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A case study of an emerging visual artist with frontotemporal lobar degeneration and amyotrophic lateral sclerosis
Published in Howard J. Rosen, Robert W. Levenson, Neurocase, 2020
Anli Liu, Kelly Werner, Subhojit Roy, John Q. Trojanowski, Ursula Morgan-Kane, Bruce L. Miller, Katherine P. Rankin
While FTLD presents with a variety of clinical syndromes depending on the brain regions affected, these clinical syndromes cannot yet be used to definitively predict the underlying neuropathological subtype. The above reports of increased creativity in FTLD describe patients whose pathological subtype was either unknown or was consistent with one of the pure FTLD pathology types, i.e., either tau-positive or tau-negative ubiquitin and TDP43-positive inclusions with no motor neuron disease (MND) pathology. To our knowledge, no reports of increased creativity in patients with the FTLD-MND pathological subtype (ubiquitin and TDP43-positive inclusions with MND pathology) have yet been published. Clinically, patients with MND can gradually lose limb, bulbar, and respiratory muscle function as a result of gradual degeneration of both upper and lower motor neurons, and up to 50% of these patients manifest some degree of cognitive impairment (Abrahams et al., 2005; Strong, Lomen-Hoerth, Caselli, Bigio, & Yang, 2003). Patients found to have mixed FTLD-MND pathology can present with clinical features anywhere on the spectrum between typical FTLD (behavior-predominant with few if any motor symptoms) and typical amyotrophic lateral sclerosis (ALS) (motor predominant with few behavior and cognitive changes).
The nervous system and the eye
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
James A.R. Nicoll, William Stewart, Fiona Roberts
Frontotemporal dementia (FTD) is relatively rare but is increasing in recognition particularly as the cause of a significant proportion of dementia in those aged <65 years. It is more likely than other dementias to be familial with a single gene mutation as the cause, resulting in an autosomal dominant pattern of inheritance. Presentation is often with behavioural or language problems. There is marked relatively selective atrophy of the frontal and or temporal lobes (frontotemporal lobar degeneration – FTLD) which may be asymmetrical. Microscopically, in affected areas there is severe degeneration of the cortical neuropil and neuronal loss. The classification is complex and changing rapidly with increasing understanding of the subtypes, e.g. in FTLD-tau there is accumulation of tau protein in neurons and glia, associated with mutations in the gene encoding tau. In FTLD-TDP-43 there is accumulation of TAR DNA-binding protein (TDP-43) in neurons, associated with mutations in the TDP-43 gene and other genes. FTLD-TDP-43 is linked with motor neuron disease in which there is accumulation of TDP-43 in motor neurons.
Neurodegenerative Disorders
Published in Andrei I. Holodny, Functional Neuroimaging, 2019
Lihong Wang, Jeffrey R. Petrella
Frontotemporal lobar degeneration (FTLD) is a heterogenous disease condition both clinically and pathologically, consisting of mainly FTD, nonfluent progressive aphasia (NFPA), and semantic dementia. In FTD, changes in social behavior and personality predominate, reflecting the orbitobasal frontal lobe focus of the pathology with relative preservation of memory and visuospatial skills (121–125). NFPA affects the phonologic and syntactic components of language. Semantic dementia shows deficits both in language production and comprehension. A variant of this syndrome affecting the right temporal lobe presents with progressive prosopagnosia, a symptom with difficulty in recognizing people by faces in spite of normal eyesight. FTLD has been characterized by frontal and temporal atrophy, with NFPA having increased rates of atrophy in the left perisylvian area and semantic dementia having increased rates of atrophy in posterior left temporal and inferior frontal regions (126). PET studies in FTLD have shown hypometabolism in frontal, anterior temporal, and mesiotemporal areas even in early stage. The lateral temporal and parietal cortices are affected only in later stages. Thus, differentiation between AD and FTLD is relatively straightforward in late-stage disease. The deficits in AD are temporal-parietal dominant and the deficits in FTLD are frontal-temporal dominant (127). However, clinical differentiation between AD and FTLD is difficult early in the disease when results on MRI are normal and clinical signs inconspicuous.
Clinicopathologic correlations in a family with a TBK1 mutation presenting as primary progressive aphasia and primary lateral sclerosis
Published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2019
Veronica Hirsch-Reinshagen, Omar A. Alfaify, Ging-Yuek R. Hsiung, Cyril Pottier, Matt Baker, Ralph B. Perkerson, Rosa Rademakers, Hanna Briemberg, Dean J. Foti, Ian R. Mackenzie
Frontotemporal dementia (FTD) is clinically characterized by abnormalities in personality, behavior, and/or language. Some patients with FTD also develop prominent extrapyramidal movement disorders, motor neuron disease (MND), or both. The neuropathological substrate of FTD is most often selective atrophy of the frontal and temporal lobes, termed frontotemporal lobar degeneration (FTLD). Four major subtypes of FTLD are recognized based on the identity of the protein that abnormally aggregates in neurons and glia. Of these, FTLD with inclusions of TAR DNA binding protein 43 (FTLD-TDP) has been suggested to be on a spectrum with MND, in particular, amyotrophic lateral sclerosis (ALS). ALS is characterized by progressive neurodegeneration of upper and lower motor neurons (UMN and LMN, respectively) and results in spasticity, hyperreflexia, weakness, muscle atrophy, and fasciculations. A related MND, primary lateral sclerosis (PLS), affects only UMN and does not lead to muscle atrophy or fasciculations. PLS is relatively rare, representing less than 5% of all MND (1), and is usually not associated with other major neurological deficits. However, both ALS and PLS have some clinical overlap with FTD: approximately half of ALS and 22% of PLS patients develop signs of frontotemporal dysfunction and approximately 15% of ALS and 3% of PLS patients develop full-blown FTD (2–5). Although half of FTD patients develop signs of MND and approximately 15% develop full-blown ALS (6), typical PLS is uncommon.
Progranulin as a therapeutic target for dementia
Published in Expert Opinion on Therapeutic Targets, 2018
Daniela Galimberti, Chiara Fenoglio, Elio Scarpini
FTLD is known as the second most common neurodegenerative dementia (after Alzheimer’s disease) with a presenile onset (before 65 years of age). The term FTLD encompasses 3 clinical syndromes: the most common behavioral variant frontotemporal dementia (FTD), characterized by behavioral disturbances, aggressiveness, lack of empathy, progressive nonfluent aphasia (PNFA), and semantic dementia (SD). Currently, there are no approved therapies for FTD and there are no treatments that can stop or alter the course of the disease. Therapies used for Alzheimer’s disease (AD) or psychiatric disorders have been tested in FTD and can be used for the management of behavioral and cognitive symptoms (see [17] for review). It must be acknowledged that, because of the heterogeneous clinical presentations, past clinical trials may have included FTD syndromes with different underlying pathology. In addition, many trials were not rigorous randomized, placebo-controlled and double-blinded, and the number of cases was often limited.
Epigenetic regulatory modifications in genetic and sporadic frontotemporal dementia
Published in Expert Review of Neurotherapeutics, 2018
Chiara Fenoglio, Elio Scarpini, Daniela Galimberti
Frontotemporal Dementia (FTD) is the second most common cause of dementia after Alzheimer’s disease (AD), affecting people from 45 to 65 years. The prevalence has been estimated as 3–26% worldwide in people more than 65 years old [1]. The term FTD encompasses three clinically distinct syndromes: behavioral variant (bv) FTD, Progressive Non-Fluent Aphasia (PNFA), and Semantic Dementia (SD) [2]. Clinical features of FTD are different according to the different subtype of disease. In general, typical features of bvFTD are the presence of behavioral disturbances, aggressiveness, lack of empathy, decline in social conduct, often associated with cognitive and executive impairment, whereas in PNFA and SD language impairment is the most prominent feature [2]. At the pathological level, all syndromes described are collectively grouped as Frontotemporal Lobar Degeneration (FTLD). At the histopathological level, based on the type of protein depositing, FTLD is classified into FTLD-Tau, FTLD-TAR DNA Binding protein (TDP)43, and FTLD fused in Sarcoma (FUS) [3].