Epidemiological pathology of Tau in the ageing brain: application of staging for neuropil threads (BrainNet Europe protocol) to the MRC cognitive function and ageing brain study

Wharton, Stephen B.; Minett, Thaı́s; Drew, David; Forster, G.; Matthews, Fiona E.; Brayne, Carol; Ince, Paul G.

doi:10.1186/s40478-016-0275-x

Cited by 51 publications

(57 citation statements)

References 34 publications

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“…ARTAG was also common in this cohort and, to our knowledge, this is the first study to show an association of ARTAG with clinical dementia in a large cohort of elderly individuals [27, 28, 43, 46]. While the importance of CVD and HS is increasingly recognized [20], ARTAG’s clinical relevance has only been suggested in a small cohort of individuals [25].…”

Section: Discussionmentioning

confidence: 93%

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Non-Alzheimer’s contributions to dementia and cognitive resilience in The 90+ Study

et al. 2018

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The diagnosis of Alzheimer's disease (AD) in the oldest-old is complicated by the increasing prevalence of age-related neurofibrillary tangles, plaques and non-AD pathologies such as cerebrovascular disease (CVD), hippocampal sclerosis (HS), aging-related tau astrogliopathy (ARTAG), as well as TDP-43 and Lewy pathology. The contribution of these non-AD pathologies to dementia and cognitive resilience is unclear. We assessed the level of AD neuropathologic change (ADNPC) and non-AD pathology in 185 participants enrolled in The 90+ Study with available cognitive assessments and brain tissue. Logistic regression models-adjusting for age, sex and education-determined the association between each pathology and dementia or between subgroups. 53% had dementia, primarily AD or mixed AD; 23% had cognitive impairment without dementia (CIND); 23% were not impaired. Both AD and non-AD pathology was prevalent. 100% had tangles, 81% had plaques, and both tangles and plaques associated with dementia. ARTAG distributed across limbic (70%), brainstem (39%) and cortical regions (24%). 49% had possible CVD and 26% had definite CVD, while HS was noted in 15%. Cortical ARTAG, CVD and HS were each associated with dementia, but limbic and brainstem ARTAGs were not. TDP-43 and Lewy pathologies were found in 36 and 17% and both associated with dementia. No pathology distinguished CIND and the not impaired. By NIA-AA criteria and dementia status, the cohort was subdivided into four groups: those with minimal ADNPC included the not dementia (ND) and Not AD dementia groups; and those with significant ADNPC included the Resilient without dementia and AD dementia groups. Compared to the ND group, the Not AD dementia group had more HS, cortical ARTAG, TDP-43, and Lewy pathology. Compared to the AD dementia group, the Resilient group had less CVD, no HS and less cortical ARTAG, TDP-43 and Lewy pathology. Our findings imply that reductions in non-AD pathologies including CVD contribute to cognitive resilience in the oldest-old.

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Section: Discussionmentioning

confidence: 93%

“…ARTAG occurs as different types in multiple anatomical areas. Gray matter ARTAG might correlate with clinical symptoms [25, 31]; however, limbic and brainstem subpial, perivascular and white matter ARTAG has not been correlated with dementia [28, 46]. …”

Section: Introductionmentioning

confidence: 99%

Non-Alzheimer’s contributions to dementia and cognitive resilience in The 90+ Study

et al. 2018

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“…Moreover, inoculation of ARTAG, containing 4Rtau astrocytes, produces 3Rtau seeding in neurons and glial cells in addition to 4Rtau deposition [106]. This also points to the likely involvement of astrocytes in the development of tau-containing neuronal processes in the aged brain [181]. The fact that a neuronal tauopathy such as PART (only containing NFTs and threads) or pure forms of ARTAG (only containing TSAs) can produce seeding in neurons, astrocytes and oligodendrocytes in WT mice is an unexpected observation.…”

Section: Disease Progression: Seeding and Spreading; Role Of Astrocytesmentioning

confidence: 83%

Section: Disease Progression: Seeding and Spreading; Role Of Astrocytesmentioning

confidence: 89%

Astrogliopathy in Tauopathies

Ferrer

2018

Neuroglia

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Astrocytes are involved in many diseases of the central nervous system, not only as reactive cells to neuronal damage but also as primary actors in the pathological process. Astrogliopathy is a term used to designate the involvement of astrocytes as key elements in the pathogenesis and pathology of diseases and injuries of the central nervous system. Astrocytopathy is utilized to name non-reactive astrogliosis covering hypertrophy, atrophy and astroglial degeneration with loss of function in astrocytes and pathological remodeling, as well as senescent changes. Astrogliopathy and astrocytopathy are hallmarks of tauopathies-neurodegenerative diseases with abnormal hyper-phosphorylated tau aggregates in neurons and glial cells. The involvement of astrocytes covers different disease-specific types such as tufted astrocytes, astrocytic plaques, thorn-shaped astrocytes, granular/fuzzy astrocytes, ramified astrocytes and astrocytes with globular inclusions, as well as others which are unnamed but not uncommon in familial frontotemporal degeneration linked to mutations in the tau gene. Knowledge of molecular differences among tau-containing astrocytes is only beginning, and their distinct functional implications remain rather poorly understood. However, tau-containing astrocytes in certain conditions have deleterious effects on neuronal function and nervous system integrity. Moreover, recent studies have shown that tau-containing astrocytes obtained from human brain tauopathies have a capacity for abnormal tau seeding and spreading in wild type mice. Inclusive conceptions include a complex scenario involving neurons, glial cells and local environmental factors that potentiate each other and promote disease progression in tauopathies.

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“…Brain banks have been indispensable to our understanding of the pathology of many brain disorders, including Alzheimer's and Parkinson's [50], and they remain powerful resources for brain research. However, brain banking faces a set of challenges that hamper progress in this area.…”

Section: ‘Brain-specific' Challenges To Personalised Medicinementioning

confidence: 99%

Gene-Tailored Treatments for Brain Disorders: Challenges and Opportunities

Esposito

Burgunder

Dunlop

et al. 2016

Public Health Genomics

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Brain disorders pose major challenges to medicine and treatment innovation. This is because their spectrum spans inflammatory, degenerative, traumatic/ischaemic, and neoplastic disease processes with a complex and often ill- understood aetiology. An improved genetic and genomic understanding of specific disease pathways offers new approaches to these challenges, but at present it is in its infancy. Here, we review different aspects of the challenges facing neuromedicine, give examples of where there are advances, and highlight challenges to be overcome. We see that some disorders such as Huntington's disease are the product of single gene mutations, whose discovery has been leading to the development of new targeted interventions. In the field of neurosurgery, the identification of a number of mutations allows an elaborated genetic analysis of brain tumours and opens the door to individualised therapies. Psychiatric disorders remain the area where progress is slow. Genetic analyses show that for major common disorders such as schizophrenia and depression there are no single gene alterations which offer options for targeted therapy development. However, new approaches are being developed to leverage genetic information to predict patients' responses to treatment. These recent developments hold promise for early diagnosis, follow-up with personalised treatments with adjusted therapeutic doses, predictable responses, reduced adverse drug reactions, and personal health planning. The scenario is promising but calls for increased support for curiosity-driven research into the mechanisms of normal brain functioning as well as challenging adaptations of health care and research infrastructures, encompassing legal frameworks for analysing large amounts of personal data, a flexible regulatory framework for correlating big data analyses in cooperative networks between academia and the drug development industry, and finally new strategies for brain banking in order to increase access to brain tissue samples. To make personalised medicine for brain disorders a reality, a joint effort between all relevant stakeholders - among which patients and patient organisations should play an important role - is required.

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Epidemiological pathology of Tau in the ageing brain: application of staging for neuropil threads (BrainNet Europe protocol) to the MRC cognitive function and ageing brain study

Cited by 51 publications

References 34 publications

Non-Alzheimer’s contributions to dementia and cognitive resilience in The 90+ Study

Non-Alzheimer’s contributions to dementia and cognitive resilience in The 90+ Study

Astrogliopathy in Tauopathies

Gene-Tailored Treatments for Brain Disorders: Challenges and Opportunities

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