Last updated: August 22, 2019
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The term Frontotemporal lobar devolution describes a pathological procedure that selectively affects the frontal and temporal cerebral mantles, while the different clinical syndromes that result from this neurodegenerative procedure is now frequently referred to as Frontotemporal Dementia or FTD ( Josephs 2008, Seelaar et Al. 2011 ) .FTD can be divided in two chief groups harmonizing to the prevailing clinical characteristics at the oncoming of the disease: a behavioral discrepancy ( bv-FTD ) characterised by early, outstanding behavioural and personality alterations, and a discrepancy characterised by a progressive linguistic communication upset frequently referred to as Primary Progressive Aphasia or PPA ( Mesulam 2003 ; Grossman 2010 ) . The latter have been traditionally subdivided in two clinical syndromes: Semantic Dementia ( SD ) and Progressive Non-Fluent Aphasia ( PFNA ) . In recent old ages, a 3rd subcategory has been described, termed Logopenic Progressive Aphasia or LPA ( Gorno-Tempini et al. 2008 ) .

In contrast to other neurodegenerative upsets, such as Alzheimer ‘s disease ( AD ) , the neuropathology of FTLD is heterogenous. There is besides a considerable convergence with extrapyramidal upsets, particularly Progressive Supranuclear Palsy ( PSP ) and Corticobasal Degeneration ( CBD ) , and with Motor nerve cell upsets such as Amyotrophic Lateral Sclerosis ( Kovari 2009 ) .The first subdivision will give a general model of the current apprehensions of the pathology and genetic sciences of FTLD, followed by the clinical and imaging findings of each of the clinical syndromes. Finally, the correlativities between the neuropathological informations and the latter syndromes will be reviewed.

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Pathology and Genetics of FTLD – Overview

The pathology of FTLD is characterised by focal wasting of the frontlet and temporal lobes macroscopically ; and neural loss, gliosis and spongiosis on microscopic scrutiny ( Cairns et al. 2007 ; Kovari 2009 ) . Advancement made in the Fieldss of molecular pathology and genetic sciences have helped in the apprehension and pathological categorization of FTLD. The current categorization divides it into three chief groups harmonizing to the type of proteins found as intracellular inclusions in neural cells ( Cairns et al.

2007, Seelaar et Al. 2011 ) :FTLD-Tau: Tau-positive inclusions ( inclusions incorporating the microtubule-associated protein Tau ) . Tau deposits contain either a three-repeat discrepancy ( 3R-Tau ) , a four-repeat ( 4R-Tau ) or a mixture of both ( 3R/4R-Tau ) ; different neuropathological entities are associated with each of this three subtypes ( Figure 2 ) :3R-Tau: Pick ‘s disease ( i.e.

FTLD with intraneuronal argyrophilic inclusions or “ Pick organic structures ” ) .4R-Tau: PSP, CBD, and much rarer Argyrophilic Grain Disease ( AGD ) and Multiple System Tauopathy with Dementia ( MSTD ) .3R/4R-Tau: Neurofibrillary tangle dementednessMAPT mutants: Mutants in the Microtubule-Associated Protein Tau ( MAPT ) cistron have been linked to any of the above discrepancies.FTLD-U: Ubiquitin positive ( Tau negative ) inclusions. These inclusions are composed of different proteins, of which the major constituent is one called TDP-43, which stands for TAR DNA-binding Protein 43 ( Cairns et al.

2007 ) . This group is hence divided in two subcategories:TDP-43 ( + ) : positive for TDP-43, and classified into four groups ( Sampathu et al. 2006 ) harmonizing to the form of distribution of the inclusions and the morphological alterations in nerve cells ( Fig 2 ) .TDP-43 ( – ) : represents merely 5-20 % of FTLD-U, and the major component of these instances is a protein called Fused in Sarcoma or FUS ( Urwin et al. 2010 ) .A subgroup that is negative for both TDP-43 and FUS has been late described, and labelled as FTLD-UPS ( Seelaar et al. 2011 ) .

The latter has been so far associated in the huge bulk of instances with mutants in the CHMBP2B cistron ( Urwin et al. 2010 ) .Dementia Lacking Distinctive Histology ( DLDH ) : is a descriptive term used when there is grounds of frontal and temporal lobe wasting without lesions in hematoxylin-eosin, Ag discoloration and all immunohistochemistry ( Josephs 2008 ) .The realization that between 10-20 % of instances have a strong familial constituent led to the find of familial mutants associated with the development of FTD ( Leyton & A ; Hodges 2010 ) . The relationship is stronger for certain clinical subtypes such as bv-FTD and FTD-MND. For practical intents, around half of the familiar instances are due to mutants in two cistrons, both located on chromosome 17:Microtubule associated protein tau ( MAPT ) : Mutants in MAPT can give rise either a clinical image resembling extrapyramidal upsets i.e.

FTD with paralysis agitans linked to chromosome 17 ( FTDP-17 ) , or bv-FTD ( Seelaar et al. 2011 ) .Progranulin ( PGRN ) : Mutants in PGRN are comparatively frequent, and are associated with the clinical phenotypes of bv-FTD, PNFA, LPA and CBD ( Pickering-Brown 2010 ) .

Other cistrons have been associated, albeit less often, with familial signifiers of FTD ( Seelaar et al. 2011 ) :Valosin incorporating protein ( VCP ) – chromosome 9Charged multivesicular organic structure protein 2 B ( CHMBP2B ) – chromosome 3TAR-DNA binding protein ( TARDP ) – chromosome 1Fused in Sarcoma ( FUS ) – chromosome 16FTLDFTLD-TauTau ( + )FTLD-UUbiquitin ( + ) , Tau ( – )3R-Tau4R-Tau3R/4R-TauTDP-43 ( + )TDP-43 ( – )Type 1: abundant dystrophic neurites ( SD )Type 2: neural cytoplasmatic inclusions ( FTD-MND )Type 3: neural intranuclear and cytoplasmatic inclusions ( PGRN )Type 4: intranuclear inclusions ( VCP )FUS ( + )FUS ( – )( Pick ‘s Disease )( PSP, CBD, AGD, MSTD )( MAPT mutants )( CHMP2B mutant ) sFigure 2. Pathological categorization of Frontotemporal lobar devolution ( FTLD ) . The two major catagories are those Ubiquitin-positive ( FTLD-U ) and Tau-positive ( FTLD-Tau ) . Each subcategory is associated with certain clinical syndromes ( shown in brackets ) . TDP-43 = TAR DNA-binding protein 43, PSP = Progressive supranuclear paralysis, CBD = Corticobasal devolution, AGD = Argyrophilic grain disease, MSTD = Multiple system tauopathy with dementedness, MAPT = Microtubule associated protein Tau cistron, SD = Semantic Dementia, MND = Motor nerve cell disease, PGRN = Progranulin cistron, VCP = Valosin incorporating protein cistron, FUS = Fused in Sarcoma, CHMP2B = Charged multivesicular organic structure protein 2B.

Frontotemporal lobar devolution – Clinical Syndromes

Behavioural discrepancy of FTD ( Bv-FTD )

ClinicalThe behavioral discrepancy of FTD is characterised by pronounced alterations in personality and behavior, taking to a profound break in societal operation and interpersonal relationships ( Piguet et al. 2011a ; Seelar et Al.

2011 ) . These alterations are sometimes so profound that relations and friends describe that the patient “ is non himself any longer ” . The oncoming is frequently insidious and, since cognitive shortages are elusive, the clinical image can be at first mistaken with neuropsychiatric upsets ( Leyton & A ; Hodges 2010 ) .

Although many of the clinical characteristics are non specific for bv-FTD, it is their predomination in early phases of the disease what helps to separate this entity from other types of dementedness, such as AD ( Piguet et al. 2011a ) . Other cognitive maps e.g.

visuospatial abilities and linguistic communication are comparatively preserved ( Piguet et al. 2011a ) ; saving of episodic memory remains controversial in visible radiation of recent grounds ( Hornberger et al. 2010 ; Pennington, Hodges & A ; Hornberger 2011 ) .The clinical image is dominated by a configuration of behavioral and cognitive perturbations which chiefly reflect damage of different frontal lobe maps, such as societal knowledge, emotion processing, motive and executive maps:Apathy: this is a frequent determination, and is normally manifested as loss of involvement in old activities, avocations and societal activities, reduced verbal and motor end product, loss of motive and volitional thrust, deficiency of personal hygiene.

Disinhibition: this is besides a really common symptom and normally coexists with apathy ( Rabinovici & A ; Miller 2010 ) . It is manifested by inappropriate remarks and/or sexual comments, infantile behavior, discourtesy, crossness and even aggressiveness.Impulsivity: pathological gaming, inordinate disbursement, foolhardy behavior ( e.g. while driving ) , shoplifiting, or even physical assault.

Repetitive/stereotyped behavior, reflected by perseveration, ritualistic behavior, rolling, irresistible impulses, stashing and utilisation behavior.Emotional blunting/lack of empathy: jobs in emotion processing and acknowledgment ( particularly for negative emotions ) , disinterest in interpersonal relationships, selfishness, and impaired perceptual experience of others ‘ ideas or emotional provinces ( i.e. theory of head ) .Changes in eating behavior: compulsive nutrient consumption, increased penchant for Sweets ( “ sweet tooth ” ) . These alterations are thought to be related non merely with orbitofrontal circuits ( Seelaar et al. 2011 ) but besides with hypothalamic dysregulation ( Piguet et al.

2011b ) .Impaired penetration: sing the nature of the disease, its behavioral symptoms and their effects in their planetary operation.Cognitive disfunction: rigidness of idea, be aftering troubles, shortages in attending and working memory, concrete thought,The presence of hallucinations and other symptoms of psychosis are comparatively rare in bv-FTD, except in those instances associated with Motor Neurone Disease ( bv-FTD/MND ) and instances linked to mutants in the FUS cistron ( Piguet et al. 2011a ) .A set of clinical standards has been developed which emphasise the nucleus clinical facets of the disease ( Table 1 ) every bit good as imagination and familial biomarkers ( Rascovsky, Hodges & A ; Kipps 2007 ; Seelaar et Al.

2011 ) ; farther research is needed to find their cogency in the clinical scene ( Piguet et al. 2011a ) .ImagingThe imaging findings in bv-FTD include ab initio wasting of the frontal lobe, particularly the orbitofrontal and median parts, insular and anterior cingulate cerebral mantle ( Piguet et al. 2011a, Seelaar et Al.

2011 ) . Other parts involved are the hippocampus, amygdalar composite, thalamus and basal ganglia ( Piguet et al. 2011a ) . These alterations may be subtle at presentation, and therefore normal structural imagination does non govern out the diagnosing.

As the disease progresses, atrophy extends to other countries such as the sidelong part of the frontal cerebral mantle, the temporal lobe and anterior parietal parts ( Seelaar et al. 2011 ) . There are some radiological forms suggestive of the likely implicit in pathology: bilateral engagement of the dorsolateral prefrontal cerebral mantle ( DLPC ) suggests Pick ‘s disease ( Whitewell et al. 2005 ) , while outstanding caudate wasting has been correlated with FUS pathology ( Seelaar et al. 2011 ) . In add-on, there seems to be a correlativity between prevailing right temporal wasting and Tau pathology, and left temporal wasting and TDP histopathology ( Whitwell et al. 2005 ) . Functional surveies such as Positron Emission Tomography ( PET ) and Single Photon Emission Computed Tomography ( SPECT )Table 1- Proposed International consensus standards for bv-FTDPossible bv-FTDThree of these characteristics must be present throughout the class of the disease:Early on ( 3 old ages ) A A disinhibitionEarly on ( 3 old ages ) apathy or inertiaEarly on ( 3 old ages ) loss of understanding or empathyEarly on ( 3 old ages ) perseverative, stereotyped, or compulsive/ritualistic behaviorHyperorality and dietetic alterationsNeuropsychological profile: executive map shortages with comparative sparing of memory and visuospatial mapsProbable bv-FTDAll the undermentioned standards must be present to run into diagnosing:Meets standards for possible bv-FTDSignificant functional diminutionImaging consequences consistent with bv-FTD ( frontal and/or anterior temporalA atrophyA on CT or MRI or frontal hypoperfusion or hypometabolism on SPECT or PET )Definite bv-FTDCriteria A and either B or C must be present to run into diagnosing:Meets standards for possible or likely bv-FTDHistopathological grounds ofA FTLDA on biopsy at postmortemPresence of a known infective mutantExclusion standards for bv-FTDCriteria A and B must be absent ; C can be positive merely for possible bv-FTD:Pattern of shortages is better accounted for by other non-degenerative nervous system or medical upsetsBehavioral perturbation is better accounted for by a psychiatric diagnosingBiomarkers strongly declarative of Alzheimer ‘s disease or other neurodegenerative procedureAdapted from ( Piguet et al.

2011a )

Semantic Dementia ( SD )

ClinicalSemantic dementedness is characterised by a loss of cognition or significance of words, objects, facts and people, and therefore differs from other upsets in which the shortage is in lexical retrieval or motor address ( Leyton & A ; Hodges 2010 ) . The latter procedure leads to a progressive poverty in vocabulary, particularly for low frequence words, every bit good as a inclination to use more familiar and broader footings for calling objects ( e.g.

“ thing ” or “ carnal ” ) . The first jobs noticed by patients are word happening troubles and naming, and hence they tend to kick ab initio of “ memory troubles ” . There is an increased trust on periphrasiss to account for these shortages ( Hodges & A ; Patterson 2007 ; Seelaar et Al.

2011 ) . The loss of semantic cognition is besides reflected by a lessened public presentation in single-word comprehension trials ( Kertesz et al. 2010 ; Seelaar et Al. 2011 ) . Semantic shortages are non restricted to linguistic communication and can impact other modes, e.

g. ocular and ( Gorno-Tempini et al. 2011 ) . A dramatic characteristic of SD, which is besides really utile in clinical appraisal, is the presence of “ surface dyslexia ” i.e. the words are read by general regulations of pronunciation and non by their significance ( Leyton & A ; Hodges 2010 ) . Speech eloquence, articulation, inflection, repeat and sentence structure are preserved every bit good as executive and visuospatial accomplishments ( Rabinovici & A ; Miller 2010 ) . Patients with besides SD tend to hold behavioral symptoms similar to bv-FTD ( Seelaar et al.

2011 ) , peculiarly those instances with prevailing right temporal wasting ( Rabinovici & A ; Miller 2010 ) . The latter group are besides prone to develop prosopagnosia, altered eating penchants and sleep upsets ( Josephs et al. 2009 ; Rabinovici & A ; Miller 2010 ) .ImagingMRI Imaging shows bilateral wasting of the anterior pole of the temporal lobe ( normally left more than right ) , anterior hippocampus and amygdaloid nucleus ( Hodges & A ; Patterson 2007 ) . Other countries often affected include the entorhinal cerebral mantle, the inferior temporal and spindle-shaped convolution ( Seelaar et al. 2011 ) .

The wasting of the anterior portion of the left temporal lobe seems to be more marked in instances with Ubiquitin positive pathology ( Rohrer et al. 2009 ) , while outstanding hippocampal wasting is normally associated with AD pathology ( Rohrer & A ; Fox 2009 ) . As with other linguistic communication discrepancies, these alterations spread to frontal lobe constructions with increase badness of the disease. There is besides a correlativity between the alterations seen in structural imagination and parts of hypometabolism in functional surveies such as PET ( Hodges & A ; Patterson 2007 ) .

Progressive Non-Fluent Aphasia ( PNFA )

ClinicalThis discrepancy has a less homogenous clinical image than SD, although some characteristics are rather typical. In contrast to SD, patients with PNFA have marked damage in speech articulation and induction ( speech apraxia ) and shortages in sentence building and correct usage of grammatical regulations ( agrammatism ) , with comparative saving of individual word comprehension and semantic cognition. Speech end product is slow, non-fluent, hesitating and disprosodic ; these changes are peculiarly apparent during self-generated address ( Grossman 2010, Rabinovici & A ; Miller 2010 ) . Agrammatism is reflected by inappropriate sentence structure, wrong usage of tenses and skip of articles, subsidiary verbs and prepositions i.

e. “ telegraphic address ” ( Henry & A ; Gorno-Tempini 2010 ) . Both address apraxia and agrammatism are besides apparent during reading and composing, severally. Other shortages include phonemic mistakes, nominal aphasia ( with preserved semantic cognition ) and impaired repeat. Behavioral perturbations and cognitive shortages ( particularly in multitasking and working memory ) might besides develop, though less frequently than bv-FTD and SD ( Grossman 2010 ) .There is frequently an convergence with extrapyramidal upsets such as Progressive Supranuclear Palsy ( PSP ) and Cortico-Basal Degeneration ( CBD ) ; therefore the neurological scrutiny might uncover characteristics consistent with these entities, such as apraxia, myoclonus, or supranuclear regard paralysis ( Josephs 2008 ) .

As with other FTD discrepancies, there is besides increased association with Motor Neurone Disease.PNFA – ImaginationImaging ab initio reveals wasting of the anterior perisylvian country of the left hemisphere ; the anterior insular cerebral mantle and left inferior frontal lobe are besides peculiarly affected ( Seelaar et al. 2011 ) . As the disease progresses, alterations extend to other countries, such as the DLPC, mesial frontal lobe constructions, anterior parietal lobe, and superior/middle temporal convolution ( Grossman 2010 ) . Although instance series with pathological and radiological correlativity are light, there seems to be a nexus between some imagination forms and pathology.

PFNA instances with inferior frontlet and superior temporal wasting have been linked to tau pathology ( Rohrer et al. 2009 ) , and

Logopenic Progressive Aphasia ( LPA )

ClinicalThis class was ab initio devised to depict those patients with a progressive linguistic communication upset who did non suit one either SD or PNFA ( Leyton & A ; Hodges 2010 ) . The most outstanding clinical characteristics are: awkwardness and decrease of address end product, word determination intermissions and calling shortages, impaired repeat and phonemic mistakes ( Henry & A ; Gorno-Tempini 2010 ; Seelar et Al. 2011 ) . LPA differs from PNFA in that motor facets of address and grammar are preserved ; whereas the major differentiation from SD is that single-word comprehension is spared ( Gorno-Tempini et al. 2011 ) . Nevertheless, patients normally have jobs to understand long, complex sentences and bids ; this has been linked to shortages in the working memory system ( Gorno-Tempini et al.

2008 ) . There are besides descriptions of troubles in practice, computation and episodic memory ( Gorno-Tempini et al. 2011 )ImagingThe most outstanding alterations occur in the left hemisphere, particularly the posterior facets of temporal lobe, and the inferior parietal lobe ( Henry & A ; Gorno-Tempini 2010 ) . The superior and in-between temporal convolutions are peculiarly affected ( Leyton & A ; Hodges 2010 ) . These abnormalcies in the temporo-parietal junction have been emphasised in the latest diagnostic standards ( Gorno-Tempini et al.

2011 ) . Other countries that can besides be involved, peculiarly in ulterior phases, are: inferior and median facets of the temporal lobe ( Grossman 2010 ) , inferior frontal lobe and contralateral temporo-parietal cerebral mantle ( Henry & A ; Gorno-Tempini 2010 ) . Functional imagination surveies ( PET and SPECT ) show perfusion abnormalcies that parallel the chief structural alterations i.e. left temporo-parietal junction ( Gorno-Tempini et al. 2011 ) .

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Figure 3. Approximate anatomical location of each of the linguistic communication syndromes in Primary Progressive Aphasia. PNFA= Progressive Non-Fluent Aphasia, SD = Semantic Dementia, LPA = Logopenic Progressive Aphasia. Adapted from ( Grossman 2010 ) .

Clinicopathological correlativities

Significant developments made in last old ages in the Fieldss of pathology and genetic sciences fostered involvement in set uping correlativities between the different clinical syndromes and neuropathological findings. These informations, along with the usage of imagination and other biomarkers, could be of great value in the anticipation of the implicit in pathology. An of import point worth to retrieve is that the clinical syndrome of FTD is associated in the huge bulk of instances with FTLD pathology ( Seelaar et al.

2011 ) , but other specific forms such as AD and LBD pathology are sometimes present ( ) . For case, about 50 % of patients with LPA have AD pathology ( Henry & A ; Gorno-Tempini 2010 ) . As mentioned before, the word picture of familial signifiers and their several cistron mutants added farther insight to the word picture of the FTLD spectrum. A sum-up of the current position sing clinicopathological associations is shown in Table 2.

Behavioral variant-FTD

The degenerative alterations involve about symmetrical wasting of both frontal and temporal lobes ( Piguet et al.

2011 ) . The selective devolution of different encephalon countries has been associated with each of the chief symptoms in bv-FTD ( Seelaar et al. 2011 ) : orbitofrontal cerebral mantle and right anterior temporal cerebral mantle ( disinhibition ) , right front tooth cingulate cerebral mantle and superior frontal convolution ( apathy ) , orbitofrontal-striatal circuit ( stereotyped behavior ) and DLPFC ( executive disfunction ) .Sing histopathology, surveies have shown that both Tau and TDP-43 represent about half of bv-FTD instances ( Leyton & A ; Hodges 2010 ) , while the balance are associated with FUS pathology ( Seelaar et al. 2010 ) . The latter group appears to hold a distinguishable phenotype consisting of early age of oncoming, outstanding behavioural and psychiatric symptoms, and wasting of the caudate on MRI ( Rohrer et al. 2010 ) . Finally, patients with bv-FTD and coexisting MND are about ever positive for TDP-43 ( Hu & A ; Grossman 2009 ) doing this one of the strongest clinicopathological associations in FTLD.

Semantic Dementia

In SD there is a discriminatory engagement of the ventral and sidelong facets of both anterior temporal cerebral mantles ( Figure 3 ) , normally more in the left ( Grossman 2010 ) . The overpowering bulk of instances are associated with TDP-43 pathology, particularly the type 1 ( i.e. abundant dystrophic neuritis ) , although there are instance studies of Tau and AD type pathology every bit good ( Seelaar et al.

2011 ) .

Progressive Non-Fluent Aphasia

The major macroscopical alterations occur chiefly in the left inferior frontal lobe and the anterior insula ( Rohrer & A ; Fox 2009 ) . These two countries have besides been linked to aphasic symptoms and apraxia of address severally ( Ratnavalli 2010 ; Seeley 2010 ) . Despite the variableness in the information from the different instance series, the neuropathology is most frequently FTLD-Tau ( Seelaar et al. 2011 ) , followed by TDP-43 and other types such as AD and LBD ( Grossman 2010 ) . Interestingly, the presence of address apraxia is extremely implicative of Tau pathology at post-mortem ( Rohrer & A ; Fox 2009, Deramecourt et Al. 2010 ) .

Logopenic Progressive Aphasia

LPA degenerative alterations involve chiefly the left temporoparietal part and inferior parietal cerebral mantle ( Gorno-Tempini et al. 2008 ; Rohrer et Al. 2010 ) ; this coincides with the impression that shortages in the phonological cringle and posterior linguistic communication webs ( Bonner, Ash & A ; Grossman 2010 ; Rohrer et Al. 2010 ) . The most common neuropathological determination LPA instances is AD pathology ( Henry & A ; Gorno-Tempini 2010 ) , followed by variable grades of Tau and TDP-43 instances ( Mesulam et al.

2008 ) .Table 2 – Clinical and pathological correlativities in FTLDClinical SyndromeNeuropathologyBehavioral variant-FTDBehavioral variant-FTD + MNDTau ( ~50 % ) , TDP-43 ( ~50 % ) , FUSTDP-43 ( ~100 % )Semantic DementiaTDP-43 ( ~100 % ) – particularly type 1Some studies of AD pathology and Pick ‘s organic structuresProgressive Non-Fluent AphasiaTau ( 70 % ) , TDP-43 ( 30 % )Some studies of LBD, AD and DLDH pathologyLogopenic AphasiaAD ( 50 % )Besides TDP-43 and TauTDP-43 = TAR DNA-binding protein 43, FUS = Fused in Sarcoma, AD = Alzheimer ‘s Disease, LBD = Lewy organic structure disease, DLDH = Dementia missing typical pathology.