The MAPT H1 haplotype is associated with tangle-predominant dementia

Santa-María, Ismael; Haggiagi, Aya; Liu, Xinmin; Wasserscheid, Jessica; Nelson, Peter T.; Dewar, Ken; Clark, Lorraine N.; Crary, John F.

doi:10.1007/s00401-012-1017-1

Cited by 74 publications

(78 citation statements)

References 66 publications

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“…In other individuals with PART, there may be mild to moderate diffuse atrophy of the neocortex, and medial temporal lobe atrophy may be pronounced in persons with dementia (Fig. 1) [110, 122]. Immunohistochemistry reveals telencephalic NFT emerging most consistently in the medial temporal lobe, particularly the hippocampal formation and adjacent regions (Fig.…”

Section: Neuropathologic Changesmentioning

confidence: 99%

“…NFT may also be seen in the amygdala, nucleus basalis of Meynert, nucleus accumbens, hypothalamus, thalamus, olfactory system (bulb and cortex), dorsal raphé nucleus, and medulla oblongata [7, 8, 53, 107, 141]. While NFT at all stages of evolution can be seen in PART, individuals with cognitive impairment often have abundant extracellular, so-called “ghost”, tangles [110, 122]. …”

Section: Neuropathologic Changesmentioning

confidence: 99%

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Primary age-related tauopathy (PART): a common pathology associated with human aging

et al. 2014

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We recommend a new term, “primary age-related tauopathy” (PART), to describe a pathology that is commonly observed in the brains of aged individuals. Many autopsy studies have reported brains with neurofibrillary tangles (NFT) that are indistinguishable from those of Alzheimer's disease (AD), in the absence of amyloid (Aβ) plaques. For these “NFT+/Aβ−” brains, for which formal criteria for AD neuropathologic changes are not met, the NFT are mostly restricted to structures in the medial temporal lobe, basal forebrain, brainstem, and olfactory areas (bulb and cortex). Symptoms in persons with PART usually range from normal to amnestic cognitive changes, with only a minority exhibiting profound impairment. Because cognitive impairment is often mild, existing clinicopathologic designations, such as “tangle-only dementia” and “tangle-predominant senile dementia”, are imprecise and not appropriate for most subjects. PART is almost universally detectable at autopsy among elderly individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time. Improved biomarkers and tau imaging may enable diagnosis of PART in clinical settings in the future. Indeed, recent studies have identified a common biomarker profile consisting of temporal lobe atrophy and tauopathy without evidence of Aβ accumulation. For both researchers and clinicians, a revised nomenclature will raise awareness of this extremely common pathologic change while providing a conceptual foundation for future studies. Prior reports that have elucidated features of the pathologic entity we refer to as PART are discussed, and working neuropathological diagnostic criteria are proposed.

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Section: Neuropathologic Changesmentioning

confidence: 99%

Section: Neuropathologic Changesmentioning

confidence: 99%

Primary age-related tauopathy (PART): a common pathology associated with human aging

et al. 2014

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Section: Problems In the Neuropathologic Diagnosis Of Alzheimer's Dismentioning

confidence: 98%

“…The "neurofibrillary tangle predominant dementia" (NFTD) with tau pathology often restricted to the limbic system, absence of neuritic plaques, no or very little (diffuse) amyloid plaques and rare amyloid angiopathy accounts for 5-7% of oldest olds with low ApoE ε4 frequency. Recent molecular and genetic analysis confirmed an identical tau isoform composition in TPD and AD [115], and demonstrated absence of soluble Aβ but elevated soluble amyloid precursor protein α (APPα) in brain tissue, and association with the tau gene MAPT H1 haplotype, classifying it as a specific tauopathy independent of amyloid [116].A recent study of autopsy-proven AD cases separated distinct subtypes: (a) hippocampal-sparing AD (HpSp-AD) with lower NFT counts in hippocampus but more frequent senile plaques compared to typical AD (11%), (b) limbic-predominant forms (LP-AD) with lower cortical NFT counts and tau burden (14%), and (c) typical AD (75%). AD subtypes havd pathologic, demographic, clinical, and genetic differences [117].…”

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confidence: 99%

Neuropathology of Dementia Disorders

Jellinger¹

2014

J Alzheimers Dis Parkinsonism

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IntroductionDementia, encompassing deficits in several cognitive domains that are severe enough to interfere with daily functioning [1], in the new DSM V classification is classified within the broad category of major neurocognitive disorders, proposing specific criteria for the various etiologies [2]. Previously defined as the manifestation of deteriorating brain functions over time due to cell deaths in the brain caused by neurodegeneration or any other disease [3], according to recent research dementia is not primarily caused by neuronal cell death/loss, but by dysfunction and loss of synapses [4] in AD [5] and in α-synucleinopathies [6]. Other causes include cholinergic neuronal and axonal abnormalities [7,8], as well as pre-and postsynaptic cortical cholinergic deficits also occurring in early AD [9]. These changes due to disconnection of major nervous circuitries causing default networks [10][11][12][13] have been demonstrated in vivo in early AD [14], suggesting that disease progress is transmitted by neuronal pathways [15]. A prionlike spread of misfolded protein aggregates in the pathogenesis and progression of neurodegeneration is a hot spot of discussion [16][17][18][19][20][21].Both the prevalence and incidence of dementia increase exponentially with age. In 2010, 35.6 million people worldwide lived with dementia, with around 8 million new cases every year. Numbers are expected to double or triple every 5-10 years, to 135 millions in 2050, 16 millions in Europe. In 2010, 58% of all demented people lived in low-cost countries, with their proportion anticipated to rise to 71% in 2050 [22]. According to recent data from China the incidence of dementia was 9.87/1000 person years and the median standardised mortality ratio was 1.94:1 [23]. With the disproportional growth of the elderly population, dementia has become a major public health and socio-economic problem that threatens to become the scourge of our century. The total costs for dementia were US$ 604 billion in 2010 worldwide, up to 70% for social care alone [24], total payments for AD for 2013 were expected to be $ 203 billion in USA alone, not included contributions of unpaid caregivers [25]. Neuropathology of Dementia DisordersKurt A Jellinger* Institute of Clinical Neurobiology, Kenyongasse 18, A 1070, Vienna, Austria AbstractDementia, being not a specific disease but a syndrome characterized by deficits in several cognitive domains, is a major public health and socio-economic problem of our century. It is caused by dysfunction/loss of synapses and neurons inducing default neuronal networks. Despite updated concensus criteria for the clinical diagnosis of the major neurodegenerative disorders and new biomarkers, the diagnostic accuracy ranges from 65 to 96% (for Alzheimer's disease /AD), with a sensitivity versus other dementias of around 85.4% and a specificity of up to 77.7%. Pathologic assessment, using genetic and molecular biological methods, based on homogenous definitions, harmonized interlaboratory and assessment standards, can achiev...

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“…Because the tau protein itself is considered the central cause of pathogenesis in tauopathies [264][265][266][267], regulating tau proteins might be the most direct and efficient way to ameliorate the disease symptoms. As previously discussed, reducing tau protein levels can mitigate the severity of neuropathology and neurodegeneration in AD mouse models [268][269][270].…”

Section: Regulation Of Tau Protein Level And/ or Immunotherapymentioning

confidence: 99%

Behind the curtain of tauopathy: a show of multiple players orchestrating tau toxicity

Huang

Zhou

2015

Cell. Mol. Life Sci.

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tau, a microtubule-associated protein, directly binds with microtubules to dynamically regulate the organization of cellular cytoskeletons, and is especially abundant in neurons of the central nervous system. Under disease conditions such as Pick's disease, progressive supranuclear palsy, frontotemporal dementia, parkinsonism linked to chromosome 17 and Alzheimer's disease, tau proteins can self-assemble to paired helical filaments progressing to neurofibrillary tangles. In these diseases, collectively referred to as "tauopathies", alterations of diverse tau modifications including phosphorylation, metal ion binding, glycosylation, as well as structural changes of tau proteins have all been observed, indicating the complexity and variability of factors in the regulation of tau toxicity. Here, we review our current knowledge and hypotheses from relevant studies on tau toxicity, emphasizing the roles of phosphorylations, metal ions, folding and clearance control underlining tau etiology and their regulations. A summary of clinical efforts and associated findings of drug candidates under development is also presented. It is hoped that a more comprehensive understanding of tau regulation will provide us with a better blueprint of tau networking in neuronal cells and offer hints for the design of more efficient strategies to tackle tau-related diseases in the future.

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The MAPT H1 haplotype is associated with tangle-predominant dementia

Cited by 74 publications

References 66 publications

Primary age-related tauopathy (PART): a common pathology associated with human aging

Primary age-related tauopathy (PART): a common pathology associated with human aging

Neuropathology of Dementia Disorders

Behind the curtain of tauopathy: a show of multiple players orchestrating tau toxicity

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