Autopsy proven sporadic frontotemporal dementia due to microvacuolar-type histology, with onset at 21 years of age

Snowden, Julie S.; Neary, David; Mann, David

doi:10.1136/jnnp.2003.028498

Cited by 22 publications

(6 citation statements)

References 10 publications

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“…There is, however, wide variation. There are published reports of patients presenting in their twenties . Conversely, between 25 and 30% of patients develop symptoms after the age of 65 years .…”

Section: Demographics and Neurologymentioning

confidence: 99%

Frontotemporal lobar degeneration: Pathogenesis, pathology and pathways to phenotype

2017

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Frontotemporal Lobar Degeneration (FTLD) is a clinically, pathologically and genetically heterogeneous group of disorders that affect principally the frontal and temporal lobes of the brain. There are three major associated clinical syndromes, behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SD) and progressive non-fluent aphasia (PNFA); three principal histologies, involving tau, TDP-43 and FUS proteins; and mutations in three major genes, MAPT, GRN and C9orf72, along with several other less common gene mutations. All three clinical syndromes can exist separately or in combination with Amyotrophic Lateral Sclerosis (ALS). SD is exclusively a TDP-43 proteinopathy, and PNFA may be so, with both showing tight clinical, histological and genetic inter-relationships. bvFTD is more of a challenge with overlapping histological and genetic features, involvement of any of the three aggregating proteins, and changes in any of the three major genes. However, when ALS is present, all cases show a clear histological phenotype with TDP-43 aggregated proteins, and familial forms are associated with expansions in C9orf72. TDP-43 and FUS are nuclear carrier proteins involved in the regulation of RNA metabolism, whereas tau protein - the product of MAPT - is responsible for the assembly/disassembly of microtubules, which are vital for intracellular transport. Mutations in TDP-43 and FUS genes are linked to clinical ALS rather than FTLD (with or without ALS), suggesting that clinical ALS may be a disorder of RNA metabolism. Conversely, the protein products of GRN and C9orf72, along with those of the other minor genes, appear to form part of the cellular protein degradation machinery. It is possible therefore that FTLD is a reflection of dysfunction within lysosomal/proteasomal systems resulting in failure to remove potentially neurotoxic (TDP-43 and tau) aggregates, which ultimately overwhelm capacity to function. Spread of aggregates along distinct pathways may account for the different clinical phenotypes, and patterns of progression of disease.

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Section: Demographics and Neurologymentioning

confidence: 99%

Frontotemporal lobar degeneration: Pathogenesis, pathology and pathways to phenotype

2017

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“…Lastly, about 5–10 % of cases of FTLD [5, 46, 51, 57, 58, 68, 73], and a few familial MND cases [39, 82] are characterized by the abnormal accumulation, as cellular inclusions, of a third protein, fused in sarcoma (FUS). Other ubiquitinated, but as yet unidentified, target proteins characterize FTLD cases with CHMP2B mutations [33], and there may still be other rare cases where the hallmark of FTLD is present as microvacuolar change, but no NCI has been detected [13, 44, 45, 72]. …”

Section: Introductionmentioning

confidence: 99%

Mechanisms of disease in frontotemporal lobar degeneration: gain of function versus loss of function effects

et al. 2012

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Frontotemporal lobar degeneration (FTLD) is clinically, pathologically and genetically heterogeneous. Three major proteins are implicated in its pathogenesis. About half of cases are characterized by depositions of the microtubule associated protein, tau (FTLD-tau). In most of the remaining cases, deposits of the transactive response (TAR) DNA-binding protein with Mw of 43 kDa, known as TDP-43 (FTLD-TDP), are seen. Lastly, about 5–10 % of cases are characterized by abnormal accumulations of a third protein, fused in sarcoma (FTLD-FUS). Depending on the protein concerned, the signature accumulations can take the form of inclusion bodies (neuronal cytoplasmic inclusions and neuronal intranuclear inclusions) or dystrophic neurites, in the cerebral cortex, hippocampus and subcortex. In some instances, glial cells are also affected by inclusion body formation. In motor neurone disease (MND), TDP-43 or FUS inclusions can present within motor neurons of the brain stem and spinal cord. This present paper attempts to critically examine the role of such proteins in the pathogenesis of FTLD and MND as to whether they might exert a direct pathogenetic effect (gain of function), or simply act as relatively innocent witnesses to a more fundamental loss of function effect. We conclude that although there is strong evidence for both gain and loss of function effects in respect of each of the proteins concerned, in reality, it is likely that each is a single face of either side of the coin, and that both will play separate, though complementary, roles in driving the damage which ultimately leads to the downfall of neurons and clinical expression of disease.

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“…About 10% of the cases occur before the age of 45 years, and about 30% occur in patients over the age of 65 years ( Finger, 2016 ). It, however, has been confirmed by histopathology in patients as young as 21 years ( Snowden, Neary, & Mann, 2004 ) and has been diagnosed in patients in their nineties ( Finger, 2016 ). It also is possible that this prevalence is an underestimate because of the lack of recognition of FTD by nonspecialists ( Finger, 2016 ).…”

Section: Case Discussionmentioning

confidence: 93%

Impulsive, Disinhibited Behavior—Dining in a Restaurant

Hamdy

Kinser

Kendall-Wilson

et al. 2018

Gerontology and Geriatric Medicine

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Dining in a restaurant with a loved one who has dementia can be an ordeal, especially if the expectations of the caregiver do not match those of the patient and the restaurant environment is not suitable for patients with dementia. The size of the dining area, lighting, background music or noise, décor of the room, number of customers, variety of the items on the menu, number of plates and cutlery on the table, in addition to flowers, candles, and other decorations on the table are all potent distractors. There are so many stimuli; the patient can be overwhelmed with information overload and not able to focus on the main purpose of the event: have dinner and especially enjoy the other person’s company. In this case scenario, we present a 62-year-old man diagnosed with behavioral variant frontotemporal dementia (bvFTD). His daughter “invited” him to have dinner with her at a very fancy restaurant to celebrate her promotion at work. Unfortunately, whereas the evening started very well, it had a catastrophic ending. We discuss what went wrong in the patient/daughter interaction and how the catastrophic ending could have been avoided or averted.

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Autopsy proven sporadic frontotemporal dementia due to microvacuolar-type histology, with onset at 21 years of age

Cited by 22 publications

References 10 publications

Frontotemporal lobar degeneration: Pathogenesis, pathology and pathways to phenotype

Frontotemporal lobar degeneration: Pathogenesis, pathology and pathways to phenotype

Mechanisms of disease in frontotemporal lobar degeneration: gain of function versus loss of function effects

Impulsive, Disinhibited Behavior—Dining in a Restaurant

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