Dataset Information

APP-derived peptides reflect neurodegeneration in frontotemporal dementia.

ABSTRACT:

Objective

We aimed to investigate the relationship between cerebrospinal fluid levels (CSF) of amyloid precursor protein (APP)-derived peptides related to the amyloidogenic pathway, cortical thickness, neuropsychological performance, and cortical gene expression profiles in frontotemporal lobar degeneration (FTLD)-related syndromes, Alzheimer's disease (AD), and healthy controls.

Methods

We included 214 participants with CSF available recruited at two centers: 93 with FTLD-related syndromes, 57 patients with AD, and 64 healthy controls. CSF levels of amyloid ? (A?)1-42, A?1-40, A?1-38, and soluble ? fragment of APP (sAPP?) were centrally analyzed. We compared CSF levels of APP-derived peptides between groups and, we studied the correlation between CSF biomarkers, cortical thickness, and domain-specific cognitive composites in each group. Then, we explored the relationship between cortical thickness, CSF levels of APP-derived peptides, and regional gene expression profile using a brain-wide regional gene expression data in combination with gene set enrichment analysis.

Results

The CSF levels of A?1-40, A?1-38, and sAPP? were lower in the FTLD-related syndromes group than in the AD and healthy controls group. CSF levels of all APP-derived peptides showed a positive correlation with cortical thickness and the executive cognitive composite in the FTLD-related syndromes group but not in the healthy control or AD groups. In the cortical regions where we observed a significant association between cortical thickness and CSF levels of APP-derived peptides, we found a reduced expression of genes related to synaptic function.

Interpretation

APP-derived peptides in CSF may reflect FTLD-related neurodegeneration. This observation has important implications as A?1-42 levels are considered an indirect biomarker of cerebral amyloidosis.

SUBMITTER: Illan-Gala I

PROVIDER: S-EPMC6917306 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Publications

APP-derived peptides reflect neurodegeneration in frontotemporal dementia.

Illán-Gala Ignacio I Pegueroles Jordi J Montal Victor V Alcolea Daniel D Vilaplana Eduard E Bejanin Alexandre A Borrego-Écija Sergi S Sampedro Frederic F Subirana Andrea A Sánchez-Saudinós María-Belén MB Rojas-García Ricard R Vanderstichele Hugo H Blesa Rafael R Clarimón Jordi J Antonell Anna A Lladó Albert A Sánchez-Valle Raquel R Fortea Juan J Lleó Alberto A

Annals of clinical and translational neurology 20191202 12

<h4>Objective</h4>We aimed to investigate the relationship between cerebrospinal fluid levels (CSF) of amyloid precursor protein (APP)-derived peptides related to the amyloidogenic pathway, cortical thickness, neuropsychological performance, and cortical gene expression profiles in frontotemporal lobar degeneration (FTLD)-related syndromes, Alzheimer's disease (AD), and healthy controls.<h4>Methods</h4>We included 214 participants with CSF available recruited at two centers: 93 with FTLD-related ...[more]

PMID: 31789459

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Project description:Frontotemporal dementia (FTD) encompasses a spectrum of neurodegenerative diseases with heterogeneous clinical presentations and two predominant types of underlying neuropathology. FTD typically comprises three distinct clinical syndromes: behavioral variant frontotemporal dementia (bvFTD), semantic variant primary progressive aphasia (svPPA), and nonfluent variant primary progressive aphasia (nfvPPA). FTD also frequently overlaps both clinically and neuropathologically with three other neurodegenerative syndromes: corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS). Each syndrome can be associated with one or more underlying neuropathological diagnoses and are referred to as frontotemporal lobar degeneration (FTLD). Although the various FTD syndromes can substantially differ in terms of clinical symptoms and underlying pathology, the symptoms can be broadly categorized into behavioral, cognitive and motor domains. Currently there are no Food and Drug Administration (FDA) approved therapies for the above syndromes except riluzole for ALS. FTD treatment strategies generally rely on off-label use of medications for symptomatic management, and most therapies lack quality evidence from randomized, placebo-controlled clinical trials. For behavioral symptoms, selective serotonin reuptake inhibitors may be effective, while case reports hint at possible efficacy with antipsychotics or anti-epileptics, but use of these latter agents is limited due to concerns regarding side effects. There are no effective therapies for cognitive complaints in FTD, which frequently involve executive function, memory, and language. Motor difficulties associated with FTD may present with parkinsonian symptoms or motor neuron disease, for which riluzole is indicated as therapy. Compared to idiopathic Parkinson's disease, FTD-related atypical parkinsonism is generally not responsive to dopamine replacement therapies, but a small percentage of patients may experience improvement with a trial of carbidopa-levodopa. Physical and occupational therapy remain an important corner stone of motor symptom management in FTD. Speech therapy may also help patients manage symptoms associated with aphasia, apraxia, and dysarthria. Recent advances in the understanding of FTLD pathophysiology and genetics have led to development of potentially disease-modifying therapies as well as symptomatic therapies aimed at ameliorating social and behavioral deficits.

Dataset Information

APP-derived peptides reflect neurodegeneration in frontotemporal dementia.

Objective

Methods

Results

Interpretation

Publications

APP-derived peptides reflect neurodegeneration in frontotemporal dementia.

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