Sporadic corticobasal syndrome due to FTLD-TDP

Tartaglia, Maria Carmela; Sidhu, M.; Laluz, Victor; Racine, Caroline A.; Rabinovici, Gil D.; Creighton, Kelly; Karydas, Anna; Rademakers, Rosa; Huang, Eric J.; Miller, Bruce L.; DeArmond, Stephen J.; Seeley, William W.

doi:10.1007/s00401-009-0605-1

Cited by 60 publications

(52 citation statements)

References 44 publications

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“…The presence of MND in patients with bvFTD was assessed by a neurologist based on the neurological examination, usually supported by electrodiagnostic testing, and was recorded prospectively in the Memory and Aging Center database. Neuropathological diagnoses were made following consensus diagnostic criteria [41, 42, 45-47] using previously described histological and immunohistochemical methods [34, 76]. Cases were selected based on clinical and neuropathological diagnoses and genetic analysis (Suppl.…”

Section: Methodsmentioning

confidence: 99%

Neurons selectively targeted in frontotemporal dementia reveal early stage TDP-43 pathobiology

et al. 2018

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TAR-DNA binding protein 43 (TDP-43) aggregation is the most common pathological hallmark in frontotemporal dementia (FTD) and characterizes nearly all patients with motor neuron disease (MND). The earliest stages of TDP-43 pathobiology are not well characterized, and whether neurodegeneration results from TDP-43 loss-of-function or aggregation remains unclear. In the behavioral variant of FTD (bvFTD), patients undergo selective dropout of von Economo neurons (VENs) and fork cells within the frontoinsular (FI) and anterior cingulate cortices. Here, we examined TDP-43 pathobiology within these vulnerable neurons in the FI across a clinical spectrum including 17 patients with sporadic bvFTD, MND, or both. In an exploratory analysis based on our initial observations, we further assessed 10 patients with C9orf72-associated bvFTD/MND. VENs and fork cells showed early, disproportionate TDP-43 aggregation that correlated with anatomical and clinical severity, including loss of emotional empathy. The presence of a TDP-43 inclusion was associated with striking nuclear and somatodendritic atrophy. An intriguing minority of neurons lacked detectable nuclear TDP-43 despite the apparent absence of a cytoplasmic TDP-43 inclusion. These cells showed neuronal atrophy comparable to inclusion-bearing neurons, suggesting that loss of nuclear TDP-43 function promotes neurodegeneration, even when TDP-43 aggregation is inconspicuous or absent.

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Section: Methodsmentioning

confidence: 99%

Neurons selectively targeted in frontotemporal dementia reveal early stage TDP-43 pathobiology

et al. 2018

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“…The spectrum of disorders that has been associated with the CBS include CBD, progressive supranuclear palsy (PSP), Alzheimer's disease (AD), Pick's disease (Pick), frontotemporal lobar degeneration with ubiquitin-and TDP-43-positive inclusions (FTLD-TDP), Lewy body disease (LBD), neurofilament inclusion body dementia (now known as frontotemporal lobar degeneration with fused in sarcoma-positive inclusions or FTLD-FUS), and CreutzfeldtJakob disease (CJD) (Fig. 2) (Boeve 2005;Boeve et al 1999;Ling et al 2010;Schneider et al 1997;Tartaglia et al 2010). Plus, mutations in the microtubule-associated protein tau (MAPT) and progranulin (PGRN) (and surely other genes) can cause neurodegeneration leading to a CBS phenotype (Rossi et al 2008;Rohrer et al 2009).…”

Section: The Multiple Histopathologies Associated With the Cbsmentioning

confidence: 99%

The Multiple Phenotypes of Corticobasal Syndrome and Corticobasal Degeneration: Implications for Further Study

Boeve

2011

J Mol Neurosci

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Corticobasal degeneration (CBD) is a complex neurodegenerative disorder which nomenclature of which its nomenclature and characterization continues to evolve. The core clinical features that have been considered characteristic of the disorder include progressive asymmetric rigidity and apraxia, with other findings suggesting additional cortical (e.g., alien limb phenomena, cortical sensory loss, myoclonus, and mirror movements) and basal ganglionic (e.g., bradykinesia, dystonia, and tremor) dysfunctions. The characteristic findings at autopsy are asymmetric cortical atrophy that is typically maximal in the frontoparietal regions, as well as basal ganglia and nigral degeneration. Microscopically, abnormal accumulations of the microtubule-associated tau protein are found in both neurons and glia, and this disorder is now considered one of the "tauopathies." CBD was initially thought to represent a distinct clinicopathologic entity. Recent studies have shown considerable clinicopathologic heterogeneity, leading some to use the term "corticobasal syndrome" (CBS) for the constellation of findings initially considered characteristic of the disorder, and the term "corticobasal degeneration" for the histopathologic disorder. In this review, the multiple phenotypes/syndromes associated with CBD pathology, and multiple diseases associated with the CBS, are presented. The clinicopathologic heterogeneity in CBS/CBD and the implications of this heterogeneity on clinical practice, on understanding the focal/asymmetric cerebral degeneration syndromes, and on future research are all reviewed.

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“…Two additional first-degree relatives and two second-degree relatives had suspected or autopsy-confirmed FTLD-MND. ApoE genotyping and genetic testing for progranulin mutations were performed as described (Agosta et al, 2009; Tartaglia et al, 2010). Superoxide dismutase 1 (SOD1) mutations were assessed by polymerase chain reaction-single strand confirmation polymorphism and DNA sequencing (Athena Diagnostics).…”

Section: Patient Comparisonmentioning

confidence: 99%

ApoE and TDP-43 neuropathology in two siblings with familial FTLD-motor neuron disease

et al. 2013

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Frontotemporal lobar degeneration with motor neuron disease (FTLD-MND) is characterized by neuronal cytoplasmic inclusions containing TDP-43. Apolipoprotein E4 (apoE4), derived from the apoE ε4 allele, enhances brain atrophy in FTLD through unknown mechanisms. Here, we studied two siblings with C9ORF72-linked familial FTLD-MND, an apoE ε4 homozygote and an apoE ε3 homozygote. The apoE ε4 homozygote had more cognitive-behavioral symptoms, fronto-insulo-temporal atrophy, and apoE fragments and aggregates in the anterior cingulate cortex. ApoE formed complexes with TDP-43 that were more abundant in the apoE ε4 homozygote. Although differences seen in a sibling pair could arise due to chance, these findings raise the possibility that apoE4 exacerbates brain pathology in FTLD through formation of neurotoxic apoE fragments and interactions with TDP-43.

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Sporadic corticobasal syndrome due to FTLD-TDP

Cited by 60 publications

References 44 publications

Neurons selectively targeted in frontotemporal dementia reveal early stage TDP-43 pathobiology

Neurons selectively targeted in frontotemporal dementia reveal early stage TDP-43 pathobiology

The Multiple Phenotypes of Corticobasal Syndrome and Corticobasal Degeneration: Implications for Further Study

ApoE and TDP-43 neuropathology in two siblings with familial FTLD-motor neuron disease

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