Progressive negative impacts
Over time, FTD patients show personality changes as well as continuous declines in self-control, communication, and decision-making and problem-solving abilities. In advanced stages, memory loss and motor dysfunction also develop, resulting in a loss of independence and necessitating intense physical, financial, and social support. As about 70% of FTD cases are in people younger than 65 years of age, the disease can decimate what would have been the patient’s most productive years, with significant financial as well as physical impacts. Receiving a timely and accurate diagnosis and having adequate risk cover may help ease a patient and family’s transition into care.
Diagnostic challenges
The presenting symptoms of FTD are complex, making these cases challenging both to diagnose and to adjudicate. Onset generally occurs in individuals ages 40 to 65, but it has been seen in people as young as age 17. As its symptoms often overlap with other psychiatric and neurological disorders, misdiagnosis can be frequent. The diagnostic process may require longer observation of its symptomatic evolution before confirmation. In addition, some who display many of the symptomatic criteria for FTD may later be diagnosed with bipolar disorder or autism spectrum disorder.
Medical researchers are working continuously to gain a better understanding of this disease group. Insights into FTD’s genetic-molecular and histopathological characteristics have added more assessment tools and biomarkers to improve the diagnostic process. However, diagnosis remains complex, as FTD continues to lack a definitive diagnostic test and requires clinical vigilance from attending physicians.
Currently, there is no single diagnostic test for FTD and its subtypes.
Underlying genetics, disease mechanisms, biomarkers, diagnostic tools
Genetics
FTD is characterized by neurodegeneration in the frontotemporal lobes, caused mainly by abnormal aggregations of three proteins: tau protein, TAR DNA-binding protein 43 (TDP-43), and fused-in-sarcoma protein (FUS). More than 20 genetic mutations have already been identified that correlate to these and related proteins, which are involved in various synthetic steps of the intracellular structures of neurons, such as microtubules and the cytoskeleton. These mutations are implicated in both familial and sporadic FTD.3,8
Up to 40% of FTD cases are known as familial, as these patients may have family histories implying a strong genetic component with some individuals showing an autosomal dominance inheritance pattern.9 At least 10 genetic mutations have shown association with these heritable FTDs. The three most frequent pathogenic gene mutations are in the progranulin (GRN), microtubule-associated protein tau (MAPT), and C9orf72 genes.
In cases with symptoms and histories suggestive of FTD, genetic testing may be a useful aid for differentiating FTD from psychiatric disorders.8 Next-generation sequencing allows multiple genes to be tested simultaneously and may in the future be incorporated in diagnosing early-stage cases.
Some of the understanding of disease-causing molecular pathways involved in FTD is also offering potential intervention targets for research directions. No effective pharmacological intervention has yet emerged, but some groundbreaking clinical trials are underway investigating therapies that target some of the genetic mechanisms.10
Imaging
Advances in imaging techniques can tap into knowledge of proteinopathies and certain lobar degeneration patterns. Structural MRI and CT scans, for example, can effectively detect FTD’s characteristic regional atrophy, even in pre-symptomatic stages. As the disease progresses, larger areas of the brain are involved, and certain characteristic patterns of atrophy, volumetric loss, and white matter hyperintensities have been observed to correlate with certain FTD molecular subtypes. At this point, however, these patterns still lack specificity.8
Functional MRI, fluorodeoxyglucose PET, and single-photon-emission CT are three types of neuroimaging scans that can detect abnormal lobar blood flow and metabolic activity. These findings align with and strengthen the changes seen on structural imaging tests and aid in diagnosis. Neuroimaging findings are not specific to FTD, but both structural and functional imaging modalities are becoming helpful tools in consolidating and correlating clinical findings.6
During the past two decades, clinical understanding of AD has advanced due to molecular scanning, a procedure in which a molecule of radioactive material (i.e., a radiotracer) is used to detect any abnormal buildup in the brain of proteins such as amyloid or tau.11 In FTD, amyloid positivity is low, so its presence either may indicate the coexistence of AD or be an incidental finding. Detection of pathological tau and TDP-43 have also shown potential in FTD assessments, but clinically applicable utility is not yet available.7,8 Current investigations into these proteins as they relate to FTD are still largely confined to specialized research facilities.
Other researchers are exploring possibilities that measurements such as volumetric change rates, structural connectivity by diffuse tensor imaging, and functional connectivity by resting-state MRI could serve as biometrics. Future research may also yield additional suitable and useful imaging biomarkers for FTD detection and monitoring.
Fluid biomarkers
Research during the past few decades has led to the discovery of novel cerebrospinal fluid (CSF) and blood biomarkers for AD evaluation. Fluid biomarkers are also an area of intense research in the effort to develop a useful test that can reliably detect, differentiate, and prognosticate FTD.
One such biomarker is neurofilament light chain (Nfl), a protein which is released into the CSF and blood in response to axonal injury in AD, FTD, multiple sclerosis, and atypical Parkinson’s disease. In all forms of FTD, Nfl levels may be a few-fold higher than is seen in healthy people and is observable in the condition’s pre-symptomatic phase. Its level of fluctuation has been predictive of the progression into the symptomatic stage and longitudinally correlates with severity of the disease, irrespective of the FTD subtype. Although presence of Nfl is not specific to FTD, it can rule out psychiatric disorders and consolidate the FTD diagnosis in conjunction with other means of assessment.8
In contrast to CSF testing that is obtained invasively with potential risks, accessibility of Nfl via blood means it may be a more useful and affordable biomarker. Other blood proteins such as tau, TDP 43, and miRNA have been investigated for their potential as biomarkers, but to date they have not shown sufficient clinical utility as they lack specificity to FTD.
The blood-brain barrier also blocks passage of many intracranial proteins into the blood, hence CSF protein levels may be more reflective of the proteinopathy and neuronal flux in FTD and other dementias. Similar disease-marking proteins in CSF were the primary candidates investigated, and they have shown some diagnostic potentials. However, the invasive nature of lumbar puncture and its cost have restricted utilization of CSF biomarkers to research.7
Currently, there is no single diagnostic test for FTD and its subtypes. Assessment and diagnosis continue to rely on symptomatology with established neurocognitive decline, and imaging investigation looks for structural and functional alterations. Where appropriate and available, genetic testing and fluid biomarkers have added much value to the diagnostic process.
Conclusion
Research is providing a better understanding of FTD – its complexities, its syndromes, and its variants. Revelations about its underlying genetic-molecular mechanisms have also opened up understanding of the many biological pathways involved in FTD, thus helping to expedite and hopefully simplify the diagnostic process, and also to discover effective medical treatment.
People affected by FTD have historically had challenging clinical experiences, with symptoms and delays in diagnosis often leading to social isolation, unemployment, and early mortality. As the disease progresses, affected individuals lose their independence and require intense social and physical support. Risk products can make a critical difference: These are the very types of health impairments the insurance industry looks to help so as to ease some of their devastating support needs. By being vigilant and by applying fresh and updated knowledge, insurers can provide meaningful help for these serious conditions.