Neurofibrillary tangles, granulovacuolar degeneration, and neuron loss in down syndrome: Quantitative comparison with alzheimer dementia

Ball, Melvyn J.; Nuttall, Kern L.

doi:10.1002/ana.410070512

Cited by 133 publications

(49 citation statements)

References 11 publications

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“…It needs to be clarified in the future whether GVD distinguishes specific types of AD or represents a late-onset AD phenomenon. An argument favoring the latter hypothesis is the finding of Ball et al [5] that GVD does not play a role in Down syndrome cases even when they show severe neurofibrillary pathology.…”

Section: Discussionmentioning

confidence: 99%

“…Other authors did not find such a correlation between GVD and AD when comparing AD cases with non-demented cases with AD-related pathology [46]. Down syndrome cases also exhibited GVD in age-related amounts rather than in relation to AD-related neurofibrillary tangle (NFT) pathology and synapse loss [5]. Moreover, GVD has been reported in association with other tauopathies, such as Guam disease [21], Pick's disease, and progressive supranuclear palsy (PSP) as well as in the synucleinopathies sporadic Parkinson's disease (PD) and dementia with Lewy bodies [35].…”

Section: Introductionmentioning

confidence: 97%

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Stages of granulovacuolar degeneration: their relation to Alzheimer’s disease and chronic stress response

et al. 2011

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Granulovacuolar degeneration (GVD) is characterized by the presence of vacuolar cytoplasmic lesions in nerve cells of the medial temporal lobe. These changes occur in older non-diseased individuals as well as in patients with Alzheimer's disease (AD), progressive supranuclear palsy (PSP), Pick's, sporadic Parkinson's (PD), and Guam diseases. We stained representative paraffin sections from all parts of the brain with anti-pTDP43, anti-CK1d or anti-CK1e from 14 non-demented elderly, 19 AD, 17 non-AD tauopathy, 9 sporadic PD, and 5 TDP43-proteinopathy [amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD)] cases. Our results showed five stages of GVD based on its distribution pattern: GVD began in the hippocampal subfields CA1, CA2, and the subiculum. In a second stage, entorhinal cortex, and CA4 neurons exhibited GVD. Additional neurons were involved in the temporal neocortex in stage 3, whereas the affection of the amygdala and/or the hypothalamus marked stage 4. A fifth and final stage was characterized by additional GVD in the cingulate cortex and occasionally in the frontal and parietal cortices as well as in the oral raphe and pedunculopontine tegmental nuclei. The GVD stages correlated with neurofibrillary tangle stages, Consortium to Establish a Registry for AD (CERAD) scores for neuritic plaque pathology, amyloid b-protein deposition phases, cerebral amyloid angiopathy stages, and clinical dementia rating (CDR) scores. No associations were seen between GVD stage and the presence of non-AD tauopathies, PD, ALS, or FTLD cases. In conclusion, GVD affects neurons in a hierarchical sequence that allows the distinction of five stages. The topographic distribution of GVD restricted to regions involved in response to chronic stress could indicate a link between GVD and chronically stressful influences. Moreover, the association of the GVD stages with those of AD-related pathology but not with other neurodegenerative disorders points to a possible role of GVD and the response to chronic stress in the pathogenesis of AD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Stages of granulovacuolar degeneration: their relation to Alzheimer’s disease and chronic stress response

et al. 2011

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“…In 34,64,65,73,74,[77][78][79][80][81][82][83][84][85][86][87][88] . Diffuse plaques are typically not associated with other forms of neuropathology, such as activated glial cells or synaptic loss, whereas densecore plaques are often associated with dystrophic neurites and activated astroglia and microglia 89 .…”

Section: Neuropathological Changes In Ad-dsmentioning

confidence: 99%

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

et al. 2015

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Down syndrome, which arises in individuals carrying an extra copy of chromosome 21, is associated with a greatly increased risk of early-onset Alzheimer disease. It is thought that this risk Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts is conferred by the presence of three copies of the gene encoding amyloid precursor protein (APP) -an Alzheimer disease risk factor -although the possession of extra copies of other chromosome 21 genes may also play a part. Further study of the mechanisms underlying the development of Alzheimer disease in people with Down syndrome could provide insights into the mechanisms that cause dementia in the general population.Down syndrome (DS) is a complex, highly variable disorder that arises from trisomy of chromosome 21. It was one of the first chromosomal disorders to be identified 1 and occurs with an incidence of approximately 1 in 800 births 2 . Its prevalence within a given population is influenced by infant mortality rates, access to health care, termination rates, average maternal age 3 and life expectancy. Indeed, despite the increased availability of prenatal diagnosis and access to the option of termination, the global prevalence of DS is rising because of improvements in life expectancy: the number of adults with DS aged over 40 years has doubled in northern Europe since 1990 and, in the United Kingdom, one-third of the estimated 40,000 people with DS are thought to be over 40 years of age 4 .DS is the most common form of intellectual disability. In addition to the features that are found in everyone with the disorder, such as the characteristic facial dysmorphology, there are many DS-associated phenotypes that have variable penetrance and severity. For example, approximately 40% of individuals with DS have heart malformations (usually atrioventricular septal defects) 5 . A key feature of DS is a striking propensity to develop early-onset Alzheimer disease (EOAD). Complete trisomy of chromosome 21 universally causes the development of amyloid plaques and neurofibrillary tangles (NFTs), which are typical characteristics of AD brain pathology, by the age of 40, and approximately twothirds of individuals with DS develop dementia by the age of 60 (REFS 6,7). However, rates of dementia do not reach 100%, even in older individuals, suggesting that some individuals with DS are protected from the onset of AD (FIG. 1).All of the features of DS arise because of aberrant dosages of coding and/or non-coding sequences present on chromosome 21. Among these sequences, the gene encoding amyloid precursor protein (APP) is thought to have a key role in the pathology of AD. The additional copy of APP may drive the development of AD in individuals with DS (AD-DS) by increasing the levels of amyloid-β (Aβ), a cleavage product of APP that misfolds and accumulates in the brain in people with AD. Consistent with this hypothesis, individuals with small internal chromosome 21 duplications that result in three copies of APP -a rare familial trait known as duplic...

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“…This is a genetic disease with mental retardation and Alzheimer-like dementia due to trisomy of chromosome 21. 65,66 Because of this unusual chromosomal abnormality, over 200 genes in chromosome 21 have three copies and are thus highly expressed in Down syndrome patients. 66 Among them, Dyrk1a is one of the most important genes highly responsible for motor deficits and early deposition of β-amyloid in Down syndrome patients, 27,67,68 in addition to the aforementioned ets2.…”

Section: Role Of the P53-mir-1246-dyrk1a-nfat Pathway In Down Syndromementioning

confidence: 99%

MiR-1246: A new link of the p53 family with cancer and Down syndrome

et al. 2012

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Neurofibrillary tangles, granulovacuolar degeneration, and neuron loss in down syndrome: Quantitative comparison with alzheimer dementia

Cited by 133 publications

References 11 publications

Stages of granulovacuolar degeneration: their relation to Alzheimer’s disease and chronic stress response

Stages of granulovacuolar degeneration: their relation to Alzheimer’s disease and chronic stress response

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

MiR-1246: A new link of the p53 family with cancer and Down syndrome

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