FTD With Motor Neuron Disease Research Articles

Multidimensional Clinical Assessment in Frontotemporal Dementia and Its Spectrum in Latin America and the Caribbean: A Narrative Review and a Glance at Future Challenges.

Frontotemporal dementia (FTD) is the third most common form of dementia across all age groups and is a leading cause of early-onset dementia. The Frontotemporal dementia (FTD) includes a spectrum of diseases that are classified according to their clinical presentation and patterns of neurodegeneration. There are two main types of FTD: behavioral FTD variant (bvFTD), characterized by a deterioration in social function, behavior, and personality; and primary progressive aphasias (PPA), characterized by a deficit in language skills. There are other types of FTD-related disorders that present motor impairment and/or parkinsonism, including FTD with motor neuron disease (FTD-MND), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS). The FTD and its associated disorders present great clinical heterogeneity. The diagnosis of FTD is based on the identification through clinical assessments of a specific clinical phenotype of impairments in different domains, complemented by an evaluation through instruments, i.e., tests and questionnaires, validated for the population under study, thus, achieving timely detection and treatment. While the prevalence of dementia in Latin America and the Caribbean (LAC) is increasing rapidly, there is still a lack of standardized instruments and consensus for FTD diagnosis. In this context, it is important to review the published tests and questionnaires adapted and/or validated in LAC for the assessment of cognition, behavior, functionality, and gait in FTD and its spectrum. Therefore, our paper has three main goals. First, to present a narrative review of the main tests and questionnaires published in LAC for the assessment of FTD and its spectrum in six dimensions: (i) Cognitive screening; (ii) Neuropsychological assessment divided by cognitive domain; (iii) Gait assessment; (iv) Behavioral and neuropsychiatric symptoms; (v) Functional assessment; and (vi) Global Rating Scale. Second, to propose a multidimensional clinical assessment of FTD in LAC identifying the main gaps. Lastly, it is proposed to create a LAC consortium that will discuss strategies to address the current challenges in the field.

Fronto temporal dementias

Frontotemporal dementias (FTD) are a heterogenous group of neurocognitive disorders which varies with regard to their clinical presentation, radiological characteristics, pathology and genetics. The core FTD clinical syndromes are behavioural variant FTD (bvFTD), semantic variant primary progressive aphasia (svPPA) and non-fluent/ agrammatic variant of primary progressive aphasia (nfvPPA). FTD related syndromes include frontotemporal dementia with motor neuron disease (FTD-MND), progressive supranuclear palsy syndrome (PSP-S) and corticobasal syndrome (CBS). This article discusses the clinical presentation, diagnosis, neuropathology, neurogenetics and therapeutics of FTDs.

Chapter 12 - Neuroimaging in aging and neurologic diseases

Neuroimaging biomarkers for neurologic diseases are important tools, both for understanding pathology associated with cognitive and clinical symptoms and for differential diagnosis. This chapter explores neuroimaging measures, including structural and functional measures from magnetic resonance imaging (MRI) and molecular measures primarily from positron emission tomography (PET), in healthy aging adults and in a number of neurologic diseases. The spectrum covers neuroimaging measures from normal aging to a variety of dementias: late-onset Alzheimer's disease [AD; including mild cognitive impairment (MCI)], familial and nonfamilial early-onset AD, atypical AD syndromes, posterior cortical atrophy (PCA), logopenic aphasia (lvPPA), cerebral amyloid angiopathy (CAA), vascular dementia (VaD), sporadic and familial behavioral-variant frontotemporal dementia (bvFTD), semantic dementia (SD), progressive nonfluent aphasia (PNFA), frontotemporal dementia with motor neuron disease (FTD-MND), frontotemporal dementia with amyotrophic lateral sclerosis (FTD-ALS), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB), Parkinson's disease (PD) with and without dementia, and multiple systems atrophy (MSA). We also include a discussion of the appropriate use criteria (AUC) for amyloid imaging and conclude with a discussion of differential diagnosis of neurologic dementia disorders in the context of neuroimaging.

Clinical value of neurofilament and phospho-tau/tau ratio in the frontotemporal dementia spectrum.

ObjectiveTo examine the clinical value of neurofilament light chain (NfL) and the phospho-tau/total tau ratio (p/t-tau) across the entire frontotemporal dementia (FTD) spectrum in a large, well-defined cohort.MethodsCSF NfL and p/t-tau levels were studied in 361 patients with FTD: 179 behavioral variant FTD, 17 FTD with motor neuron disease (FTD-MND), 36 semantic variant primary progressive aphasia (PPA), 19 nonfluent variant PPA, 4 logopenic variant PPA (lvPPA), 42 corticobasal syndrome, and 64 progressive supranuclear palsy. Forty-five cognitively healthy controls were also included. Definite pathology was known in 68 patients (49 frontotemporal lobar degeneration [FTLD]-TDP, 18 FTLD-tau, 1 FTLD-FUS).ResultsNfL was higher in all diagnoses, except lvPPA (n = 4), than in controls, equally elevated in behavioral variant FTD, semantic variant PPA, nonfluent variant PPA, and corticobasal syndrome, and highest in FTD-MND. The p/t-tau was lower in all clinical groups, except lvPPA, than in controls and lowest in FTD-MND. NfL did not discriminate between TDP and tau pathology, while the p/t-tau ratio had a good specificity (76%) and moderate sensitivity (67%). Both high NfL and low p/t-tau were associated with poor survival (hazard ratio on tertiles 1.7 for NfL, 0.7 for p/t-tau).ConclusionNfL and p/t-tau similarly discriminated FTD from controls, but not between clinical subtypes, apart from FTD-MND. Both markers predicted survival and are promising monitoring biomarkers for clinical trials. Of note, p/t-tau, but not NfL, was specific to discriminate TDP from tau pathology in vivo.Classification of evidenceThis study provides Class III evidence that for patients with cognitive issues, CSF NfL and p/t-tau levels discriminate between those with and without FTD spectrum disorders.

NEUROFILAMENT LIGHT CHAIN AND PHOSPHOTAU/TAU RATIO AS CSF BIOMARKERS IN FRONTOTEMPORAL DEMENTIA

Neurofilament light chain (NfL) in cerebrospinal fluid (CSF) is elevated and the phosphotau/tau ratio (p/t-tau) decreased in frontotemporal dementia (FTD), and are both potential biomarkers for disease severity and prognosis. Additionally, p/t-tau may discriminate FTD with TDP43 inclusions (FTLD-TDP) from FTD with tau pathology (FTLD-tau). We examined the diagnostic potential of these individual biomarkers in a large and clinically well-defined FTD cohort. CSF NfL and p/t-tau levels were compared between 45 cognitively healthy control subjects, 181 behavioral variant FTD (bvFTD), 16 FTD with motor neuron disease (FTD-MND), 36 semantic dementia (SD), 19 progressive non-fluent aphasia (PNFA), 42 corticobasal syndrome (CBS), and 64 progressive supranuclear palsy (PSP) patients. In 73 patients, a definite FTD was diagnosed (underlying pathology: TDP n=50, tau n=23). CSF NfL levels were higher in all patient groups than in controls (p<0.001, sensitivity 79%, specificity 89%). CSF NfL levels were equally elevated in bvFTD, SD, PNFA, CBS, and PSP; FTD-MND patients had higher NfL levels than all other patients. CSF p/t-tau was lower in all patients than controls (p<0.001, sensitivity 73%, specificity 93%), with the lowest values in FTD-MND patients. CSF NfL did not discriminate between underlying TDP and tau pathology (p=0.08). The p/t-tau ratio had a high specificity (81%) and moderate sensitivity (65%) to discriminate FTLD-TDP from FTLD-tau patients. In all patients combined, High NfL and low p/t-tau levels were associated with a high CDR-SB (rs=0.38, p=0.005 for NfL, rs=-0.29 for p/t-tau) and with a poor survival (estimated hazard ratio on tertiles 1.7 for NfL and 0.7 for p/t-tau). We confirmed that CSF NfL and the p/t-tau ratio are potential biomarkers for disease severity and prognosis in FTD and are therefore interesting surrogate endpoints in clinical trials. Both biomarkers discriminated FTD from controls, but not the individual subtypes, apart from FTD-MND. Additionally, the p/t-tau ratio was specific to discriminate TDP from tau pathology in vivo.

Increased prevalence of autoimmune disease within C9 and FTD/MND cohorts: Completing the picture.

Objective:To determine the prevalence of autoimmune disease in symptomatic C9ORF72 (C9) mutation carriers and frontotemporal dementia with motor neuron disease (FTD/MND) cohorts.Methods:In this case-control study, we reviewed the clinical histories of 66 patients with FTD/MND and 57 symptomatic C9 carriers (24 overlapping cases), a total of 99 charts, for history of autoimmune disease. The prevalence of autoimmune disease in C9 and FTD/MND cohorts was determined by χ2 and Fisher exact comparisons between the combined C9 and FTD/MND group with normal control, Alzheimer disease, and progressive supranuclear palsy cohorts, as well as comparisons within C9 and FTD/MND cohorts.Results:Our combined C9 and FTD/MND cohort has a 12% prevalence of nonthyroid autoimmune disease. The prevalence of nonthyroid autoimmune disease in C9 and FTD/MND is similar to the rates in previously detailed progranulin and semantic variant primary progressive aphasia cohorts and elevated in comparison to previously collected normal control and typical Alzheimer disease cohorts, as well as a newly screened progressive supranuclear palsy cohort. Furthermore, the types of autoimmune disease in this combined C9 and FTD/MND cohort cluster within the same 3 categories previously described in progranulin and semantic variant primary progressive aphasia: inflammatory arthritides, cutaneous conditions, and gastrointestinal disorders.Conclusions:The association between selective autoimmune disease and neurodegenerative disorders unified by the underlying pathology frontotemporal lobar degeneration with TDP-43–positive inclusions (FTLD-TDP) extends to C9 and FTD/MND cohorts, providing further evidence that select autoimmune inflammation may be intrinsically linked to FTLD-TDP pathophysiology.

Family history of frontotemporal lobar degeneration in Asia – an international multi-center research

Previous studies in western countries have shown that about 30%-50% of patients with frontotemporal lobar degeneration (FTLD) have a positive family history, whereas the few epidemiological studies on FTLD done in Asia reported much lower frequencies. It is not clear the reason why the frequencies of FTLD with positive family history were lower in Asia. Furthermore, these findings were not from studies focused on family history. Therefore, it is necessary to conduct further studies on the family history of FTLD in Asia. This international multi-center research aims to investigate the family histories in patients with FTLD and related neurodegenerative diseases such as progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and motor neuron diseases in a larger Asian cohort. Participants were collected from five countries: India, Indonesia, Japan, Taiwan, and Philippines. All patients were diagnosed with behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SD), progressive non-fluent aphasia (PA), frontotemporal dementia with motor neuron disease (FTD/MND), PSP, and corticobasal degeneration (CBD) according to international consensus criteria. Family histories of FTLD and related neurodegenerative diseases were investigated in each patient. Ninety-one patients were included in this study. Forty-two patients were diagnosed to have bvFTD, two patients had FTD/MND, 22 had SD, 15 had PA, one had PA/CBS, five had CBS and four patients had PSP. Family history of any FTLD spectrum disorder was reported in 9.5% in bvFTD patients but in none of the SD or PA. In contrast to patients of the western countries, few Asian FTLD patients have positive family histories of dementia.

Prevalence of cerebrospinal fluid Alzheimer disease-like pattern in atypical dementias

BACKGROUND: Differential diagnosis between Frontotemporal Dementia (FTD), Corticobasal Syndrome (CBS), Progressive Supranuclear Palsy Syndrome (PSP), FTD with motor neuron disease (FTD-MND) is often challenging, because of the occurrence of atypical cases. Autopsy series have identified Alzheimer Disease (AD) pathology in a consistent percentage of patients with atypical dementias. It has been demonstrated that Cerebrospinal Fluid (CSF) Tau/Aβ42 dosage is a reliable marker for AD. OBJECTIVE: To evaluate the presence and percentage of CSF AD-like patterns (high CSF tau/Aβ42 ratio) in patients with atypical dementias in order to identify an ongoing AD neurodegenerative process. METHODS: One hundred seventy two consecutive patients fulfilling current clinical criteria for behavioural variant FTD (bvFTD, n = 73), agrammatic variant of Primary Progressive Aphasia (avPPA, n = 19), semantic variant of PPA (svPPA, n = 12), FTD-MND (n = 5), CBS (n = 42), PSP (n = 21) were recruited and underwent CSF analysis. CSF AD-like and non AD (nAD-like) patterns were identified. RESULTS: CSF AD-like pattern was reported in 6 out of 73 cases (8.2%) in the bvFTD group, in 3 out of 19 (15.8%) in the avPPA group, and in 7 out of 42 (16.7%) in the CBS group. One out of 12 (8.3%) of svPPA had CSF AD-like pattern. None of patients FTD-MND and PSP had CSF AD-like pattern. No differences in demographic characteristics were detected between subgroups in each phenotype. CONCLUSIONS: Our findings convey that the CSF tau/ Aβ42 ratio could be found in a proportion of cases with clinical bvFTD, avPPA and CBD. Detecting anon-going AD pathological process in atypical dementias has several implications for defining distinctive therapeutic approaches, guiding genetic screening and helping in patients’ selection in future clinical trials.

Right temporal variant frontotemporal dementia with motor neuron disease

Patterns of atrophy in frontotemporal dementia (FTD) correlate with the clinical subtypes of behavioral variant FTD (bvFTD), semantic dementia, progressive non-fluent aphasia (PNFA) and FTD with motor neuron disease (FTD-MND). Right temporal variant FTD is associated with behavioral dyscontrol and semantic impairment, with tau abnormalities more common in right temporal bvFTD and TDP-43 accumulation in right temporal semantic dementia. However, no clinical and anatomical correlation has been described for patients with predominant right temporal atrophy and FTD-MND. Therefore, we performed a database screen for all patients diagnosed with FTD-MND at Mayo Clinic and reviewed their MRI scans to identify those with striking, dominant, right temporal lobe atrophy. For cases with volumetric MRI we performed voxel based morphometry and for those with brain tissue we performed pathological examination. Of three such patients identified, each patient had different presenting behavioral and/or aphasic characteristics. MRI, including diffusion tensor imaging in one patient, and FDG positron emission tomography revealed striking and dominant right temporal lobe atrophy, right corticospinal tract degeneration, and right temporal hypometabolism. Archived brain tissue was available in two patients; both demonstrating TDP-43 type 3 pathology (Mackenzie scheme) with predominant neuronal cytoplasmic inclusions. In one case, neurofibrillary tangles (Braak V) and neuritic plaques were also present in keeping with a diagnosis of Alzheimer’s disease. There appears to be an association between FTD-MND and severe right temporal lobe atrophy. Until further characterization of such cases are determined, they may be best classified as right temporal variant FTD-MND.

Major Genetic Subtypes of Frontotemporal Dementia

To explore the genetics of frontotemporal dementia (FTD), researchers evaluated a large cohort of patients diagnosed with FTD-spectrum disorders at an academic dementia center in Rotterdam, the Netherlands. Among the 364 patients, major subgroups of FTD were behavioral-variant FTD in 246 patients, semantic dementia in 56, FTD with motor neuron disease (FTD-MND) in 25, and progressive …

Progranulin Leu271LeufsX10 is one of the most common FTLD and CBS associated mutations worldwide

Mutations in the progranulin gene ( PGRN) are a major cause of frontotemporal lobar degeneration (FTLD). Herein we estimated the contribution of the PGRN Leu271LeufsX10 mutation to FTLD and related disorders in the Brescia cohort. The PGRN Leu271LeufsX10 mutation was found in 31% of corticobasal syndrome (CBS), 29% of frontotemporal dementia with motorneuron disease (FTD-MND), 15% of behavioral variant frontotemporal dementia (FTD), 9.5% of primary progressive aphasia (PPA), 2% dementia with Lewy bodies and 0% of progressive supranuclear palsy and multiple system atrophy cases. The prevalence strongly increased in familial forms (75% CBS, 50% FTD-MND, 27% FTD, 18% PPA): in our cohort this mutation is a major disease determinant for FTLD-related disorders with a prominent motor component. MAPT haplotype was demonstrated to be a disease modifier in PGRN Leu271LeufsX10 carriers: in H1H2 subjects the disease onset was earlier than in H2H2 individuals. Sequencing of the whole PGRN gene disclosed a previously described mutation (c.2T > C, Met1X) and three novel ones (c.709-3; c.1011delG, His340ThrfsX21; c.1021C > T, Gln341X) in single families. In the Brescia cohort, while MAPT mutations have low prevalence, mutations in PGRN were shown in 28% of familial FTLD and 75% of familial CBS cases. The PGRN Leu271LeufsX10 mutation becomes one of the most common mutations worldwide, since it was identified in 38 patients belonging to 27 unrelated families.

Slow vertical saccades in the frontotemporal dementia with motor neuron disease

Ocular motor abnormalities play an important role in differential diagnoses of Pick complex diseases. We evaluated how frequently supranuclear vertical saccadic impairment was observed in patients with frontotemporal dementia with motor neuron disease (FTD-MND). In addition, we tried to characterize their vertical saccadic abnormalities. Eleven patients with FTD-MND were recruited. Supranuclear vertical saccadic impairment on gross examination was defined as slow saccades with or without reduction in the final amplitude of the movement accompanied by intact oculocephalic reflex. We also recorded their saccades in 6 out of 11 patients using 2-dimensional videooculography (VOG). We measured the amplitude and peak velocity of each saccade. On bedside examination, supranuclear vertical saccadic impairment was observed in 9 of 11 patients. One of the two remaining patients could not be evaluated due to poor cooperation and the other showed normal saccades. Five of nine patients with ocular abnormalities and one patient with normal saccade on gross examination underwent the VOG studies. The results showed that all the five patients with gross ocular abnormalities, compared with age-matched controls, had slowing of vertical saccades. Three out of five patients also showed slowing even in the large horizontal saccades. Our results showed that slow vertical saccades are common in FTDMND. FTD-MND could be another disease that affects vertical gaze among Pick complex disease. Future pathologic studies are needed to confirm the involvement of the burst neurons in the dorsal midbrain in patients with FTDMND.

Pattern of glucose hypometabolism in frontotemporal dementia with motor neuron disease

Frontotemporal dementia (FTD) often coexists with motor neuron disease (MND). To characterize glucose hypometabolism in patients with FTD with MND (FTD/MND), the authors compared the glucose metabolism of 8 patients with FTD/MND with that of 29 patients with FTD. All of the patients with FTD/MND showed glucose hypometabolism only in the frontal area, whereas most patients with FTD had hypometabolism in the frontal and temporal areas. FTD/MND also showed a more symmetric pattern of glucose hypometabolism than FTD.