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  • April 2024

Non-Alzheimer’s Dementias: A Closer Look

Elderly
In Brief

The World Health Organization (WHO) estimates that by the year 2030 – less than 10 years from now – about 78 million people will be living with dementia. This number is projected to nearly double, to 139 million, by 2050.1 This article from 69É«ÇéƬ's explores non-Alzheimer's dementias and their insurance implications.

Abstract

Non-Alzheimer’s dementias present with a broad spectrum of clinical features. Many overlap with psychiatric conditions such as mood disorders and schizophrenia and with neurological conditions such as autism spectrum disorder and motor neuron disease. This means diagnosis of these dementias may be delayed and arrived at only after long and complex clinical investigative processes.3,4

This article, the first of two parts, explores frontotemporal dementia, an important cause of presenile dementia. Two other types of non-Alzheimer’s dementias, Lewy body dementia (LBD) and Parkinson’s disease dementia (PDD), will be covered in Part Two.

Introduction

Most people associate dementia with memory loss, which is the dominant symptom of early Alzheimer’s disease (AD). As AD is the cause of dementia in about 70% of affected people, it has become dementia’s archetype.2 Other dementia types, however, have different early symptoms that may not include memory loss but can include language dysfunction, loss of executive function, motor dysfunction, and even personality changes.

Incidence of non-Alzheimer’s dementias, such as frontotemporal dementia (FTD), Lewy body dementia (LBD), and Parkinson’s disease dementia (PDD),3,4 is on the rise. Non-Alzheimer’s dementias other than these three may be a consequence of other disorders, such as: vascular dementia, caused by impaired blood flow to the brain; secondary dementia occurring after traumatic brain injury; severe stroke; untreated HIV infection; and brain injury due to toxins such as alcohol.

Non-Alzheimer’s dementias have a broad spectrum of clinical features that often overlap with psychiatric and neurological disorders. These dementias are more likely to affect a younger cohort (under age 65), and clinical diagnosis may be delayed due to atypical and complex symptoms and might be arrived at only after long and complex investigative processes.3,4 These cases are challenging both to clinicians and insurers, as they can be difficult to understand and adjudicate.

In recent years, many insurance markets have expanded living benefit coverage of a range of mental health and neurological disorders of varying severity levels, such as dementias and psychiatric, neurodegenerative, and neurodevelopmental conditions. It is more important than ever now that all such cases be recognized and correctly diagnosed, using available medical evidence, to facilitate appropriate adjudication and compensation.

Frontotemporal dementia

FTD is one of the leading causes of early-onset dementia, and it has a mortality rate higher than AD. Multiple studies from around the world estimate its prevalence at 3% to 26% among cohorts of people with early onset dementia, which means its main impact is on insured populations.5

The condition was first described by psychiatrist and neurologist Arnold Pick in 1892. A patient had presented to him with a constellation of symptoms, including aphasia (which can be disordered speech alone or dysfunction in writing or speaking), brain lobar atrophy, and presenile dementia. While it is sometimes referred to as Pick’s disease, FTD is the preferred term, based on its characteristic clinical and histopathological features.3

The observable pathology in FTD is a neurodegenerative process that initially affects the brain’s frontal and temporal lobes. The cause is abnormal intracellular aggregation of certain proteins, leading to neuronal loss, microvacuole formation, and fibrosis of neurons in the affected brain regions. This condition also spreads throughout the brain over time, destroying additional areas and causing progressive and extensive cognitive dysfunction.

The extent and many sites of neuronal destruction in FTD give rise to the variations in its clinical presentation and its heterogeneity.

Elderly

FTD variants 

FTD is grouped into two main variant categories: a behavioral variant (bvFTD) and at least two language variants.6,7 bvFTD is by far the most common subtype of FTD, accounting for about 50% of cases.5 The earliest presentations of bvFTD can mimic certain psychiatric disorders, as symptoms can include personality changes with altered social behavior, disinhibition with impulsiveness, apathy with loss of social insight, aggression, inappropriate sexual remarks or behavior, personal hygiene neglect, and dysfunctions in abstract thinking and executive function. The degree of the resulting dysfunctions may lead to unemployment and social isolation, with dire consequences.

The language variants of FTD manifest as primary progressive aphasia (PPA). This form has two main subtypes: semantic variant (svFTD) and non-fluent variant FTD (nfvFTD).3,5

Individuals with the svFTD subtype lose vocabulary, have difficulty naming objects and faces, and experience impaired comprehension of verbal language over time. Written communication may be initially preserved but also declines as the disease progresses. Those with the nfvFTD subtype, although they may have trouble understanding complex sentences and speak with disjointed speech and scrambled words, selectively retain certain cognitive functions intact, such as abstract thinking and calculation abilities, until the disease reaches later stages.3,5,7

In all FTD variants, memory remains adequate in the early stage of the disease. A small number of affected people may experience abnormal motor symptoms such as spasticity, exaggerated reflexes, muscle weakness, atrophy, and fasciculations (which can resemble motor neuron disease).

While not the focus of this article, it is also worth noting that amyotrophic lateral sclerosis (ALS) has been linked to some FTD syndromes, as it shares with it a pathogenic mutation on the chromosome 9 open reading frame 72 (C9orf72) gene.3,5,7 

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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.

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.

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.

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.

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.

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Meet the Authors & Experts

Karneen Tam
Author
Dr. Karneen Tam
Medical Consultant, 69É«ÇéƬ Asia Pacific

References

  1. https://www.who.int/news/item/02-09-2021-world-failing-to-address-dementia-challenge
  2. https://www.who.int/news-room/fact-sheets/detail/dementia
  3. https://www.ncbi.nlm.nih.gov/books/NBK559286/
  4. https://pubmed.ncbi.nlm.nih.gov/26595642/
  5. https://pubmed.ncbi.nlm.nih.gov/26595641/
  6. https://pubmed.ncbi.nlm.nih.gov/34389969/
  7. https://www.sciencedirect.com/science/article/pii/S2666144623000059?via%3Dihub
  8. https://pubmed.ncbi.nlm.nih.gov/31119452/
  9. https://www.frontiersin.org/articles/10.3389/fnins.2018.00473/full
  10. https://doi.org/10.1038/s41582-020-0330-x
  11. https://link.springer.com/article/10.1007/s00415-020-10040-0