Pre-dementia clinical stages in presenilin 1 E280A familial early-onset Alzheimer's disease: a retrospective cohort study

Acosta‐Baena, Natalia; Sepulveda‐Falla, Diego; Gómez, Carlos Mario Lopera; Jaramillo-Elorza, Mario César; Moreno, Sonia; Aguirre-Acevedo, Daniel Camilo; Saldarriaga, Amanda; Lopera, Francisco

doi:10.1016/s1474-4422(10)70323-9

Cited by 203 publications

(287 citation statements)

References 37 publications

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“…Recent studies with cases of familial Alzheimer's disease indicate that the early stages of neuron dysfunction in neurodegenerative diseases begin decades before the presentation of clinical syndromes (Acosta-Baena et al, 2011) and the same may be true for ALS. Genetic studies suggest roles for TDP-43 in neuronal biology.…”

Section: Discussionmentioning

confidence: 99%

ALS-Linked Mutations Enlarge TDP-43-Enriched Neuronal RNA Granules in the Dendritic Arbor

Liu-Yesucevitz¹,

Lin²,

Ebata³

et al. 2014

J. Neurosci.

102

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Trans-activating response region (TAR) DNA-binding protein of 43 kDa (TDP-43) is an RNA-binding protein that is mutated in familial amyotrophic lateral sclerosis (ALS). Disease-linked mutations in TDP-43 increase the tendency of TDP-43 to aggregate, leading to a corresponding increase in formation of stress granules, cytoplasmic protein/RNA complexes that form in response to stress. Although the field has focused on stress granules, TDP-43 also forms other types of RNA granules. For example, TDP-43 is associated with RNA granules that are prevalent throughout the dendritic arbor in neurons. Because aggregation of TDP-43 is also important for the formation of these neuronal RNA granules, we hypothesized that disease-linked mutations might alter granule formation even in the absence of stress. We now report that ALS-linked mutations in TDP-43 (A315T and Q343R) increase the size of neuronal TDP-43 granules in the dendritic arbor of rat hippocampal neurons. The mutations correspondingly reduce the granule density, movement, and mobility of TDP-43 granules. Depolarization of rat hippocampal neurons with KCl stimulates TDP-43 granule migration into dendrites, but A315T and Q343R TDP-43 granules migrate shorter distances and into fewer dendrites than wild-type TDP-43. These findings highlight novel elements of TDP-43 biology that are affected by disease-linked mutations and suggest a neuronally selective mechanism through which TDP-43 mutations might elicit neuronal dysfunction.

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Section: Discussionmentioning

confidence: 99%

ALS-Linked Mutations Enlarge TDP-43-Enriched Neuronal RNA Granules in the Dendritic Arbor

Liu-Yesucevitz¹,

Lin²,

Ebata³

et al. 2014

J. Neurosci.

102

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“…Twenty-nine subjects were tested for cerebellar function and grouped as follows: 9 PS1-E280A carriers showing cognitive impairment were classified as symptomatic (sPS1), 10 PS1-E280A carriers without cognitive impairment were classified as asymptomatic (aPS1) following previously described parameters (14), and, finally, 10 healthy subjects belonging to the PS1-E280A genealogies, without carrying the PS1-E280A mutation, were chosen as controls.…”

Section: Behavioral Testsmentioning

confidence: 99%

Familial Alzheimer’s disease–associated presenilin-1 alters cerebellar activity and calcium homeostasis

Sepulveda‐Falla¹,

Barrera-Ocampo²,

Hagel³

et al. 2014

J. Clin. Invest.

Self Cite

114

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Familial Alzheimer's disease (FAD) is characterized by autosomal dominant heritability and early disease onset. Mutations in the gene encoding presenilin-1 (PS1) are found in approximately 80% of cases of FAD, with some of these patients presenting cerebellar damage with amyloid plaques and ataxia with unclear pathophysiology. A Colombian kindred carrying the PS1-E280A mutation is the largest known cohort of PS1-FAD patients. Here, we investigated PS1-E280A-associated cerebellar dysfunction and found that it occurs early in PS1-E208A carriers, while cerebellar signs are highly prevalent in patients with dementia. Postmortem analysis of cerebella of PS1-E280A carrier revealed greater Purkinje cell (PC) loss and more abnormal mitochondria compared with controls. In PS1-E280A tissue, ER/mitochondria tethering was impaired, Ca 2+ channels IP3Rs and CACNA1A were downregulated, and Ca 2+ -dependent mitochondrial transport proteins MIRO1 and KIF5C were reduced. Accordingly, expression of PS1-E280A in a neuronal cell line altered ER/ mitochondria tethering and transport compared with that in cells expressing wild-type PS1. In a murine model of PS1-FAD, animals exhibited mild ataxia and reduced PC simple spike activity prior to cerebellar β-amyloid deposition. Our data suggest that impaired calcium homeostasis and mitochondrial dysfunction in PS1-FAD PCs reduces their activity and contributes to motor coordination deficits prior to Aβ aggregation and dementia. We propose that PS1-E280A affects both Ca 2+ homeostasis and Aβ precursor processing, leading to FAD and neurodegeneration.

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“…Participants were divided into two groups, the NonC group who were cognitively normal and did not carry the mutation, and the PreC group who carried the mutation but did not present cognitive dysfunction or dementia symptoms at the time of EEG acquisition (in 1999). This group can be more specifically described (at the time of EEG acquisition) as comprising cognitively unimpaired carriers [3]. The two groups were similar in sex and educational level and were matched on the Spanish version of the Barthel scale indicating that they functioned at a similar level in everyday activities.…”

Section: Subjectsmentioning

confidence: 99%

“…This has been facilitated, for example, by two large international projects; the Dominantly Inherited Alzheimer Network (DIAN) study [1], a US/UK/Australian project, and the Alzheimer's Prevention Initiative (API), which studies a large Colombian kindred affected by the PSEN1 E280A mutation [3].…”

Section: Introductionmentioning

confidence: 99%

Dynamic Causal Modeling of Preclinical Autosomal-Dominant Alzheimer’s Disease

Penny

Iglesias-Fuster

Quiroz

et al. 2018

JAD

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Abstract. Dynamic causal modeling (DCM) is a framework for making inferences about changes in brain connectivity using neuroimaging data. We fitted DCMs to high-density EEG data from subjects performing a semantic picture matching task. The subjects are carriers of the PSEN1 mutation, which leads to early onset Alzheimer's disease, but at the time of EEG acquisition in 1999, these subjects were cognitively unimpaired. We asked 1) what is the optimal model architecture for explaining the event-related potentials in this population, 2) which connections are different between this Presymptomatic Carrier (PreC) group and a Non-Carrier (NonC) group performing the same task, and 3) which network connections are predictive of subsequent Mini-Mental State Exam (MMSE) trajectories. We found 1) a model with hierarchical rather than lateral connections between hemispheres to be optimal, 2) that a pathway from right inferotemporal cortex (IT) to left medial temporal lobe (MTL) was preferentially activated by incongruent items for subjects in the PreC group but not the NonC group, and 3) that increased effective connectivity among left MTL, right IT, and right MTL was predictive of subsequent MMSE scores.

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Pre-dementia clinical stages in presenilin 1 E280A familial early-onset Alzheimer's disease: a retrospective cohort study

Cited by 203 publications

References 37 publications

ALS-Linked Mutations Enlarge TDP-43-Enriched Neuronal RNA Granules in the Dendritic Arbor

ALS-Linked Mutations Enlarge TDP-43-Enriched Neuronal RNA Granules in the Dendritic Arbor

Familial Alzheimer’s disease–associated presenilin-1 alters cerebellar activity and calcium homeostasis

Dynamic Causal Modeling of Preclinical Autosomal-Dominant Alzheimer’s Disease

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