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1.
Proc Natl Acad Sci U S A ; 118(11)2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33649184

RESUMO

Kv1.3 potassium channels, expressed by proinflammatory central nervous system mononuclear phagocytes (CNS-MPs), are promising therapeutic targets for modulating neuroinflammation in Alzheimer's disease (AD). The molecular characteristics of Kv1.3-high CNS-MPs and their cellular origin from microglia or CNS-infiltrating monocytes are unclear. While Kv1.3 blockade reduces amyloid beta (Aß) burden in mouse models, the downstream immune effects on molecular profiles of CNS-MPs remain unknown. We show that functional Kv1.3 channels are selectively expressed by a subset of CD11b+CD45+ CNS-MPs acutely isolated from an Aß mouse model (5xFAD) as well as fresh postmortem human AD brain. Transcriptomic profiling of purified CD11b+Kv1.3+ CNS-MPs, CD11b+CD45int Kv1.3neg microglia, and peripheral monocytes from 5xFAD mice revealed that Kv1.3-high CNS-MPs highly express canonical microglial markers (Tmem119, P2ry12) and are distinct from peripheral Ly6chigh/Ly6clow monocytes. Unlike homeostatic microglia, Kv1.3-high CNS-MPs express relatively lower levels of homeostatic genes, higher levels of CD11c, and increased levels of glutamatergic transcripts, potentially representing phagocytic uptake of neuronal elements. Using irradiation bone marrow CD45.1/CD45.2 chimerism in 5xFAD mice, we show that Kv1.3+ CNS-MPs originate from microglia and not blood-derived monocytes. We show that Kv1.3 channels regulate membrane potential and early signaling events in microglia. Finally, in vivo blockade of Kv1.3 channels in 5xFAD mice by ShK-223 reduced Aß burden, increased CD11c+ CNS-MPs, and expression of phagocytic genes while suppressing proinflammatory genes (IL1b). Our results confirm the microglial origin and identify unique molecular features of Kv1.3-expressing CNS-MPs. In addition, we provide evidence for CNS immunomodulation by Kv1.3 blockers in AD mouse models resulting in a prophagocytic phenotype.

2.
Am J Hum Genet ; 2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33571421

RESUMO

We generated an online brain pQTL resource for 7,376 proteins through the analysis of genetic and proteomic data derived from post-mortem samples of the dorsolateral prefrontal cortex of 330 older adults. The identified pQTLs tend to be non-synonymous variation, are over-represented among variants associated with brain diseases, and replicate well (77%) in an independent brain dataset. Comparison to a large study of brain eQTLs revealed that about 75% of pQTLs are also eQTLs. In contrast, about 40% of eQTLs were identified as pQTLs. These results are consistent with lower pQTL mapping power and greater evolutionary constraint on protein abundance. The latter is additionally supported by observations of pQTLs with large effects' tending to be rare, deleterious, and associated with proteins that have evidence for fewer protein-protein interactions. Mediation analyses using matched transcriptomic and proteomic data provided additional evidence that pQTL effects are often, but not always, mediated by mRNA. Specifically, we identified roughly 1.6 times more mRNA-mediated pQTLs than mRNA-independent pQTLs (550 versus 341). Our pQTL resource provides insight into the functional consequences of genetic variation in the human brain and a basis for novel investigations of genetics and disease.

3.
Nat Genet ; 53(2): 143-146, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33510477

RESUMO

Genome-wide association studies (GWAS) have identified many risk loci for Alzheimer's disease (AD)1,2, but how these loci confer AD risk is unclear. Here, we aimed to identify loci that confer AD risk through their effects on brain protein abundance to provide new insights into AD pathogenesis. To that end, we integrated AD GWAS results with human brain proteomes to perform a proteome-wide association study (PWAS) of AD, followed by Mendelian randomization and colocalization analysis. We identified 11 genes that are consistent with being causal in AD, acting via their cis-regulated brain protein abundance. Nine replicated in a confirmation PWAS and eight represent new AD risk genes not identified before by AD GWAS. Furthermore, we demonstrated that our results were independent of APOE e4. Together, our findings provide new insights into AD pathogenesis and promising targets for further mechanistic and therapeutic studies.

4.
Alzheimers Dement ; 2021 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-33480174

RESUMO

Intron retention (IR) has been implicated in the pathogenesis of complex diseases such as cancers; its association with Alzheimer's disease (AD) remains unexplored. We performed genome-wide analysis of IR through integrating genetic, transcriptomic, and proteomic data of AD subjects and mouse models from the Accelerating Medicines Partnership-Alzheimer's Disease project. We identified 4535 and 4086 IR events in 2173 human and 1736 mouse genes, respectively. Quantitation of IR enabled the identification of differentially expressed genes that conventional exon-level approaches did not reveal. There were significant correlations of intron expression within innate immune genes, like HMBOX1, with AD in humans. Peptides with a high probability of translation from intron-retained mRNAs were identified using mass spectrometry. Further, we established AD-specific intron expression Quantitative Trait Loci, and identified splicing-related genes that may regulate IR. Our analysis provides a novel resource for the search for new AD biomarkers and pathological mechanisms.

5.
Neuropsychopharmacology ; 46(1): 98-115, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32898852

RESUMO

The repeated failures of amyloid-targeting therapies have challenged our narrow understanding of Alzheimer's disease (AD) pathogenesis and inspired wide-ranging investigations into the underlying mechanisms of disease. Increasing evidence indicates that AD develops from an intricate web of biochemical and cellular processes that extend far beyond amyloid and tau accumulation. This growing recognition surrounding the diversity of AD pathophysiology underscores the need for holistic systems-based approaches to explore AD pathogenesis. Here we describe how network-based proteomics has emerged as a powerful tool and how its application to the AD brain has provided an informative framework for the complex protein pathophysiology underlying the disease. Furthermore, we outline how the AD brain network proteome can be leveraged to advance additional scientific and translational efforts, including the discovery of novel protein biomarkers of disease.

6.
J Psychosom Res ; 141: 110342, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33360843

RESUMO

OBJECTIVE: To understand if presence of mental stress-induced myocardial ischemia (MSIMI) is associated with higher prevalence of cognitive impairment at baseline and its decline over time. METHODS: A cohort of participants with stable coronary atherosclerosis underwent acute mental stress testing using a series of standardized speech/arithmetic stressors. The stress/rest digital vasomotor response to mental stress (sPAT) was assessed to measure microvascular constriction during mental stress. Patients received 99mTc-sestamibi myocardial perfusion imaging at rest, with mental stress and with conventional (exercise/pharmacological) stress. Cognitive function was assessed both at baseline and at a 2 year follow-up using the Trail Making Test parts A and B and the verbal and visual memory subtests of the Wechsler Memory Scale. RESULTS: We studied 486 individuals (72% male, 32.1% Black, 62 ± 9 (mean ± SD) years old). After multivariable adjustment for baseline demographics, risk factors, and medication use, presence of MSIMI was associated with 21% and 20% slower completion of Trail-A and Trail-B, respectively (p for all <0.01). After a 2-year follow-up period, presence of MSIMI was associated with a 33% slower completion of Trail-B, denoting cognitive decline (B = 0.33, 95% CI, 0.04, 0.62). A lower sPAT, indicating greater vasoconstriction, mediated the association between MSIMI and worsening Trail-B performance by 18.2%. Ischemia with a conventional stress test was not associated with any of the cognitive tests over time. CONCLUSION: MSIMI is associated with slower visuomotor processing and worse executive function at baseline and with greater decline in these abilities over time.

7.
Stress Health ; 2020 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-33319483

RESUMO

Greater psychological distress is associated with cognitive impairment in healthy adults. Whether such associations also exist in patients with coronary artery disease (CAD) is uncertain. We assessed cognitive function in 496 individuals with CAD using the verbal and visual memory subtests of the Wechsler Memory Scale and executive functioning measured by the Trail Making Test Parts A and B. We used a composite score of psychological distress derived through summation of Z-transformed psychological distress symptom scales (depression, posttraumatic stress, anxiety, anger, hostility and perceived stress) and scores for each individual psychological scale. Multivariable linear regression models were used to determine the association between memory scores (as outcomes) and the psychological distress scores (both composite score and individual scales). After adjusting for demographic and cardiovascular risk factors, a higher psychological distress score was independently associated with worse memory and executive functioning. Each standard deviation increase in psychological distress score was associated with 3% (95% confidence interval [CI], 1%-5%) to 5% (95% CI, 3-7%) worse cognitive performance (higher Trail A and Trail B, and lower verbal and visual memory scores). Among individuals with CAD, a higher level of psychological distress is independently associated with worse cognitive performance. These findings suggest that psychological risk factors play a role in cognitive trajectories of persons with CAD.

8.
Nat Commun ; 11(1): 6075, 2020 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-33247100

RESUMO

Our memories enable us to form expectations for our future experiences, yet the precise neural mechanisms underlying how we compare any experience to our memory remain unknown. Here, using intracranial EEG recordings, we show that episodic memories formed after a single visual experience establish expectations for future experience within neocortical-medial temporal lobe circuits. When subsequent experiences violate these expectations, we find a 80-120 Hz prediction error signal that emerges in both visual association areas and the medial temporal lobe. Critically, this error signal emerges in visual association areas first and then propagates to the medial temporal lobe. This error signal is accompanied by alpha coherence between the two regions. Our data therefore suggest that internal models formed from episodic memories are generated throughout the visual hierarchy after just a single exposure, and that these internal models are then used for comparison with future experiences.

9.
Sci Adv ; 6(43)2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33087358

RESUMO

Alzheimer's disease (AD) lacks protein biomarkers reflective of its diverse underlying pathophysiology, hindering diagnostic and therapeutic advancements. Here, we used integrative proteomics to identify cerebrospinal fluid (CSF) biomarkers representing a wide spectrum of AD pathophysiology. Multiplex mass spectrometry identified ~3500 and ~12,000 proteins in AD CSF and brain, respectively. Network analysis of the brain proteome resolved 44 biologically diverse modules, 15 of which overlapped with the CSF proteome. CSF AD markers in these overlapping modules were collapsed into five protein panels representing distinct pathophysiological processes. Synaptic and metabolic panels were decreased in AD brain but increased in CSF, while glial-enriched myelination and immunity panels were increased in brain and CSF. The consistency and disease specificity of panel changes were confirmed in >500 additional CSF samples. These panels also identified biological subpopulations within asymptomatic AD. Overall, these results are a promising step toward a network-based biomarker tool for AD clinical applications.

10.
Sci Data ; 7(1): 315, 2020 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-32985496

RESUMO

Alzheimer's disease (AD) is characterized by an early, asymptomatic phase (AsymAD) in which individuals exhibit amyloid-beta (Aß) plaque accumulation in the absence of clinically detectable cognitive decline. Here we report an unbiased multiplex quantitative proteomic and phosphoproteomic analysis using tandem mass tag (TMT) isobaric labeling of human post-mortem cortex (n = 27) across pathology-free controls, AsymAD and symptomatic AD individuals. With off-line high-pH fractionation and liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) on an Orbitrap Lumos mass spectrometer, we identified 11,378 protein groups across three TMT 11-plex batches. Immobilized metal affinity chromatography (IMAC) was used to enrich for phosphopeptides from the same TMT-labeled cases and 51,736 phosphopeptides were identified. Of these, 48,992 were quantified by TMT reporter ions representing 33,652 unique phosphosites. Two reference standards in each TMT 11-plex were included to assess intra- and inter-batch variance at the protein and peptide level. This comprehensive human brain proteome and phosphoproteome dataset will serve as a valuable resource for the identification of biochemical, cellular and signaling pathways altered during AD progression.

11.
Nat Commun ; 11(1): 3942, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32770063

RESUMO

Though discovered over 100 years ago, the molecular foundation of sporadic Alzheimer's disease (AD) remains elusive. To better characterize the complex nature of AD, we constructed multiscale causal networks on a large human AD multi-omics dataset, integrating clinical features of AD, DNA variation, and gene- and protein-expression. These probabilistic causal models enabled detection, prioritization and replication of high-confidence master regulators of AD-associated networks, including the top predicted regulator, VGF. Overexpression of neuropeptide precursor VGF in 5xFAD mice partially rescued beta-amyloid-mediated memory impairment and neuropathology. Molecular validation of network predictions downstream of VGF was also achieved in this AD model, with significant enrichment for homologous genes identified as differentially expressed in 5xFAD brains overexpressing VGF. Our findings support a causal role for VGF in protecting against AD pathogenesis and progression.


Assuntos
Doença de Alzheimer/etiologia , Encéfalo/patologia , Fatores de Crescimento Neural/metabolismo , Mapas de Interação de Proteínas , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Animais , Conjuntos de Dados como Assunto , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Estudo de Associação Genômica Ampla , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Fatores de Crescimento Neural/genética , Mapeamento de Interação de Proteínas , Proteômica
12.
JAMA Psychiatry ; 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32609320

RESUMO

Importance: Identifying genes and proteins for cognitive resilience (ie, targets that may be associated with slowing or preventing cognitive decline regardless of the presence, number, or combination of common neuropathologic conditions) provides a complementary approach to developing novel therapeutics for the treatment and prevention of Alzheimer disease and related dementias. Objective: To identify proteins associated with cognitive resilience via a proteome-wide association study of the human dorsolateral prefrontal cortex. Design, Setting, and Participants: This study used data from 391 community-dwelling older persons who participated in the Religious Orders Study and the Rush Memory and Aging Project. The Religious Orders Study began enrollment January 1, 1994, and the Rush Memory and Aging Project began enrollment September 1, 1997, and data were collected and analyzed through October 23, 2019. Exposures: Participants had undergone annual detailed clinical examinations, postmortem evaluations, and tandem mass tag proteomics analyses. Main Outcomes and Measures: The outcome of cognitive resilience was defined as a longitudinal change in cognition over time after controlling for common age-related neuropathologic indices, including Alzheimer disease, Lewy bodies, transactive response DNA-binding protein 43, hippocampal sclerosis, infarcts, and vessel diseases. More than 8000 high abundance proteins were quantified from frozen dorsolateral prefrontal cortex tissue using tandem mass tag and liquid chromatography-mass spectrometry. Results: There were 391 participants (273 women); their mean (SD) age was 79.7 (6.7) years at baseline and 89.2 (6.5) years at death. Eight cortical proteins were identified in association with cognitive resilience: a higher level of NRN1 (estimate, 0.140; SE, 0.024; P = 7.35 × 10-9), ACTN4 (estimate, 0.321; SE, 0.065; P = 9.94 × 10-7), EPHX4 (estimate, 0.198; SE, 0.042; P = 2.13 × 10-6), RPH3A (estimate, 0.148; SE, 0.031; P = 2.58 × 10-6), SGTB (estimate, 0.211; SE, 0.045; P = 3.28 × 10-6), CPLX1 (estimate, 0.136; SE, 0.029; P = 4.06 × 10-6), and SH3GL1 (estimate, 0.179; SE, 0.039; P = 4.21 × 10-6) and a lower level of UBA1 (estimate, -0.366; SE, 0.076; P = 1.43 × 10-6) were associated with greater resilience. Conclusions and Relevance: These protein signals may represent novel targets for the maintenance of cognition in old age.

13.
Clin Proteomics ; 17: 19, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32514259

RESUMO

Introduction: Alzheimer's disease (AD) is the most common cause of dementia, characterized by progressive cognitive decline. Protein biomarkers of AD brain pathology, including ß-amyloid and Tau, are reflected in cerebrospinal fluid (CSF), yet the identification of additional biomarkers linked to other brain pathophysiologies remains elusive. We recently reported a multiplex tandem-mass tag (TMT) CSF proteomic analysis of nearly 3000 proteins, following depletion of highly abundant proteins and off-line fractionation, across control and AD cases. Of these, over 500 proteins were significantly increased or decreased in AD, including markers reflecting diverse biological functions in brain. Here, we use a targeted mass spectrometry (MS) approach, termed parallel reaction monitoring (PRM), to quantify select CSF biomarkers without pre-depletion or fractionation to assess the reproducibility of our findings and the specificity of changes for AD versus other causes of cognitive impairment. Method: We nominated 41 proteins (94 peptides) from the TMT CSF discovery dataset, representing a variety of brain cell-types and biological functions, for label-free PRM analysis in a replication cohort of 88 individuals that included 20 normal controls, 37 clinically diagnosed AD cases and 31 cases with non-AD cognitive impairment. To control for technical variables, isotopically labeled synthetic heavy peptide standards were added into each of the 88 CSF tryptic digests. Furthermore, a peptide pool, representing an equivalent amount of peptide from all samples, was analyzed (n = 10) across each batch. Together, this approach enabled us to assess both the intra- and inter-sample differences in peptide signal response and retention time. Results: Despite differences in sample preparation, quantitative MS approaches and patient samples, 25 proteins, including Tau, had a consistent and significant change in AD in both the discovery and replication cohorts. Validated CSF markers with low coefficient of variation included the protein products for neuronal/synaptic (GDA, GAP43, SYN1, BASP1, YWHAB, YWHAZ, UCHL1, STMN1 and MAP1B), glial/inflammation (SMOC1, ITGAM, CHI3L1, SPP1, and CHIT1) and metabolic (PKM, ALDOA and FABP3) related genes. Logistical regression analyses revealed several proteins with high sensitivity and specificity for classifying AD cases from controls and other non-AD dementias. SMOC1, YWHAZ, ALDOA and MAP1B emerged as biomarker candidates that could best discriminate between individuals with AD and non-AD cognitive impairment as well as Tau/ß-amyloid ratio. Notably, SMOC1 levels in postmortem brain are highly correlated with AD pathology even in the preclinical stage of disease, indicating that CSF SMOC1 levels reflect underlying brain pathology specific for AD. Conclusion: Collectively these findings highlight the utility of targeted MS approaches to quantify biomarkers associated with AD that could be used for monitoring disease progression, stratifying patients for clinical trials and measuring therapeutic response.

14.
J Alzheimers Dis ; 76(1): 27-31, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32568212

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic led to an abrupt halt of many Alzheimer's disease (AD) research studies at sites spanning the world. This is especially true for studies requiring in-person contact, such as studies collecting biofluids. Since COVID-19 is likely to remain a threat for an extended period, the resumption of fluid biomarker studies requires the development and implementation of procedures that minimize the risk of in-person visits to participants, staff, and individuals handling the biofluid samples. Some issues to consider include structuring the visit workflow to minimize contacts and promote social distancing; screening and/or testing participants and staff for COVID-19; wearing masks and performing hand hygiene; and precautions for handling, storing, and analyzing biofluids. AD fluid biomarker research remains a vitally important public health priority and resuming studies requires appropriate safety procedures to protect research participants and staff.


Assuntos
Doença de Alzheimer/metabolismo , Betacoronavirus , Infecções por Coronavirus/metabolismo , Pessoal de Saúde/tendências , Segurança do Paciente , Equipamento de Proteção Individual , Pneumonia Viral/metabolismo , Doença de Alzheimer/diagnóstico , Biomarcadores/metabolismo , Líquidos Corporais/metabolismo , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/transmissão , Humanos , Pandemias , Equipamento de Proteção Individual/tendências , Pneumonia Viral/diagnóstico , Pneumonia Viral/transmissão
15.
Cell Rep ; 31(12): 107807, 2020 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-32579933

RESUMO

Data-driven analyses are increasingly valued in modern medicine. We integrate quantitative proteomics and transcriptomics from over 1,000 post-mortem brains from six cohorts representing Alzheimer's disease (AD), asymptomatic AD, progressive supranuclear palsy (PSP), and control patients from the Accelerating Medicines Partnership - Alzheimer's Disease consortium. We define robust co-expression trajectories related to disease progression, including early neuronal, microglial, astrocyte, and immune response modules, and later mRNA splicing and mitochondrial modules. The majority of, but not all, modules are conserved at the transcriptomic level, including module C3, which is only observed in proteome networks and enriched in mitogen-activated protein kinase (MAPK) signaling. Genetic risk enriches in modules changing early in disease and indicates that AD and PSP have distinct causal biological drivers at the pathway level, despite aspects of similar pathology, including synaptic loss and glial inflammatory changes. The conserved, high-confidence proteomic changes enriched in genetic risk represent targets for drug discovery.

17.
Nat Neurosci ; 23(6): 696-700, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32424284

RESUMO

Cerebral atherosclerosis contributes to dementia via unclear processes. We performed proteomic sequencing of dorsolateral prefrontal cortex in 438 older individuals and found associations between cerebral atherosclerosis and reduced synaptic signaling and between RNA splicing and increased oligodendrocyte development and myelination. Consistently, single-cell RNA sequencing showed cerebral atherosclerosis associated with higher oligodendrocyte abundance. A subset of proteins and modules associated with cerebral atherosclerosis was also associated with Alzheimer's disease, suggesting shared mechanisms.


Assuntos
Envelhecimento/metabolismo , Doença de Alzheimer/metabolismo , Arteriosclerose Intracraniana/metabolismo , Proteínas do Tecido Nervoso/biossíntese , Córtex Pré-Frontal/metabolismo , Proteômica , Doença de Alzheimer/complicações , Bases de Dados Factuais , Humanos , Arteriosclerose Intracraniana/complicações
18.
Mol Neurodegener ; 15(1): 28, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32381088

RESUMO

BACKGROUND: Proteomic characterization of microglia provides the most proximate assessment of functionally relevant molecular mechanisms of neuroinflammation. However, microglial proteomics studies have been limited by low cellular yield and contamination by non-microglial proteins using existing enrichment strategies. METHODS: We coupled magnetic-activated cell sorting (MACS) and fluorescence activated cell sorting (FACS) of microglia with tandem mass tag-mass spectrometry (TMT-MS) to obtain a highly-pure microglial proteome and identified a core set of highly-abundant microglial proteins in adult mouse brain. We interrogated existing human proteomic data for Alzheimer's disease (AD) relevance of highly-abundant microglial proteins and performed immuno-histochemical and in-vitro validation studies. RESULTS: Quantitative multiplexed proteomics by TMT-MS of CD11b + MACS-enriched (N = 5 mice) and FACS-isolated (N = 5 mice), from adult wild-type mice, identified 1791 proteins. A total of 203 proteins were highly abundant in both datasets, representing a core-set of highly abundant microglial proteins. In addition, we found 953 differentially enriched proteins comparing MACS and FACS-based approaches, indicating significant differences between both strategies. The FACS-isolated microglia proteome was enriched with cytosolic, endoplasmic reticulum, and ribosomal proteins involved in protein metabolism and immune system functions, as well as an abundance of canonical microglial proteins. Conversely, the MACS-enriched microglia proteome was enriched with mitochondrial and synaptic proteins and higher abundance of neuronal, oligodendrocytic and astrocytic proteins. From the 203 consensus microglial proteins with high abundance in both datasets, we confirmed microglial expression of moesin (Msn) in wild-type and 5xFAD mouse brains as well as in human AD brains. Msn expression is nearly exclusively found in microglia that surround Aß plaques in 5xFAD brains. In in-vitro primary microglial studies, Msn silencing by siRNA decreased Aß phagocytosis and increased lipopolysaccharide-induced production of the pro-inflammatory cytokine, tumor necrosis factor (TNF). In network analysis of human brain proteomic data, Msn was a hub protein of an inflammatory co-expression module positively associated with AD neuropathological features and cognitive dysfunction. CONCLUSIONS: Using FACS coupled with TMT-MS as the method of choice for microglial proteomics, we define a core set of highly-abundant adult microglial proteins. Among these, we validate Msn as highly-abundant in plaque-associated microglia with relevance to human AD.

19.
Artigo em Inglês | MEDLINE | ID: mdl-32461027

RESUMO

The public health burden of Alzheimer's disease (AD) is related not only to cognitive symptoms, but also to neuropsychiatric symptoms, including apathy. Apathy is defined as a quantitative reduction of goal-directed activity in comparison to a previous level of functioning and affects 30%-70% of persons with AD. Previous attempts to treat apathy in AD-both nonpharmacologically and pharmacologically-have been wanting. Catecholaminergic treatment with methylphenidate has shown encouraging results in initial trials of apathy in AD. Understanding the neuronal circuits underlying motivated behavior and their reliance on catecholamine actions helps provide a rationale for methylphenidate actions in the treatment of apathy in patients with AD. Anatomical, physiological, and behavioral studies have identified parallel, cortical-basal ganglia circuits that govern action, cognition, and emotion and play key roles in motivated behavior. Understanding the distinct contributions to motivated behavior of subregions of the prefrontal cortex-dorsolateral, orbital-ventromedial, and dorsomedial-helps to explain why degeneration of these areas in AD results in apathetic behaviors. We propose that the degeneration of the prefrontal cortex in AD produces symptoms of apathy. We further propose that methylphenidate treatment may ameliorate those symptoms by boosting norepinephrine and dopamine actions in prefrontal-striatal-thalamocortical circuits.

20.
IEEE Trans Biomed Eng ; PP2020 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-32340935

RESUMO

OBJECTIVE: Alzheimer's disease is a neurodegenerative disorder that initially presents with memory loss in the presence of underlying neurofibrillary tangle and amyloid plaque pathology. This period offers an early window for detecting subtle cognitive impairment prior to progressive decline and dementia. We recently developed the Visuospatial Memory Eye-Tracking Test (VisMET), a passive task capable of predicting cognitive impairment in AD in under five minutes. Here we describe the development of a mobile version of VisMET to enable efficient and widespread administration of the task. METHODS: We delivered VisMET on iPad devices and used a transfer learning approach to train a deep neural network to track eyegaze. Eye movements were used to extract memory features to assess cognitive status in a population of 250 individuals. RESULTS: Mild to severe cognitive impairment was identifiable with a test accuracy of 70%. By enforcing a minimal eye tracking calibration error of 2cm, we achieved an accuracy of 76% which is equivalent to the accuracy obtained using commercial hardware for eye-tracking. CONCLUSION: This work demonstrates a mobile version of VisMET capable of predicting the severity of cognitive impairment. SIGNIFICANCE: Given the ubiquity of tablet devices, our approach has the potential to scale globally.

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