercellular transportation”. To address a role of secreted exosomes in neuronal homeostasis in AD, we harvested exosomes from the conditioned medium of HEK293-APP Swe/Ind cells. We have demonstrated that these exosomes contained APP and were capable of efficiently transferring APP to normal primary neurons. Moreover, these exosomes had dose-dependent detrimental effect on cultured neurons. Our results suggest a key mechanism underlying the spread of amyloid protein in the brain and the acceleration of pathology in AD; exosomes secretion serves to amplify and propagate Alzheimer's disease related pathology.

The Oral Pretreatment of Glycyrrhizin Prevents Surgery-Induced Cognitive Impairment in Aged Mice by Reducing Neuroinflammation and Alzheimer's-Related Pathology via HMGB1 Inhibition.

Neuroinflammation and Alzheimer's-related pathology play essential roles in postoperative cognitive dysfunction (POCD). High-mobility group box 1 (HMGB1) is well known as a pivotal mediator in neuroinflammation, and its associations with Alzheimer's-related pathology and POCD have been also revealed. Glycyrrhizin is a nature inhibitor of HMGB1 and is reported with neuroprotective effects through oral administration. Therefore, the present study aims to test the hypothesis that the oral pretreatment of glycyrrhizin prevents POCD by inhibiting HMGB1-induced neuroinflammation and Alzheimer's-related pathology in aged mice. Aged male C57BL/6 mice were subjected to the splenectomy surgery under general anesthesia and the oral pretreatment of glycyrrhizin. The postoperative cognitive changes were evaluated by using Morris water maze (MWM) test. The protein expressions of HMGB1, TLR4, NF-κB, p-Tau, and pro-inflammatory cytokines were determined by Western blot assay. The hippocampal level of β-amyloid (Aβ) was assessed by ELISA assay. We found that the oral pretreatment of glycyrrhizin inhibited HMGB1 cytosolic expression, increased the PSD-95 protein expression, and attenuated the severity of postoperative memory impairment, as indicated by the shorter swimming latency and distance in MWM trials when compared with the mice subjected to the surgery alone. Additionally, the pretreatment of glycyrrhizin reduced the postoperative neuroinflammation (production of pro-inflammatory cytokines including IL-1β, TNF-α, and IL-6 as well as NF-κB nuclear expression) and Alzheimer's-related pathology (Tau phosphorylation at the site of AT-8 and Ser396 as well as Aβ40 and 42 concentrations) in the hippocampus of the aged mice undergoing splenectomy surgery. In conclusion, our results suggest that the oral pretreatment of glycyrrhizin can prevent the postoperative cognitive impairment by reducing neuroinflammation and Alzheimer's-related pathology in the hippocampus of aged mice via HMGB1 inhibition.

The effects of apolipoprotein E genotype, α-synuclein deficiency, and sex on brain synaptic and Alzheimer's disease–related pathology

IntroductionAlzheimer's disease (AD) and synucleinopathies share common pathological mechanisms. Apolipoprotein E4 (apoE4), the most prevalent genetic risk factor for AD, also increases the risk for dementia in pure synucleinopathies. We presently examined the effects of α-synuclein deficiency (α-syn−/−) and sex on apoE4-driven pathologies. MethodsAD-related, synaptic, and vascular markers were analyzed in female and male α-syn−/− and α-syn+/+ apoE4, apoE3, and apoE3/E4 mice. ResultsApoE4 was hypolipidated, and this effect was unchanged by α-syn−/− and sex. The levels of synaptic markers were lower, and the levels of AD-related parameters were higher in female α-syn−/− apoE4 mice compared with the corresponding apoE3 mice. By comparison, apoE4 had small effects on the AD parameters of male and female α-syn+/+ apoE4 mice. DiscussionAlthough α-syn−/− does not affect the upstream lipidation impairment of apoE4, it acts as a “second hit” enhancer of the subsequent apoE4-driven pathologies.

CEREBRAL AMYLOID ANGIOPATHY TREATMENT VIA INNATE IMMUNITY STIMULATION IN AGED NON-HUMAN PRIMATES

Immunotherapeutic approaches for Alzheimer's disease (AD) are hampered by complications related to ineffectual clearance of cerebral amyloid angiopathy (CAA). Given the independent correlation of the degree of CAA pathology with the severity of cognitive impairment, as well as the key role of CAA in the pathophysiology leading to development of amyloid-related imaging abnormalities, our studies were designed to determine whether stimulation of innate immunity with TLR9 agonist CpG oligodeoxynucleotides (ODNs) could have beneficial effects in a non-human primate model of sporadic CAA, squirrel monkey (Saimiri Boliviensis). Our prior work has shown that treatment with CpG ODN is effective at improving cognitive deficits in aged monkeys without inducing adverse events. Elderly female monkeys with expected CAA deposits were subcutaneously injected with either predetermined non-toxic dosages of the class B CpG ODN or saline for a 25 month period. Animals were continuously examined for signs of toxicity. Plasma taken at specific times in the course of treatment was analyzed to identify immune responses and AD biomarkers. Histological and biochemical brain analyses commenced upon completion of the behavioral protocols. Long term treatment with CpG ODN significantly reduced total amyloid burden (6E10/4G8 immunohistochemistry), which in this model corresponds primarily to CAA. Histological evaluation of CpG ODN effect on pyroglutamate levels (AβpE3 immunohistochemistry) revealed region specific reduction in AβpE3 burden in monkeys treated with CpG ODN. These favorable histological data will be corroborated by measurements of Aβ levels in the brain homogenates. Our initial biomarker analyses exhibited a noticeable increase in AβpE3 plasma levels in CpG ODN-treated animals. Subsequent evaluation showed no increase in the extent of Iba1 microgliosis and GFAP astrogliosis in CpG ODN group at the end of the treatment. Additionally, there was no evidence of increased microhemorrhages or T cell infiltration in association with CpG ODN treatment, further supporting the viability of our approach. Concluding assessment of microglia/macrophage activation is currently in progress. Overall, the present findings together with our earlier experimental evidence validate this novel concept of immunomodulation as a safe method to successfully ameliorate AD related pathology, suggesting CpG ODN would have a significant potential of achieving clinical efficacy.

Evaluation of Small-Animal PET Outcome Measures to Detect Disease Modification Induced by BACE Inhibition in a Transgenic Mouse Model of Alzheimer Disease.

In this study, we investigated the effects of chronic administration of an inhibitor of the β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) on Alzheimer-related pathology by multitracer PET imaging in transgenic APPPS1-21 (TG) mice. Methods: Wild-type (WT) and TG mice received vehicle or BACE inhibitor (60 mg/kg) starting at 7 wk of age. Outcome measures of brain metabolism, neuroinflammation, and amyloid-β pathology were obtained through small-animal PET imaging with 18F-FDG, 18F-peripheral benzodiazepine receptor (18F-PBR), and 18F-florbetapir (18F-AV45), respectively. Baseline scans were acquired at 6-7 wk of age and follow-up scans at 4, 7, and 12 mo. 18F-AV45 uptake was measured at 8 and 13 mo of age. After the final scans, histologic measures of amyloid-β (4G8), microglia (ionized calcium binding adaptor molecule 1), astrocytes (glial fibrillary acidic protein), and neuronal nuclei were performed. Results: TG mice demonstrated significant age-associated increases in 18F-AV45 uptake. An effect of treatment was observed in the cortex (P = 0.0014), hippocampus (P = 0.0005), and thalamus (P < 0.0001). Histology confirmed reduction of amyloid-β pathology in TG-BACE mice. Regardless of treatment, TG mice demonstrated significantly lower 18F-FDG uptake than WT mice in the thalamus (P = 0.0004) and hippocampus (P = 0.0332). Neuronal nucleus staining was lower in both TG groups in the thalamus and cortex. 18F-PBR111 detected a significant age-related increase in TG mice (P < 0.0001) but did not detect the treatment-induced reduction in activated microglia as demonstrated by histology. Conclusion: Although 18F-FDG, 18F-PBR111, and 18F-AV45 all detected pathologic alterations between TG and WT mice, only 18F-AV45 could detect an effect of BACE inhibitor treatment. However, changes in WT binding of 18F-AV45 undermine the specificity of this effect.

Associations between APOE genotype and cerebral small-vessel disease: a longitudinal study.

ObjectiveIt remains unclear if and how the interactions between APOE genotypes and cerebral small-vessel diseases (CSVD) lead to cognitive decline in the long term. Based on ADNI cohort, this longitudinal study aimed to clarify the potential relationship among APOE genotype, CSVD and cognition by integrating multi-level data.MethodThere were 135 healthy elderly (including ε2, ε4 allele carriers and ε3 homozygotes) who had completed two years’ follow-up. MRI markers of CSVD, including white matter hyperintensities (WMH), dilated perivascular space (dPVS), microbleeds and lacune, were assessed. Besides, neuropathological factors including Alzheimer's disease-related pathology measured by CSF and PiB-PET were assessed. Repeated measurements ANOVAs were performed to test impact of different APOE genotypes on CSVD.ResultsWe found that APOE ε4 carriers had significantly more frontal WMH burden and basal ganglia dPVS at baseline and faster progression of frontal WMH burden during follow-up. Furthermore, our results showed that APOE ε4 carriers had significantly decreased Aβ1-42 level, and its level was negatively related with baseline and progressive total WMH burden. Then, general linear modals indicated interaction between basal frontal WMH burden and ε4 allele was related with declining trend of cognition.ConclusionOur findings suggested APOE ε4 allele was associated with increased Aβ deposition, which may lead to the formation and progression of WMH, especially in frontal lobe. Besides, interaction between the increased frontal WMH burden and ε4 allele can exert long-term detrimental effects on individual's trajectory of cognition.

Obesity Accelerates Alzheimer-Related Pathology in APOE4 but not APOE3 Mice.

Alzheimer’s disease (AD) risk is modified by both genetic and environmental risk factors, which are believed to interact to cooperatively modify pathogenesis. Although numerous genetic and environmental risk factors for AD have been identified, relatively little is known about potential gene-environment interactions in regulating disease risk. The strongest genetic risk factor for late-onset AD is the ε4 allele of apolipoprotein E (APOE4). An important modifiable risk factor for AD is obesity, which has been shown to increase AD risk in humans and accelerate development of AD-related pathology in rodent models. Potential interactions between APOE4 and obesity are suggested by the literature but have not been thoroughly investigated. In the current study, we evaluated this relationship by studying the effects of diet-induced obesity (DIO) in the EFAD mouse model, which combines familial AD transgenes with human APOE3 or APOE4. Male E3FAD and E4FAD mice were maintained for 12 weeks on either a control diet or a Western diet high in saturated fat and sugars. We observed that metabolic outcomes of DIO were similar in E3FAD and E4FAD mice. Importantly, our data showed a significant interaction between diet and APOE genotype on AD-related outcomes in which Western diet was associated with robust increases in amyloid deposits, β-amyloid burden, and glial activation in E4FAD but not in E3FAD mice. These findings demonstrate an important gene-environment interaction in an AD mouse model that suggests that AD risk associated with obesity is strongly influenced by APOE genotype.

Tau and amyloid β proteins distinctively associate to functional network changes in the aging brain

IntroductionMisfolded tau and amyloid β (Aβ) proteins progressively accumulate in the human brain, causing altered neuronal function and neurodegeneration. This study sought to investigate whether the wide spectrum of functional reorganization in aging brains of cognitively normal individuals relates to specific pathological patterns of tau and Aβ deposits. MethodsWe used functional connectivity neuroimaging and in vivo tau and Aβ positron emission tomography scans to study cortical spatial relationships between imaging modalities. ResultsWe found that a negative association between tau and functional connectivity combined with a positive association between Aβ and functional connectivity is the most frequent cortical pattern among elderly subjects. Moreover, we found specific brain areas that interrelate hypoconnectivity and hyperconnectivity regions. DiscussionOur findings have critical implications to understanding how the two main elements of Alzheimer's disease–related pathology affect the aging brain and how they cause alterations in large-scale neuronal circuits.

Regional Overlap of Pathologies in Lewy Body Disorders.

Lewy body disorders (LBD) are common neurodegenerative diseases characterized by the presence of aggregated α-synuclein in Lewy bodies and Lewy neurites in the central and peripheral nervous systems. The brains of patients with LBD often display other comorbid pathologies, i.e. insoluble tau, β-amyloid aggregates, TAR DNA-binding protein 43 (TDP-43) deposits, and argyrophilic grain disease (AGD). The incidence and physiological relevance of these concurrent pathological findings remain controversial. We performed a semiquantitative detailed mapping of α-synuclein, tau, β-amyloid (Aβ), TDP-43, and AGD pathologies in 17 areas in 63 LBD cases (44 with Parkinson disease [PD], 28 with dementia, and 19 with dementia with Lewy bodies). APOE and MAPT genetic variants were also investigated. A majority of LBD cases had 2 or 3 concomitant findings, particularly Alzheimer disease-related pathology. Pathological stages of tau, β-amyloid and α-synuclein pathologies were increased in cases with dementia. Aβ score was the best correlate of the time to dementia in PD. In addition, β-amyloid deposition correlated with α-synuclein load in all groups. MAPT H1 haplotype did not influence any assessed pathology in PD. These results highlight the common concurrence of pathologies in patients with LBD that may have an impact on the clinical expression of the diseases.

18F-AV-1451 positron emission tomography in Alzheimer's disease and progressive supranuclear palsy.

The ability to assess the distribution and extent of tau pathology in Alzheimer's disease and progressive supranuclear palsy in vivo would help to develop biomarkers for these tauopathies and clinical trials of disease-modifying therapies. New radioligands for positron emission tomography have generated considerable interest, and controversy, in their potential as tau biomarkers. We assessed the radiotracer 18F-AV-1451 with positron emission tomography imaging to compare the distribution and intensity of tau pathology in 15 patients with Alzheimer's pathology (including amyloid-positive mild cognitive impairment), 19 patients with progressive supranuclear palsy, and 13 age- and sex-matched controls. Regional analysis of variance and a support vector machine were used to compare and discriminate the clinical groups, respectively. We also examined the 18F-AV-1451 autoradiographic binding in post-mortem tissue from patients with Alzheimer's disease, progressive supranuclear palsy, and a control case to assess the 18F-AV-1451 binding specificity to Alzheimer's and non-Alzheimer's tau pathology. There was increased 18F-AV-1451 binding in multiple regions in living patients with Alzheimer's disease and progressive supranuclear palsy relative to controls [main effect of group, F(2,41) = 17.5, P < 0.0001; region of interest × group interaction, F(2,68) = 7.5, P < 0.00001]. More specifically, 18F-AV-1451 binding was significantly increased in patients with Alzheimer's disease, relative to patients with progressive supranuclear palsy and with control subjects, in the hippocampus and in occipital, parietal, temporal, and frontal cortices (t's > 2.2, P's < 0.04). Conversely, in patients with progressive supranuclear palsy, relative to patients with Alzheimer's disease, 18F-AV-1451 binding was elevated in the midbrain (t = 2.1, P < 0.04); while patients with progressive supranuclear palsy showed, relative to controls, increased 18F-AV-1451 uptake in the putamen, pallidum, thalamus, midbrain, and in the dentate nucleus of the cerebellum (t's > 2.7, P's < 0.02). The support vector machine assigned patients' diagnoses with 94% accuracy. The post-mortem autoradiographic data showed that 18F-AV-1451 strongly bound to Alzheimer-related tau pathology, but less specifically in progressive supranuclear palsy. 18F-AV-1451 binding to the basal ganglia was strong in all groups in vivo. Postmortem histochemical staining showed absence of neuromelanin-containing cells in the basal ganglia, indicating that off-target binding to neuromelanin is an insufficient explanation of 18F-AV-1451 positron emission tomography data in vivo, at least in the basal ganglia. Overall, we confirm the potential of 18F-AV-1451 as a heuristic biomarker, but caution is indicated in the neuropathological interpretation of its binding. Off-target binding may contribute to disease profiles of 18F-AV-1451 positron emission tomography, especially in primary tauopathies such as progressive supranuclear palsy. We suggest that 18F-AV-1451 positron emission tomography is a useful biomarker to assess tau pathology in Alzheimer's disease and to distinguish it from other tauopathies with distinct clinical and pathological characteristics such as progressive supranuclear palsy.

Rod-shaped microglia morphology is associated with aging in 2 human autopsy series

A subtype of microglia is defined by the morphological appearance of the cells as rod shaped. Little is known about this intriguing cell type, as there are only a few case reports describing rod-shaped microglia in the neuropathological literature. Rod-shaped microglia were shown recently to account for a substantial proportion of the microglia cells in the hippocampus of both demented and cognitively intact aged individuals. We hypothesized that aging could be a defining feature in the occurrence of rod-shaped microglia. To test this hypothesis, 2 independent series of autopsy cases (total n = 168 cases), which covered the adult lifespan from 20 to 100+ years old, were included in the study. The presence or absence of rod-shaped microglia was scored on IBA1 immunohistochemically stained slides for the hippocampus and cortex. We found that age was one of the strongest determinants for the presence of rod-shaped microglia in the hippocampus and the cortex. We found no association with the presence of rod-shaped microglia and a self-reported history of a TBI. Alzheimer's disease–related pathology was found to influence the presence of rod-shaped microglia, but only in the parietal cortex and not in the hippocampus or temporal cortex. Future studies are warranted to determine the functional relevance of rod-shaped microglia in supporting the health of neurons in the aged brain, and the signaling processes that regulate the formation of rod-shaped microglia.

Presynaptic proteins complexin-I and complexin-II differentially influence cognitive function in early and late stages of Alzheimer's disease.

Progressive accumulation of Alzheimer's disease-related pathology is associated with cognitive dysfunction. Differences in cognitive reserve may contribute to individual differences in cognitive function in the presence of comparable neuropathology. The protective effects of cognitive reserve could contribute differentially in early versus late stages of the disease. We investigated presynaptic proteins as measures of brain reserve (a subset of total cognitive reserve), and used Braak staging to estimate the progression of Alzheimer's disease. Antemortem evaluations of cognitive function, postmortem assessments of pathologic indices, and presynaptic protein analyses, including the complexins I and II as respective measures of inhibitory and excitatory terminal function, were assayed in multiple key brain regions in 418 deceased participants from a community study. After covarying for demographic variables, pathologic indices, and overall synapse density, lower brain complexin-I and -II levels contributed to cognitive dysfunction (P<0.01). Each complexin appeared to be dysregulated at a different Braak stage. Inhibitory complexin-I explained 14.4% of the variance in global cognition in Braak 0-II, while excitatory complexin-II explained 7.3% of the variance in Braak V-VI. Unlike other presynaptic proteins, complexins did not colocalize with pathologic tau within neuritic plaques, suggesting that these functional components of the synaptic machinery are cleared early from dystrophic neurites. Moreover, complexin levels showed distinct patterns of change related to memory challenges in a rat model, supporting the functional specificity of these proteins. The present results suggest that disruption of inhibitory synaptic terminals may trigger early cognitive impairment, while excitatory terminal disruption may contribute relatively more to later cognitive impairment.

High fat diet exacerbates Alzheimer's disease-related pathology in APPswe/PS1 mice.

Alzheimer's disease (AD) is mainly characterized by the accumulation and aggregation of amyloid-β (Aβ) peptides in brain parenchyma and cerebral microvasculature. Unfortunately, the exact causes of the disease are still unclear. However, blood-brain barrier (BBB) dysfunction and activation of inflammatory pathways are implicated in AD pathogenesis. Importantly, advanced age and high fat diet, two major risk factors associated with AD, were shown to deeply affect BBB function and modulate the immune response. As such, this study evaluated the impact of age and high fat diet on AD progression. For this purpose, 3 (i.e. young) and 12 (i.e. aged) months old APPswe/PS1 mice were fed for 4 months with a high fat diet (i.e. Western diet (WD)) or normal diet. Interestingly, neurobehavioral tests revealed that WD accelerates age-associated cognitive decline without affecting parenchymal Aβ. Nonetheless, WD decreases matrix metalloproteinase-9 enzymatic activity and brain-derived neurotrophic factor mRNA and protein levels in brain, suggesting loss of synaptic plasticity. In the periphery, WD promotes systemic inflammation by increasing the levels of blood-circulating monocytes and monocyte chemotactic protein-1 production, which is accompanied by an augmentation of oxidized-low density lipoprotein levels in blood circulation. At the BBB, WD potentiates the age-induced increase of Aβ 1-40 accumulation and exacerbates the oxidative stress, specifically in cerebral microvasculature. These effects were accompanied by the dysfunction of pericytes, thus altering BBB functionality without compromising its integrity. Our study provides new insights into the implication of high fat diet in accelerating the cognitive decline in AD.

TREM2 p.R47H substitution is not associated with dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) is the second leading cause of neurodegenerative dementia in the elderly and is clinically characterized by the presence of cognitive decline, parkinsonism, REM sleep behavior disorder, and visual hallucinations.(1,2) At autopsy, α-synuclein-positive Lewy-related pathology is observed throughout the brain. Concomitant Alzheimer disease-related pathology including amyloid plaques and, to a lesser degree, neurofibrillary tangles are often present.(2) The clinical characteristics of DLB share overlapping features with Alzheimer disease dementia (AD) and Parkinson disease (PD). A recent genetic association study examining known hits from PD and AD identified variants at both the α-synuclein (SNCA) and APOE loci as influencing the individual risk to DLB.(3) These findings would suggest that DLB may be a distinct disease with shared genetic risk factors with PD and AD.