Computational modeling of tau pathology spread reveals patterns of regional vulnerability and the impact of a genetic risk factor

Neuropathological staging studies have suggested that tau pathology spreads through the brain in Alzheimer’s disease (AD) and other tauopathies, but it is unclear how neuroanatomical connections, spatial proximity, and regional vulnerability contribute. In this study, we seed tau pathology in the brains of nontransgenic mice with AD tau and quantify pathology development over 9 months in 134 brain regions. Network modeling of pathology progression shows that diffusion through the connectome is the best predictor of tau pathology patterns. Further, deviations from pure neuroanatomical spread are used to estimate regional vulnerability to tau pathology and identify related gene expression patterns. Last, we show that pathology spread is altered in mice harboring a mutation in leucine-rich repeat kinase 2. While tau pathology spread is still constrained by anatomical connectivity in these mice, it spreads preferentially in a retrograde direction. This study provides a framework for understanding neuropathological progression in tauopathies.

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Tau pathology spreads between anatomically-connected regions of the brain and is modulated by a LRRK2 mutation

10.1101/2020.10.13.337857 ◽

2020 ◽

Author(s):

Michael X. Henderson ◽

Eli J. Cornblath ◽

Howard L. Li ◽

Lakshmi Changolkar ◽

Bin Zhang ◽

...

Keyword(s):

Expression Patterns ◽

Network Models ◽

Spatial Proximity ◽

Spatiotemporal Pattern ◽

Diagnostic Feature ◽

Tau Pathology ◽

Anatomical Connectivity ◽

Regional Vulnerability ◽

Kinetics Of ◽

The Brain

ABSTRACTTau pathology is a diagnostic feature of Alzheimer’s disease (AD) but is also a prominent feature of Parkinson’s disease (PD), including genetic forms of PD with mutations in leucine-rich repeat kinase 2 (LRRK2). In both diseases, tau pathology is progressive and correlates with cognitive decline. Neuropathological staging studies in humans and mouse models have suggested that tau spreads through the brain, but it is unclear how neuroanatomical connections, spatial proximity, and regional vulnerability contribute to pathology spread. Further, it is unknown how mutations in the LRRK2 gene may modulate susceptibility to tau pathology’s initiation or spread. In this study, we used seed-based models of tauopathy to capture spatiotemporal patterns of pathology in mice. Following the injection of AD brain-derived tau into the brains of non-transgenic mice, tau pathology spreads progressively through the brain in a spatiotemporal pattern that is well-explained by anatomical connectivity. We validated and compared network models based on diffusion along anatomical connections to predict tau spread, estimate regional vulnerability to tau pathology, and investigate gene expression patterns related to regional vulnerability. We further investigated tau pathology spread in mice harboring a mutation in LRRK2 and found that while tau pathology spread is still constrained by anatomical connectivity, it spreads preferentially in a retrograde direction to regions that are otherwise resilient in wildtype mice. This study provides a quantitative demonstration that tau pathology spreads along anatomical connections, explores the kinetics of this spread, and provides a platform for investigating the effect of genetic risk factors and treatments on the progression of tauopathies.

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Neuroticism alters the transcriptome of the frontal cortex to contribute to the cognitive decline and onset of Alzheimer’s disease

10.1101/2020.08.21.261677 ◽

2020 ◽

Author(s):

Céline H. De Jager ◽

Charles C. White ◽

David A. Bennett ◽

Yiyi Ma

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Brain Regions ◽

Personality Characteristics ◽

Related Gene ◽

Tau Pathology ◽

Postmortem Human Brain ◽

Neo Five Factor Inventory ◽

The Impact

AbstractAccumulating evidence has suggested that the molecular transcriptional mechanism contributes to Alzheimer’s disease (AD) and its endophenotypes of cognitive decline and neuropathological traits, β-amyloid (Aβ) and phosphorylated tangles (TAU). However, it is unknown what is the impact of the AD risk factors, personality characteristics assessed by the NEO Five-Factor Inventory, on the human brain’s transcriptome. Using postmortem human brain samples from 466 subjects, we found that neuroticism has a significant overall impact on the brain transcriptome (omnibus P=0.005) but not the other 4 personality characteristics. Focused on those cognitive decline related gene co-expressed modules, neuroticism has nominally significant associations (P<0.05) with four neuronal modules, which are more related to PHFtau than Aβ across all eight brain regions. Furthermore, the effect of neuroticism on cognitive decline and AD might be mediated through the expression of module 7 and TAU pathology (P=0.008). To conclude, neuroticism has overall impact on human brains’ transcriptome and its effect on cognitive decline and AD might be mediated through TAU pathology related gene transcription mechanism.

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Neuroticism alters the transcriptome of the frontal cortex to contribute to the cognitive decline and onset of Alzheimer’s disease

Translational Psychiatry ◽

10.1038/s41398-021-01253-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Céline H. De Jager ◽

Charles C. White ◽

David A. Bennett ◽

Yiyi Ma

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Brain Regions ◽

Personality Characteristics ◽

Tau Pathology ◽

Postmortem Human Brain ◽

Brain Transcriptome ◽

Neo Five Factor Inventory ◽

The Impact

AbstractAccumulating evidence has suggested that the molecular transcriptional mechanism contributes to Alzheimer’s disease (AD) and its endophenotypes of cognitive decline and neuropathological traits, β-amyloid (Aβ) and phosphorylated tangles (TAU). However, it is unknown what is the impact of the AD risk factors, personality characteristics assessed by the NEO Five-Factor Inventory, on the human brain’s transcriptome. Using postmortem human brain samples from 466 subjects, we found that neuroticism has a significant overall impact on the brain transcriptome (omnibus P = 0.005) but not the other four personality characteristics. Focused on those cognitive decline related gene co-expressed modules, neuroticism has nominally significant associations (P < 0.05) with four neuronal modules, which are more related to PHFtau than Aβ across all eight brain regions. Furthermore, the effect of neuroticism on cognitive decline and AD might be mediated through the expression of module 7 and TAU pathology (P = 0.008). To conclude, neuroticism has a broad impact on the transcriptome of human brains, and its effect on cognitive decline and AD may be mediated through gene transcription programs related to TAU pathology.

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Developmental cannabidiol exposure increases anxiety and modifies genome-wide brain DNA methylation in adult female mice

Clinical Epigenetics ◽

10.1186/s13148-020-00993-4 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Nicole M. Wanner ◽

Mathia Colwell ◽

Chelsea Drown ◽

Christopher Faulk

Keyword(s):

Dna Methylation ◽

Molecular Mechanisms ◽

Coat Color ◽

Brain Regions ◽

Functional Enrichment ◽

Positive Effects ◽

Genome Wide ◽

Nulliparous Female ◽

The Impact ◽

The Brain

Abstract Background Use of cannabidiol (CBD), the primary non-psychoactive compound found in cannabis, has recently risen dramatically, while relatively little is known about the underlying molecular mechanisms of its effects. Previous work indicates that direct CBD exposure strongly impacts the brain, with anxiolytic, antidepressant, antipsychotic, and other effects being observed in animal and human studies. The epigenome, particularly DNA methylation, is responsive to environmental input and can direct persistent patterns of gene regulation impacting phenotype. Epigenetic perturbation is particularly impactful during embryogenesis, when exogenous exposures can disrupt critical resetting of epigenetic marks and impart phenotypic effects lasting into adulthood. The impact of prenatal CBD exposure has not been evaluated; however, studies using the psychomimetic cannabinoid Δ9-tetrahydrocannabinol (THC) have identified detrimental effects on psychological outcomes in developmentally exposed adult offspring. We hypothesized that developmental CBD exposure would have similar negative effects on behavior mediated in part by the epigenome. Nulliparous female wild-type Agouti viable yellow (Avy) mice were exposed to 20 mg/kg CBD or vehicle daily from two weeks prior to mating through gestation and lactation. Coat color shifts, a readout of DNA methylation at the Agouti locus in this strain, were measured in F1 Avy/a offspring. Young adult F1 a/a offspring were then subjected to tests of working spatial memory and anxiety/compulsive behavior. Reduced-representation bisulfite sequencing was performed on both F0 and F1 cerebral cortex and F1 hippocampus to identify genome-wide changes in DNA methylation for direct and developmental exposure, respectively. Results F1 offspring exposed to CBD during development exhibited increased anxiety and improved memory behavior in a sex-specific manner. Further, while no significant coat color shift was observed in Avy/a offspring, thousands of differentially methylated loci (DMLs) were identified in both brain regions with functional enrichment for neurogenesis, substance use phenotypes, and other psychologically relevant terms. Conclusions These findings demonstrate for the first time that despite positive effects of direct exposure, developmental CBD is associated with mixed behavioral outcomes and perturbation of the brain epigenome.

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Neurotoxic astrocytic glypican-4 drives APOE4-dependent tau pathology

10.1101/2021.07.07.451493 ◽

2021 ◽

Author(s):

Sivaprakasam Ramamoorthy ◽

Kirill Gorbachev ◽

Ana Pereira

Keyword(s):

Late Onset ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Brain Regions ◽

Tau Proteins ◽

Tau Pathology ◽

Density Lipoprotein Receptor ◽

Apoe Receptor ◽

The Brain

Apolipoprotein E4 (APOE4) is the crucial genetic risk factor of late-onset Alzheimer disease (AD). Aggregation of tau proteins into insoluble filaments and their spreading across the brain regions are major drivers of neurodegeneration in tauopathies, including in AD. However, the exact mechanisms through which APOE4 induces tau pathology remains unknown. Here, we report that the astrocyte-secreted protein glypican-4 (GPC-4), a novel binding partner of APOE4, drives tau pathology. GPC-4 preferentially interacts with APOE4 in comparison to other APOE isoforms and post-mortem APOE4-carrying AD brains highly express GPC-4 in neurotoxic astrocytes. The astrocyte-secreted GPC-4 induced both tau accumulation and propagation in vitro. CRISPR/dCas9 mediated activation of GPC-4 in a tauopathy animal model robustly induced tau pathology. Further, APOE4-induced tau pathology was greatly diminished in the absence of GPC-4. We found that GPC-4 promoted the stabilization of the APOE receptor low-density lipoprotein receptor-related protein 1 (LRP1) on the cellular surface, which effectively facilitates endocytosis of tau protein. Together, our data comprehensively demonstrate that one of the key APOE4-induced tau pathologies is directly mediated by GPC-4.

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Multimodal Imaging of Alzheimer Pathophysiology in the Brain's Default Mode Network

International Journal of Alzheimer s Disease ◽

10.4061/2011/687945 ◽

2011 ◽

Vol 2011 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

Jonghan Shin ◽

Vladimir Kepe ◽

Gary W. Small ◽

Michael E. Phelps ◽

Jorge R. Barrio

Keyword(s):

Default Mode Network ◽

Multimodal Imaging ◽

Temporal Cortex ◽

Brain Regions ◽

Default Network ◽

Spatial Correlations ◽

Tau Pathology ◽

Significant Discrepancy ◽

Default Mode ◽

The Brain

The spatial correlations between the brain's default mode network (DMN) and the brain regions known to develop pathophysiology in Alzheimer's disease (AD) have recently attracted much attention. In this paper, we compare results of different functional and structural imaging modalities, including MRI and PET, and highlight different patterns of anomalies observed within the DMN. Multitracer PET imaging in subjects with and without dementia has demonstrated that [C-11]PIB- and [F-18]FDDNP-binding patterns in patients with AD overlap within nodes of the brain's default network including the prefrontal, lateral parietal, lateral temporal, and posterior cingulate cortices, with the exception of the medial temporal cortex (especially, the hippocampus) where significant discrepancy between increased [F-18]FDDNP binding and negligible [C-11]PIB-binding was observed. [F-18]FDDNP binding in the medial temporal cortex—a key constituent of the DMN—coincides with both the presence of amyloid and tau pathology, and also with cortical areas with maximal atrophy as demonstrated by T1-weighted MR imaging of AD patients.

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Neurorehabilitation in Multiple Sclerosis – Resilience in Practice

European Neurological Review ◽

10.17925/enr.2017.12.01.31 ◽

2017 ◽

Vol 12 (01) ◽

pp. 31 ◽

Cited By ~ 2

Author(s):

Jürg Kesselring ◽

Keyword(s):

Multiple Sclerosis ◽

Best Practice ◽

Healthcare Providers ◽

Brain Regions ◽

Standards Of Care ◽

Key Factors ◽

Disease Modifying Drugs ◽

Randomised Controlled ◽

The Impact ◽

The Brain

In recent years, enormous strides have been made in increasing the range and efficacy of disease-modifying drugs available for the treatment of multiple sclerosis (MS) in its early and remitting stages, and more continue to emerge. Another equally important concept of successful treatment of MS is neurorehabilitation, which must be pursued alongside these medications. Key factors that contribute to the impact of neurorehabilitation include resilience and neuroplasticity. In the former, components such as nutrition, self-belief and physical activity provide a stronger response to the disease and improved responses to treatment. Neuroplasticity is the capacity of the brain to establish new neuronal networks after lesion damage has occurred and distant brain regions assume control of lost functions. In MS, it is vital that each patient is treated by a coordinated multidisciplinary team. This enables all aspects of the disease including problems with mobility, gait, bladder/bowel disturbances, fatigue and depression to be effectively treated. It is also important that the treating team adopts current best practice and provides internationally agreed standards of care. A further vital aspect of MS management is patient engagement, in which individuals are fully involved and are encouraged to strive and put effort into meeting treatment goals. In this approach, healthcare providers become motivators and patients need less intervention and consume fewer resources. Numerous interventions that promote neurorehabilitation are available, though evidence to support their use is limited by a lack of data from large randomised controlled trials. Combining interventions that promote neurorehabilitation with newer, more effective treatments creates a promising potential to substantially improve the outlook for patients at all stages of MS.

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Same Brain, Different Look?—The Impact of Scanner, Sequence and Preprocessing on Diffusion Imaging Outcome Parameters

Journal of Clinical Medicine ◽

10.3390/jcm10214987 ◽

2021 ◽

Vol 10 (21) ◽

pp. 4987

Author(s):

Ronja Thieleking ◽

Rui Zhang ◽

Maria Paerisch ◽

Kerstin Wirkner ◽

Alfred Anwander ◽

...

Keyword(s):

Data Acquisition ◽

Diffusion Imaging ◽

Mean Diffusivity ◽

Brain Regions ◽

Clinical Diagnostics ◽

Neuroimaging Data ◽

Age Range ◽

The Impact ◽

The Brain ◽

Healthy Participants

In clinical diagnostics and longitudinal studies, the reproducibility of MRI assessments is of high importance in order to detect pathological changes, but developments in MRI hard- and software often outrun extended periods of data acquisition and analysis. This could potentially introduce artefactual changes or mask pathological alterations. However, if and how changes of MRI hardware, scanning protocols or preprocessing software affect complex neuroimaging outcomes from, e.g., diffusion weighted imaging (DWI) remains largely understudied. We therefore compared DWI outcomes and artefact severity of 121 healthy participants (age range 19–54 years) who underwent two matched DWI protocols (Siemens product and Center for Magnetic Resonance Research sequence) at two sites (Siemens 3T Magnetom Verio and Skyrafit). After different preprocessing steps, fractional anisotropy (FA) and mean diffusivity (MD) maps, obtained by tensor fitting, were processed with tract-based spatial statistics (TBSS). Inter-scanner and inter-sequence variability of skeletonised FA values reached up to 5% and differed largely in magnitude and direction across the brain. Skeletonised MD values differed up to 14% between scanners. We here demonstrate that DTI outcome measures strongly depend on imaging site and software, and that these biases vary between brain regions. These regionally inhomogeneous biases may exceed and considerably confound physiological effects such as ageing, highlighting the need to harmonise data acquisition and analysis. Future studies thus need to implement novel strategies to augment neuroimaging data reliability and replicability.

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Brain hubs defined in the group do not overlap with regions of high inter-individual variability

10.1101/2021.10.17.464723 ◽

2021 ◽

Author(s):

Derek Martin Smith ◽

Brian T Kraus ◽

Ally Dworetsky ◽

Evan M Gordon ◽

Caterina Gratton

Keyword(s):

Functional Connectivity ◽

Brain Function ◽

Critical Role ◽

Brain Regions ◽

Individual Variability ◽

Spatial Proximity ◽

Functional Magnetic Resonance ◽

Multiple Networks ◽

Human Connectome Project ◽

The Brain

Connector 'hubs' are brain regions with links to multiple networks. These regions are hypothesized to play a critical role in brain function. While hubs are often identified based on group-average functional magnetic resonance imaging (fMRI) data, there is considerable inter-subject variation in the functional connectivity profiles of the brain, especially in association regions where hubs tend to be located. Here we investigated how group hubs are related to locations of inter-individual variability, to better understand if hubs are (a) relatively conserved across people, (b) locations with malleable connectivity, leading individuals to show variable hub profiles, or (c) artifacts arising from cross-person variation. To answer this question, we compared the locations of hubs and regions of strong idiosyncratic functional connectivity ("variants") in both the Midnight Scan Club and Human Connectome Project datasets. Group hubs defined based on the participation coefficient did not overlap strongly with variants. These hubs have relatively strong similarity across participants and consistent cross-network profiles. Consistency across participants was further improved when participation coefficient hubs were allowed to shift slightly in local position. Thus, our results demonstrate that group hubs defined with the participation coefficient are generally consistent across people, suggesting they may represent conserved cross-network bridges. More caution is warranted with alternative hub measures, such as community density, which are based on spatial proximity and show higher correspondence to locations of individual variability.

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The Brain in a Physician’s Life

10.1093/med/9780190237493.003.0028 ◽

2017 ◽

Author(s):

Peggy Mason

Keyword(s):

Nervous System ◽

Brain Regions ◽

Altered State ◽

Compassionate Care ◽

Clinical Impairment ◽

Altered State Of Consciousness ◽

Individual Nature ◽

The Impact ◽

The Brain

With the knowledge acquired from this book, the brain regions responsible for each of the symptoms suffered by Jean-Dominique Bauby can be identified. It is also possible to understand why thought, language, and memory were unaffected in Bauby. Bauby’s narrative is used to launch a consideration of the role of embodiment in affective experience. The experience of Clive Wearing who, after a bout of encephalitis, was left without the ability to make new declarative memories is introduced to illustrate the highly personal and individual nature of people’s reactions to disease or clinical impairment. The impact of disease does not stop with the patient but extends to the patient’s loved ones and caregivers. This is particularly true of patients with dementia or those in an altered state of consciousness. Finally the reader is encouraged to use their understanding of the nervous system to provide compassionate care for patients.

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