FTD and ALS: A Tale of Two Diseases

Abstract

The first reports of disorders that in terms of cognitive and behavioral symptoms resemble frontotemporal dementia (FTD) and in terms of motor symptoms resemble amyotrophic lateral sclerosis (ALS) bring us back to the second half of the 1800s. Over the last 150 years, and especially in the last two decades, there has been growing evidence that FTD signs can be seen in patients primarily diagnosed with ALS, implying clinical overlap among these two disorders. In the last decade pathological investigations and genetic screening have contributed tremendously in elucidating the pathology and genetic variability associated with FTD and ALS. To the most important recentdiscoveries belong TAR DNA binding protein [TARDBP or TDP-43] and the fused in sarcoma gene [FUS] and their implication in these disorders. FTD and ALS are the focus of this review which aims to 1. summarize clinical features by describing the diagnostic criteria and specific symptomatology, 2. describe the morphological aspects and related pathology, 3. describe the genetic factors associated with the diseases and 4. summarize the current status of clinical trials and treatment options. A better understanding of the clinical, pathological and genetic features characterizing FTD and ALS will shed light into overlaps among these two disorders and the underpinning mechanisms that contribute to the onset and development. Nevertheless, advancements in the knowledge of the biology of these two disorders will help developing novel and, hopefully, more effective diagnostic and treatment options.

Modeling human neurodegenerative diseases in transgenic systems

“…Among the most common are age-related neurodegenerative disorders, such as Alzheimer's disease (Selkoe 2011), Parkinson's disease (Shulman et al 2011), Huntington's disease (Finkbeiner 2011), the frontotemporal dementias (Ferrari et al 2011;Seelaar et al 2011), and ALS (Ferrari et al 2011). In each of these disorders, there is a selective vulnerability of distinct neuronal populations to the neurodegenerative process, and the clinical manifestations of each disorder reXect the distinctive subpopulations of neurons involved.…”

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

“…In PD and related disorders such as PD dementia, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), the protein α-synuclein (α-syn) accumulates in neuronal and non-neuronal cells in cortical and subcortical nuclei as Lewy bodies, neuronal cytoplasmic inclusions, or glial cytoplasmic inclusions [4,5]. Furthermore, in FTD (amyotrophic lateral sclerosis spectrum disorder) aggregates of either tau, superoxide dismutase 1, TAR DNA-binding protein , or fused in sarcoma are found [6,7]. In addition, recent studies have shown that α-syn can accumulate in selected brain regions in AD [8], and that TDP-43 aggregates are found in the limbic system in AD and DLB [9].…”

Frontotemporal Dysfunction in Amyotrophic Lateral Sclerosis: A Discriminant Function Analysis

“…The discriminant function was significant (Wilk's λ [7] = 0.372, p < 0.001), and all measures were included in the canonical function with loadings >0.40 (table 3). The canonical variable (raw score) was estimated using the following equation:…”

“…The clinical picture of ALS-FTD may be depicted as a tale of two illnesses [7]: a motor neuron disease paired with progressive cognitive impairment. The suggested continuum (leading from ALS to FTD) [8] is supposed to follow a course between two extremes over time, beginning with mild cognitive impairment and finally progressing to FTD (with the latter being a prognostic factor for poor survival) [9,10,11].…”