Researchers at the University of Kentucky’s College of Medicine have found that a class of antibiotics called aminoglycosides could be a promising treatment for frontotemporal dementia.
Results of their proof of concept study, which was a collaborative effort between UK’s Department of Molecular and Cellular Biochemistry and the University of California San Francisco’s Department of Pathology, were recently published in the journal, Human Molecular Genetics.
Frontotemporal dementia is the most common type of early onset dementia. It typically begins between ages 40 and 65 and affects the frontal and temporal lobes of the brain, which leads to behavior changes, difficulty speaking and writing, and memory deterioration.
A subgroup of patients with frontotemporal dementia have a specific genetic mutation that prevents brain cells from making a protein called progranulin.
Although progranulin is not widely understood, its absence is linked to the disease.
A group led by Haining Zhu, a professor in UK’s Department of Molecular and Cellular Biochemistry, discovered that after aminoglycoside antibiotics were added to neuronal cells with this mutation, the cells started making the full-length progranulin protein by skipping the mutation.
“These patients’ brain cells have a mutation that prevents progranulin from being made. The team found that by adding a small antibiotic molecule to the cells, they could ‘trick’ the cellular machinery into making it,” said Matthew Gentry, a co-author of the study and the Antonio S. Turco Endowed Professor in the Department of Molecular and Cellular Biochemistry.
The researchers found two specific aminoglycoside antibiotics – Gentamicin and G418 – were both effective in fixing the mutation and making the functional progranulin protein.
After adding Gentamicin or G418 molecules to the affected cells, the progranulin protein level was recovered up to about 50 to 60%.
These results could be promising to drug development. Currently, there are no effective therapies for any type of dementia.
The researchers found two specific aminoglycoside antibiotics – Gentamicin and G418 – were both effective in fixing the mutation and making the functional progranulin protein.
After this preclinical proof of concept study, the next step is to study the antibiotics’ effects on mice with the mutation that causes frontotemporal dementia, Zhu says.
Another focus is to possibly develop new compounds from Gentamicin and G418 that could be safer and more effective. Although Gentamicin is an FDA-approved medication, its clinical usage is limited as it is associated with a number of adverse side effects.
“If we can get the right resources and physician to work with, we could potentially repurpose this drug.
This is an early stage of the study, but it provides an important proof of concept that these aminoglycoside antibiotics or their derivatives can be a therapeutic avenue for frontotemporal dementia,” said Zhu.
Frontotemporal dementia (FTD) is an insidious neurodegenerative clinical syndrome that is characterized by progressive disturbances in behavior as well as deficits in executive function and language. FTD is a common early-onset dementia (occurring in patients aged < 65 years), has a prevalence rate of 3–26%, and is one of the most common forms of dementia across all age groups (1). Arnold Pick, a Czech psychiatrist, first identified the clinical syndrome of FTD in 1892 (2).
He described a patient with aphasia, focal frontal and temporal lobar atrophy, and presenile dementia. Alois Alzheimer, a German psychiatrist and neuropathologist, later characterized Pick bodies as being associated with FTD and named the disorder Pick’s disease in 1911 (3). Although, the term Pick’s disease initially referred to both the clinical syndrome and the pathological diagnosis, modern nomenclature designates Pick’s disease as only the pathological diagnosis, whereas a clinical diagnosis for prominent behavioral changes is known as behavioral-variant FTD (bvFTD). Mesulam described primary progressive aphasia (PPA), the language subtype of FTD, in 1982 (4). Revised diagnostic criteria were issued in 2011 (5, 6).
Precision medicine, also called “personalized medicine” or “individualized medicine,” is a rapidly advancing field in medical, clinical, and research settings.
It aims to optimize the effectiveness of disease prevention and treatment and simultaneously minimize side effects in individuals who are less likely to respond to a particular therapy, by considering an individual’s specific makeup with regard to genetics, biomarkers, phenotype, and psychosocial characteristics.
In this review, we discuss the precision medicine of FTD, from clinical phenotypes, epidemiology, genetics, neuroimaging to neuropathological biomarkers. We further review recent advancements in therapeutic strategies and potential personalized treatment for FTD (7–13). This review improves the understanding of accurate diagnosis and personalized effective disease treatment strategies.
Cognitive and Behavioral Markers
FTD is an umbrella term for three recognizable clinical syndromes, namely bvFTD, semantic-variant PPA (svPPA), and non-fluent-variant PPA (nfvPPA) (Table 1). FTD also frequently overlaps clinically with three neurodegenerative diseases that exhibit motor deficits, namely corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (14).
Behavioral-Variant Frontotemporal Dementia
The symptoms of bvFTD include progressive personality and behavioral changes, apathy, and disinhibition in interpersonal interactions. Patients may experience early changes in disinhibition, stereotypic behavior, alterations in food preferences and eating behavior, alterations in empathy, apathy, and dysexecutive symptoms (5, 15).
Some of these early symptoms, such as decreased empathy, may have diagnostic value for bvFTD, but they have not been ascertained in clinical practice. Apathy may manifest as reduced interest in work, hobbies, social interaction, and hygiene; however, apathy can be misdiagnosed as depression.
Symptoms similar to those detected in psychiatric disorders are frequently observed in patients with bvFTD. Thus, discriminating the behavioral features of bvFTD from those of primary psychiatric disorders such as depression, schizophrenia, bipolar disorder, and borderline personality disorder may be challenging (16, 17).
Although psychotic symptoms such as hallucinations and delusions are rare in bvFTD, cases of these symptoms have been reported (17), particularly in patients carrying the chromosome 9 open reading frame 72 (C9orf72) repeat expansion (18).
Primary Progressive Aphasia
Patients with PPA exhibit a progressive decline in linguistic skills during the early phase of the disease. Language dysfunction is the main symptom during the first 2 years of PPA. Deficits in object naming, syntax, or word comprehension may become apparent during conversation or may be identified using speech and language assessment.
The subtypes of PPA are differentiated by specific types of speech or language deficits. The three PPA subtypes are the semantic, non-fluent, and logopenic variants (19). Each subtype has a distinct pattern of language deficits. Naming difficulty is common to all three subtypes; therefore, it is not a distinguishing feature.
The non-fluent (or agrammatic) variant and the semantic variant are classified as FTD, whereas the logopenic variant, most often associated with temporoparietal atrophy, is typically due to underlying Alzheimer’s pathology; hence, it is not discussed in this review.
Semantic-Variant Primary Progressive Aphasia
In svPPA, a syndrome characterized by semantic aphasia and associative agnosia, anterior temporal lobe degeneration disrupts semantic memory (Table 1) (6). Anomia and single-word comprehension deficits, starting with low-frequency items, are essential for diagnosis (20). In contrast to patients with nfvPPA, those with svPPA maintain fluent speech and correct grammar during the early stages of this disease. Early symptoms of semantic PPA include anomia, word-finding difficulties, and repetitive speech, whereas early behavioral syndrome presents with irritability and emotional distance or coldness.
Non-fluent/Agrammatic-Variant Primary Progressive Aphasia
Articulation deficits resulting in slow, labored, and halting speech production as well as incorrect grammar or syntax (agrammatism) characterize nfvPPA. The core criteria of nfvPPA are agrammatism and effortful speech, and at least one of the criteria should be present (Table 1) (6).
Patients tend to exhibit motor speech disorders characterized by a slow speech rate, abnormal prosody, and distorted sound substitutions, additions, repetitions, and prolongations, which are occasionally accompanied by groping, trial-and-error articulatory movements (21), or agrammatic errors. Repetition is less impaired than is spontaneous speech, and semantic knowledge for words typically remains well-preserved throughout the disease process.
Motor Symptoms
The three FTD-spectrum motor syndromes are FTD with motor neuron disease (FTD-MND) and two variants with parkinsonism, namely corticobasal syndrome (CBS) and progressive supranuclear palsy syndrome (PSP-S). Up to 15% of patients with FTD have concomitant MND, and nearly 30% of patients present with mild features of MND (9, 22).
MND may include upper motor neuron signs (hyperreflexia, extensor plantar response, and spasticity), lower motor neuron signs (weakness, muscle atrophy, and fasciculations), dysarthria, dysphagia, and pseudobulbar affect (22).
Up to 20% of patients with FTD present with parkinsonism, which is most often observed in patients with bvFTD, followed by those with nfvPPA (23).
Patients with FTD may exhibit features of CBS or PSP-S. CBS is a heterogeneous syndrome featuring behavioral, cognitive, and motor changes.
The clinical criteria for probable CBS include asymmetric presentation with any two symptoms among
(A) limb rigidity or akinesia,
(B) limb dystonia, and
(C) limb myoclonus, as well as any two symptoms among
(D) orobuccal or limb apraxia,
(E) cortical sensory deficit, and
(F) alien limb phenomena (more than simple levitation) (24).
Finally, PSP-S is characterized by atypical parkinsonism with axial and symmetrical rigidity, supranuclear gaze palsy (most prominent in the vertical plane), decreased saccadic velocity, early postural instability with falls, and prominent frontal lobe dysfunction (25, 26).
Taken together, the vast heterogeneity and overlap of clinical phenotypes in FTD often poses diagnostic challenges for clinicians, in particular the presenting psychiatric symptoms that may easily be mistaken for psychiatric disorders. The accurate diagnosis of each subtype of FTD, therefore, requires a precision medicine approach.
Source:
University of Kentucky
Media Contacts:
Elizabeth Chapin – University of Kentucky
Original Research: Open access
“Frontotemporal dementia nonsense mutation of progranulin rescued by aminoglycosides”. Haining Zhu et al.
Human Molecular Genetics doi:10.1093/hmg/ddz280.
