Effect of abutment finish lines on the mechanical behavior and marginal fit of screw-retained implant crowns: An in vitro study.

STATEMENT OF PROBLEM: The design of the implant-abutment connection has been widely researched, but the impact of different crown-abutment geometries remains unclear. PURPOSE: The purpose of this in vitro study was to evaluate the effect of different crown-abutment margin geometries on the mechanical behavior and fit of screw-retained implant-supported single-crown restorations by using mechanical static and fatigue tests and mastication simulation. MATERIAL AND METHODS: A total of 45 cobalt-chromium premolar-shaped metal frameworks were fabricated for single-unit implant-supported screw-retained restorations on stock abutments and internal hexagon Ø4.25×11-mm cylindrical implants. They were divided into 3 groups according to margin geometry: S, shoulder; C, chamfer; and F, feather-edge. Three static load until fracture and 24 dynamic load tests were performed by using the International Organization for Standardization 14801:2016 standard (ISO 14801:2016) (number of cycles limit: 5×106 cycles, frequency: 6 Hz). The ProFatigue software program was used to optimize the procedure (S, n=12 specimens; C, n=7 specimens; and F, n=5 specimens). Six additional specimens from each group were subjected to a mastication simulation (limit number of cycles: 1×106 cycles, cyclic loading from Pmin=30 N to Pmax=300 N, frequency: 6 Hz). Results from the fatigue tests were reported descriptively, and the Fisher exact test was used to analyze the difference in failure modes. Data from maximum misfit were evaluated by photogrammetry and statistically analyzed with the Anderson-Darling test and the Kruskal-Wallis and Dunn multiple comparison tests (α=.05). RESULTS: The fatigue limit was 456 N for group S, 512 N for group C, and 514 N for group F. The mean ±standard deviation misfit was 2.6 ±0.1 µm for group S, 3.8 ±1.1 µm for group C, and 3.6 ±0.8 µm for group F. Differences in misfit between groups S and C and between groups S and F were statistically significant (P<.05). CONCLUSIONS: Crown-abutment connections with chamfer and feather-edge margins showed better mechanical behavior, while shoulder margin exhibited better fit. However, high levels of fit were achieved for all the evaluated geometries.

Probabilistic Assessment of Fracture Toughness of Epoxy Resin EPOLAM 2025 Including the Notch Radii Effect.

Many design scenarios of components made of polymer materials are concerned with notches as representative constructive details. The failure hazard assessment of these components using models based on the assumption of cracked components leads to over-conservative failure estimations. Among the different alternative approaches proposed that are based on the apparent fracture toughness, KcN is considered. In so doing, the current deterministic underlying concept must be replaced by a probabilistic one to take into account the variability observed in the failure results in order to ensure a reliable design. In this paper, an approach based on the critical distance principle is proposed for the failure assessment of notched EPOLAM 2025 CT samples with each different notch radii (ρ) including a probabilistic assessment of the failure prediction. First, each apparent fracture toughness is transformed into the equivalent fracture toughness for ρ=0 based on the critical distances theory. Then, once all results are normalized to the same basic conditions, a Weibull cumulative distribution function is fitted, allowing the probability of failure to be predicted for different notch radii. In this way, the total number of the specimens tested in the experimental campaign is reduced, whereas the reliability of the material characterization improves. Finally, the applicability of the proposed methodology is illustrated by an example using the own experimental campaign performed on EPOLAM 2025 CT specimens with different notch radii (ρ).

Effect of region-dependent viscoelastic properties on the TMJ articular disc relaxation under prolonged clenching.

The disc of the temporomandibular joint (TMJ) is located between the mandibular condyle and temporal bone, and has an important load-bearing and stress absorbing function. The TMJ disc presents viscoelastic characteristics that are largely dependent on its collagen fibre and proteoglycan composition and organization. The purpose of this study is to investigate the possible effects of region-specific dynamic viscoelastic properties on stress relaxation during prolonged clenching. Two finite element models were used to compare the stress distribution within the TMJ disc, namely, one with uniform disc material property and another one with region-specific disc material properties. Similar results were observed in both models with slight differences in the location of maximum stress. Larger stresses were observed in all cases for the model with uniform disc material property. Moreover, the higher values for the model with uniform disc material property appeared in the lateral region, while in the model with region-specific disc properties, these values moved to the lateral and central region. This investigation confirms that both models are sufficiently accurate to investigate stress distribution in the TMJ disc, and, particularly, the model with the region-specific disc material properties ensure better simulations of the TMJ disc behaviour.

Optimized Planning and Evaluation of Dental Implant Fatigue Testing: A Specific Software Application.

Mechanical complications in implant-supported fixed dental prostheses are often related to implant and prosthetic design. Although the current ISO 14801 provides a framework for the evaluation of dental implant mechanical reliability, strict adherence to it may be difficult to achieve due to the large number of test specimens which it requires as well as the fact that it does not offer any probabilistic reference for determining the endurance limit. In order to address these issues, a new software program called ProFatigue is presented as a potentially powerful tool to optimize fatigue testing of implant-supported prostheses. The present work provides a brief description of some concepts such as load, fatigue and stress-number of cycles to failure curves (S-N curves), before subsequently describing the current regulatory situation. After analyzing the two most recent versions of the ISO recommendation (from 2008 and 2016), some limitations inherent to the experimental methods which they propose are highlighted. Finally, the main advantages and instructions for the correct implementation of the ProFatigue free software are given. This software will contribute to improving the performance of fatigue testing in a more accurate and optimized way, helping researchers to gain a better understanding of the behavior of dental implants in this type of mechanical test.

Effects of loading direction in prolonged clenching on stress distribution in the temporomandibular joint.

Parafunctional habits, such as bruxism and prolonged clenching, have been associated with dysfunctional hyperactivity of the masticatory muscles, including the lateral pterygoid muscle. The resultant loading to the temporomandibular joint (TMJ) is subject to the degradation of bone, cartilage and disc in the TMJ. In this study, we examined the effect of clenching direction on the stress distribution in the TMJ. In this line, we hypothesised that asymmetrical clenching involved in parafunction might result in increased stresses on the TMJ disc as well as on the condylar and temporal articular surfaces. The distribution of stress for various directional loadings was analysed using a three-dimensional finite element model of the TMJ, with viscoelastic properties for the disc. The numerical results revealed that load direction influenced the amount and distribution of stresses on the disc surfaces. In particular, the lateral region of the disc suffered higher stress values. Moreover, the results showed a significant stress relaxation in the disc that revealed its capacity for stress energy dissipation. From the present study, it can be established that during prolonged clenching, the higher stresses are concentrated in the lateral region, which could imply that TMJ disorders related to damage or wear in the disc and the condylar cartilage, overall, occur when lateral dysfunctional displacements are present.

A Probabilistic Approach to Assessing and Predicting the Failure of Notched Components.

This work presents a probabilistic model to evaluate the strength results obtained from an experimental characterisation program on notched components. The generalised local method (GLM) is applied to the derivation of the primary failure cumulative distribution function (PFCDF) as a material property (i.e., independent of the test type, load conditions and specimen geometry selected for the experimental campaign), which guarantees transferability in component design. To illustrate the applicability of the GLM methodology, an experimental program is performed using specimens of EPOLAM 2025 epoxy resin. Three different samples, each with a specific notch geometry, are tested. As a first scenario, a single assessment of each sample is obtained and the PFCDFs are used to perform cross predictions of failure. Some discrepancies are noticeable among the experimental results and cross-failure predictions, although they are within the expected margins. A possible reason for the disagreement can be assigned to the inherent statistical variability of the results and the limited number of tests per each sample. As a second scenario, a joint assessment of the three samples is performed, from which a unique PFCDF is provided, according to the GLM. In the latter case, a more reliable assessment of the experimental results from the geometry conditions is achieved, the suitability of the selected driving force is verified, and the transferability of the present material characterisation is confirmed.

Viscoelastic properties of the central region of porcine temporomandibular joint disc in shear stress-relaxation.

In this study, shear relaxation properties of the porcine temporomandibular joint (TMJ) disc are investigated. Previous studies have shown that, in fatigue failure and damage of cartilage and fibrocartilage, shear loads could be one of the biggest contributors to the failure. The aim of the present study is to develop an evaluation method to study shear properties of the disc and to do a mathematical characterization of it. For the experiments, twelve porcine discs were used. Each disc was dissected from the TMJ and, then, static strain control tests were carried out to obtain the shear relaxation modulus for the central region of the discs. From the results, it was found that the disc presents a viscoelastic behavior under shear loads. Relaxation modulus decreased with time. Shear relaxation was 10% of the instantaneous stress, which implies that the viscous properties of the disc cannot be neglected. The present results lead to a better understanding of the discs mechanical behavior under realistic TMJ working conditions.

Dynamic and stress relaxation properties of the whole porcine temporomandibular joint disc under compression.

In this study, the dynamic and static compressive properties of the whole porcine temporomandibular joint (TMJ) disc were investigated. The aim of the study was to develop a new simple method for the evaluation of joint viscoelasticity, enabling examination of the load-bearing capacity and joint flexibility of the entire disc. For the experiments, a novel testing fixture that reproduces the condylar and fossa surfaces of the TMJ was developed to replicate TMJ disc geometry. Ten porcine discs were used in the experiments. Each disc was dissected from the TMJ and sinusoidal compressive strain was applied to obtain the storage and loss moduli. Static strain control tests were carried out to obtain the relaxation modulus. The result of static and dynamic tests indicated that the whole disc presented viscoelastic behavior under compression. Storage and loss moduli increased with frequency and the relaxation modulus decreased over time. The loss tangent showed less frequency dependence, with values ranging from 0.2 to 0.3, suggesting that the viscous properties of the disc cannot be neglected. These results provide a better understanding of whole disc mechanical compression behavior under realistic TMJ working conditions.

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Multiple organ involvement by alpha-synuclein pathology in Lewy body disorders.

Lewy body (LB) diseases are characterized by alpha-synuclein (AS) aggregates in the central nervous system (CNS). Involvement of the peripheral autonomic nervous system (pANS) is increasingly recognized, although less studied. The aim of this study was to systematically analyze the distribution and severity of AS pathology in the CNS and pANS. Detailed postmortem histopathological study of brain and peripheral tissues from 28 brain bank donors (10 with Parkinson's disease [PD], 5 with dementia with LB [DLB], and 13 with non-LB diseases including atypical parkinsonism and non-LB dementia). AS aggregates were found in the pANS of all 15 LB disease cases (PD, DLB) in stellate and sympathetic ganglia (100%), vagus nerve (86.7%), gastrointestinal tract (86.7%), adrenal gland and/or surrounding fat (53.3%), heart (100%), and genitourinary tract (13.3%), as well as in 1 case of incidental Lewy body disease (iLBD). A craniocaudal gradient of AS burden in sympathetic chain and gastrointestinal tract was observed. DLB cases showed higher amounts of CNS AS aggregates than PD cases, but this was not the case in the pANS. No pANS AS aggregates were detected in Alzheimer's disease (AD) cases with or without CNS AS aggregates. All pathologically confirmed LB disease cases including 1 case of iLBD had AS aggregates in the pANS with a craniocaudal gradient of pathology burden in sympathetic chain and gastrointestinal tract. AS was not detected in the pANS of any AD case. These findings may help in the search of peripheral AS aggregates in vivo for the early diagnosis of PD.

A common BACE1 polymorphism is a risk factor for sporadic Creutzfeldt-Jakob disease.

The ß site APP cleaving enzyme 1 (BACE1) is the rate-limiting ß-secretase enzyme in the amyloidogenic processing of APP and Aß formation, and therefore it has a prominent role in Alzheimer's disease (AD) pathology. Recent evidence suggests that the prion protein (PrP) interacts directly with BACE1 regulating its ß-secretase activity. Moreover, PrP has been proposed as the cellular receptor involved in the impairment of synaptic plasticity and toxicity caused by Aß oligomers. Provided that common pathophysiologic mechanisms are shared by Alzheimer's and Creutzfeldt-Jakob (CJD) diseases, we investigated for the first time to the best of our knowledge a possible association of a common synonymous BACE1 polymorphism (rs638405) with sporadic CJD (sCJD). Our results indicate that BACE1 C-allele is associated with an increased risk for developing sCJD, mainly in PRNP M129M homozygous subjects with early onset. These results extend the very short list of genes (other than PRNP) involved in the development of human prion diseases; and support the notion that similar to AD, in sCJD several loci may contribute with modest overall effects to disease risk. These findings underscore the interplay in both pathologies of APP, Aß oligomers, ApoE, PrP and BACE1, and suggest that aging and perhaps vascular risk factors may modulate disease pathologies in part through these key players.

Genetic variability of the gene cluster CALHM 1-3 in sporadic Creutzfeldt-Jakob disease.

Perturbations of calcium homeostasis have been associated with several neurodegenerative disorders. A common polymorphism (rs2986017) in the CALHM1 gene, coding for a regulator of calcium homeostasis, is a genetic risk factor for the development of Alzheimer disease (AD). Although some authors failed to confirm these results, a meta-analysis has shown that this polymorphism modulates the age at disease onset. Furthermore, a recent association study has explored the genetic variability of CALHM1 gene and two adjacent paralog genes (CALHM3 and CALHM2) in an Asian population. Since several lines of evidence suggest that AD and prion diseases share pathophysiologic mechanisms, we investigated for the first time the genetic variability of the gene cluster formed by CALHM1 and its paralogs in a series of 235 sporadic Creutzfeldt-Jakob disease (sCJD) patients, and compared the genotypic and allelic frequencies with those presented in 329 controls from the same ancestry. As such, this work also represents the first association analysis of CALHM genes in sCJD. Sequencing analysis of the complete coding regions of the genes demonstrated the presence of 10 single nucleotide polymorphisms (SNP) within the CALHM genes. We observed that rs4918016-rs2986017-rs2986018 and rs41287502-rs41287500 polymorphic sites at CALHM1 were in linkage disequilibrium. We found marginal associations for sCJD risk at CALHM1 polymorphic sites rs41287502 and rs41287500 [coding for two linked missense mutations (p.(Met323Ile); (Gly282Cys)], and rs2986017 [p.(Leu86Pro)]. Interestingly, a TGG haplotype defined by the rs4918016-rs2986017-rs2986018 block was associated with sCJD. These findings underscore the need of future multinational collaborative initiatives in order to corroborate these seminal data.

Phenotypic variability within the inclusion body spectrum of basophilic inclusion body disease and neuronal intermediate filament inclusion disease in frontotemporal lobar degenerations with FUS-positive inclusions.

Basophilic inclusion body disease and neuronal intermediate filament inclusion disease (NIFID) are rare diseases included among frontotemporal lobar degenerations with FUS-positive inclusions (FTLD-FUS). We report clinical and pathologic features of 2 new patients and reevaluate neuropathologic characteristics of 2 previously described cases, including an early-onset case of basophilic inclusion body disease (aged 38 years) with a 5-year disease course and abundant FUS-positive inclusion bodies and 3 NIFID cases. One NIFID case (aged 37 years) presented with early-onset psychiatric disturbances and rapidly progressive cognitive decline. Two NIFID cases had later onset (aged 64 years and 70 years) and complex neurologic deficits. Postmortem neuropathologic studies in late-onset NIFID cases disclosed α-internexin-positive "hyaline conglomerate"-type inclusions that were positive with 1 commercial anti-FUS antibody directed to residues 200 and 250, but these were negative to amino acids 90 and 220 of human FUS. Early-onset NIFID had similar inclusions that were positive with both commercial anti-FUS antibodies. Genetic testing performed on all cases revealed no FUS gene mutations. These findings indicate that phenotypic variability in NIFID, including clinical manifestations and particular neuropathologic findings, may be related to the age at onset and individual differences in the evolution of lesions.

"Preclinical" MSA in definite Creutzfeldt-Jakob disease.

Multiple system atrophy (MSA) is a sporadic alpha-synucleinopathy clinically characterized by variable degrees of parkinsonism, cerebellar ataxia and autonomic dysfunction. The histopathological hallmark of MSA is glial cytoplasmic inclusion (GCI). It is considered to represent the earliest stage of the degenerative process in MSA and to precede neuronal degeneration. Sporadic Creutzfeldt-Jakob disease (sCJD) is a fatal, rapidly progressive dementia generally associated with ataxia, pyramidal and extrapyramidal symptoms and myoclonus. Definite diagnosis needs neuropathological demonstration of variable degrees of spongiform degeneration of neuropil, neuronal loss, astro- and microgliosis, and the presence of abnormal deposits of the misfolded prion protein PrP(res) . Both diseases, CJD and MSA are infrequent among neurodegenerative diseases. In the present report we describe clinical and neuropathological findings of a previously healthy 64-year-old woman who developed symptoms of classical CJD. At post mortem examination, the brain showed in addition to classical methionine/methionine PrP(res) type 1 (MM1) sCJD changes and moderate Alzheimer-type pathology, features of "preclinical" MSA with minimal histopathological changes. These were characterized by discrete amounts of alpha-synuclein immunoreacive glial cytoplasmic inclusions in the striato-nigral system, isolated intraneuronal inclusions in pigmented neurons of the substantia nigra, as well as some vermiform intranuclear inclusions. To our knowledge, this is the first report on the coexistence of definite sCJD and "minimal changes" MSA in the same patient.

Genetic cross-interaction between APOE and PRNP in sporadic Alzheimer's and Creutzfeldt-Jakob diseases.

Alzheimer's disease (AD) and Creutzfeldt-Jakob disease (CJD) represent two distinct clinical entities belonging to a wider group, generically named as conformational disorders that share common pathophysiologic mechanisms. It is well-established that the APOE ε4 allele and homozygosity at polymorphic codon 129 in the PRNP gene are the major genetic risk factors for AD and human prion diseases, respectively. However, the roles of PRNP in AD, and APOE in CJD are controversial. In this work, we investigated for the first time, APOE and PRNP genotypes simultaneously in 474 AD and 175 sporadic CJD (sCJD) patients compared to a common control population of 335 subjects. Differences in genotype distribution between patients and control subjects were studied by logistic regression analysis using age and gender as covariates. The effect size of risk association and synergy factors were calculated using the logistic odds ratio estimates. Our data confirmed that the presence of APOE ε4 allele is associated with a higher risk of developing AD, while homozygosity at PRNP gene constitutes a risk for sCJD. Opposite, we found no association for PRNP with AD, nor for APOE with sCJD. Interestingly, when AD and sCJD patients were stratified according to their respective main risk genes (APOE for AD, and PRNP for sCJD), we found statistically significant associations for the other gene in those strata at higher previous risk. Synergy factor analysis showed a synergistic age-dependent interaction between APOE and PRNP in both AD (SF = 3.59, p = 0.027), and sCJD (SF = 7.26, p = 0.005). We propose that this statistical epistasis can partially explain divergent data from different association studies. Moreover, these results suggest that the genetic interaction between APOE and PRNP may have a biological correlate that is indicative of shared neurodegenerative pathways involved in AD and sCJD.

Rapidly progressive diffuse Lewy body disease.

BACKGROUND: Lewy body syndromes (mainly Parkinson's disease and dementia with Lewy bodies) share many clinical features and usually have a slowly progressive course. Some patients may show rapid symptoms progression. OBJECTIVE: To evaluate clinical and neuropathological features of patients with a rapidly progressive diffuse Lewy Body disease. METHODS: Review clinical records and pathological findings of 6 cases with diffuse Lewy Body disease and rapid disease progression (less than 18 months before death). RESULTS: Mean age at disease onset was 72.5 years, and mean disease duration was 9 months. Onset consisted of delirium in 3 patients and rapidly progressive dementia in the other three. All cases presented visual hallucinations and delusions; cognitive symptoms were fluctuating in two, parkinsonism occurred in four, and myoclonus in three. Brain MRI did not show cortical or basal ganglia hyperintensities. Periodic sharp waves were absent on EEG. 14.3.3 protein in CSF was negative. Myocardial (123) I-metaiodo-benzyl-guanidine SPECT showed marked reduction in tracer uptake in the 2 patients tested. Neuropathological studies did not identify any particular feature that could differentiate rapidly progressive diffuse Lewy body disease from classical diffuse Lewy body disease. CONCLUSIONS: Diffuse Lewy body disease is a possible cause of rapidly progressive dementia and should be included in the differential diagnosis of confusional states of undetermined cause. In patients with rapidly progressive dementia, the presence of fluctuating cognition, parkinsonism, hallucinations, delusions, or severe dysautonomia, should raise the suspicion of diffuse Lewy body disease. Neuroimaging studies such as (123) I-metaiodo-benzyl-guanidine myocardial scintigraphy may support the clinical diagnosis of diffuse Lewy body disease. © 2011 Movement Disorder Society.

G2019S LRRK2 mutation causing Parkinson's disease without Lewy bodies.

The G2019S leucine-rich repeat kinase 2 gene (LRRK2) mutation has been identified in a significant proportion of familial and sporadic cases of Parkinson's disease (PD). Until now, information on the neuropathological changes associated with the G2019S LRRK2 mutation has been sparse. We report a 77-year-old patient who presented with a 14 year history of PD but, unexpectedly, histopathological examination disclosed mild neuronal loss in the substantia nigra without α-synuclein, tau or ubiquitin cytoplasmic inclusions. A G2019S LRRK2 mutation was eventually detected. The present case confirms that clinical PD caused by G2019S mutations can be associated with non-specific nigral degeneration without Lewy.

Screening for the LRRK2 G2019S and codon-1441 mutations in a pathological series of parkinsonian syndromes and frontotemporal lobar degeneration.

BACKGROUND: The neuropathology associated with LRRK2 mutations is heterogeneous but Lewy body (LB) type pathology is the most common substrate encountered. While the prevalence of LRRK2 mutations has been extensively studied in Parkinson's disease (PD), limited information is available on the frequency of LRRK2 mutations in dementia with Lewy bodies (DLB) and in other pathological conditions associated with these mutations, such as non-specific nigral degeneration without LB, tau-immunopositive neurofibrillary tangle pathology, and ubiquitin-positive neuronal inclusions resembling those observed in a subtype of frontotemporal lobar degeneration (FTLD-U). OBJECTIVE: To further investigate the neuropathology associated with LRRK2 mutations. METHODS: We have screened for the LRRK2 G2019S and codon-1441 (R1441G/C/H) mutations in 110 cases from a Spanish Brain Bank, which include: 66 synucleinopathies (33 PD, 25 DLB and 8 multiple system atrophy cases), 29 tauopathies (21 progressive supranuclear palsy, 3 corticobasal degeneration and 5 tau-positive FTLD cases), 3 cases of non-specific nigral degeneration and 12 tau-negative FTLD (9 FTLD-U and 3 dementia lacking distinctive histology cases). RESULTS: The G2019S mutation was found in two cases: One case had a clinical and pathological diagnosis of PD and the other suffered from typical PD and on neuropathological examination had non-specific nigral degeneration without LB. A synonymous variant (R1441R; c.4323C>T) was detected in another PD case. CONCLUSIONS: In this brain bank-based series, LRRK2 G2019S mutation occurred in patients with parkinsonism associated with either typical brainstem LB pathology or non-specific nigral degeneration. LRRK2 mutations were not encountered in other neurodegenerative disorders associated with synuclein and tau deposition.

Clinicopathological and genetic correlates of frontotemporal lobar degeneration and corticobasal degeneration.

OBJECTIVE: To correlate clinical diagnosis and genetic features with different pathological substrates in patients with frontotemporal lobar degeneration (FTLD) and corticobasal degeneration (CBD). METHODS: 32 cases with pathological proven FTLD or CBD were selected. Patients were classified clinically as frontotemporal dementia (FTD), progressive nonfluent aphasia (PNFA), semantic dementia (SD), CBD or FLTD with motor neuron disease (FLTDMND). Coding exons 1 and 9-13 of MAPT and exons 0-12 of the PGRN gene were screened by direct sequencing. Regarding the neuropathological findings, cases were classified as tau-positive, ubiquitinpositive tau-negative (FTLD-U), neuronal intermediate filaments inclusions disease (NIFID), dementia lacking distinctive histology (DLDH) or CBD. RESULTS: 17 patients were clinically diagnosed with FTD. Ten showed tau pathology, 3 FTLD-U, 1 NIFID and 3 DLDH. All patients clinically classified as FTLD-MND (6 patients) or SD (3 patients) were FTLD-U. Tau-positive pathology was the substrate of the three patients with PNFA. All three patients classified clinically as CBD presented neuropathologic features of CBD. The three individuals with familial history of early onset FTD and tau-positive pathology carried the P301L mutation in the MAPT gene. One out of 3 cases with FTLD-U and intranuclear inclusions carried a mutation in the PGRN gene. CONCLUSIONS: We found that pathology underlying sporadic FTD is heterogeneous and not predictable. MAPT mutations and clinical diagnosis of PNFA and CBD were associated with tau-positive pathology. The presence of signs of lower MND and SD correlated with FTLD-U.A genetic study of MAPT is only recommended when familial history of early onset DFT is present.