Systematic Review: Genetic, Neuroimaging, and Fluids Biomarkers for Frontotemporal Dementia Across Latin America Countries

Abstract

Frontotemporal dementia (FTD) includes a group of clinically, genetically, and pathologically heterogeneous neurodegenerative disorders, affecting the fronto-insular-temporal regions of the brain. Clinically, FTD is characterized by progressive deficits in behavior, executive function, and language and its diagnosis relies mainly on the clinical expertise of the physician/consensus group and the use of neuropsychological tests and/or structural/functional neuroimaging, depending on local availability. The modest correlation between clinical findings and FTD neuropathology makes the diagnosis difficult using clinical criteria and often leads to underdiagnosis or misdiagnosis, primarily due to lack of recognition or awareness of FTD as a disease and symptom overlap with psychiatric disorders. Despite advances in understanding the underlying neuropathology of FTD, accurate and sensitive diagnosis for this disease is still lacking. One of the major challenges is to improve diagnosis in FTD patients as early as possible. In this context, biomarkers have emerged as useful methods to provide and/or complement clinical diagnosis for this complex syndrome, although more evidence is needed to incorporate most of them into clinical practice. However, most biomarker studies have been performed using North American or European populations, with little representation of the Latin American and the Caribbean (LAC) region. In the LAC region, there are additional challenges, particularly the lack of awareness and knowledge about FTD, even in specialists. Also, LAC genetic heritage and cultures are complex, and both likely influence clinical presentations and may modify baseline biomarker levels. Even more, due to diagnostic delay, the clinical presentation might be further complicated by both neurological and psychiatric comorbidity, such as vascular brain damage, substance abuse, mood disorders, among others. This systematic review provides a brief update and an overview of the current knowledge on genetic, neuroimaging, and fluid biomarkers for FTD in LAC countries. Our review highlights the need for extensive research on biomarkers in FTD in LAC to contribute to a more comprehensive understanding of the disease and its associated biomarkers. Dementia research is certainly reduced in the LAC region, highlighting an urgent need for harmonized, innovative, and cross-regional studies with a global perspective across multiple areas of dementia knowledge.

A predictive coding framework of allostatic–interoceptive overload in frontotemporal dementia

“…Importantly, multiple biomarker signatures of allostatic load can be assessed through an allostatic load battery. Specifically, multisystemic biomarkers associated with allostatic overload include: (i) cardiovascular [50,51]: arterial tension and resting pulse rate; (ii) metabolic [51,52]: body mass index, waist-hip ratio, total cholesterol, high-density lipoprotein, lowdensity lipoprotein, triglycerides, glycated hemoglobin, fasting glucose, creatinine, and albumin; (iii) inflammatory [51,[53][54][55][56][57][58][59][60]: tumor necrosis factor-α, tumor growth factor-β, C-reactive protein, interleukin-2, interleukin-6; (iv) stress hormone [61]: cortisol; and (v) neurodegenerative parameters [54,[62][63][64][65][66][67]: neurofilament light chain and progranulin. A weighted allostatic load battery based on multimodal cut-off scores being used can lead to an integrative biomarkers score.…”

“…Second, bvFTD patients show metabolic abnormalities associated with malnutrition [52]. Third, changes in inflammatory peripheral biomarkers have been reported in different frontotemporal dementia subtypes, suggesting that inflammatory factors play an important role in the pathogenesis of the disease [53,54]. Specifically, high levels of tumor necrosis factor-α and tumor growth factor-β [55][56][57], but low levels of interleukin-12, have been found in patients with bvFTD [58].…”

“…Fourth, bvFTD patients show low cortisol levels, which would serve as a compensatory mechanism to regulate the top-down cognitive control deficits [61]. Fifth, neurodegenerative parameters have been also found dysregulated in bvFTD [54]. Neurofilament light chain is a component of the neuronal cytoskeleton [62] and its concentration levels have been shown to increase in serum and plasma of frontotemporal dementia patients, predicting disease severity and brain volume loss [63][64][65][66].…”

“…Finally, a third level presumes a direct causal link between an initial malfunction of predictive coding of allostatic interoception processes and a concomitant pathophysiology of neurodegenerative mechanisms. For instance, chronic stress plays an important role in immune regulation [130,131] that in turn impacts FTD etiology [53,54,132,133] and other neurodegenerative conditions [130]. Allostatic overload may be an important factor causing neurodegenerative disease and contributing to TDP-43 aggregation [134] associated with frontotemporal dementia [135].…”

The Latin American Brain Health Institute, a regional initiative to reduce the scale and impact of dementia

“…BrainLat supports ReDLat by providing dedicated research positions (faculty positions, postdocs), seed grants, and funds for mobility. The institute complements ReDLat research by focusing on novel and affordable biomarkers (e.g., electroencephalogram, functional magnetic resonance imaging, blood‐based biomarkers) relevant to the region 7,8 . BrainLat, in association with LAC‐CD and the International Society to Advance Alzheimer's Research and Treatment is currently delivering webinars focused on dementia with content that includes biomarkers, technology, care, and interventions after surveying regional experts’ knowledge on these topics.…”