Behavioural variant frontotemporal dementia: Clinical and therapeutic approaches

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Fernández-Matarrubia, J.A. Matías-Guiu, T. Moreno-Ramos, J. Matías-Guiu" "autores" => array:4 [ 0 => array:4 [ "nombre" => "M." "apellidos" => "Fernández-Matarrubia" "email" => array:2 [ 0 => "martafmatarrubia@gmail.com" 1 => "marta_fm1@hotmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "J.A." "apellidos" => "Matías-Guiu" ] 2 => array:2 [ "nombre" => "T." "apellidos" => "Moreno-Ramos" ] 3 => array:2 [ "nombre" => "J." "apellidos" => "Matías-Guiu" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Servicio de Neurología, Hospital Clínico San Carlos, Madrid, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Demencia frontotemporal variante conductual: aproximación clínica y terapéutica" ] ] "textoCompleto" => "Introduction and conceptsSince Pick described the first case in 1892, it has taken nearly a century for neurology to renew its interest in frontotemporal dementia (FTD).<a class="elsevierStyleCrossRef" href="#bib0005">1</a> In the past 20 years, developments in molecular biology and genetics have produced an undeniable revolution in our knowledge of different types of FTDs. This has enabled researchers to make significant progress in understanding their causal mechanisms. As a result, new diagnostic criteria and classifications that give shape to the current FTD classification scheme have been drafted.FTDs are listed as the third most common cause of degenerative dementia after Alzheimer disease (AD) and dementia with Lewy bodies. In patients younger than 65, they represent the second most common cause.<a class="elsevierStyleCrossRefs" href="#bib0010">2,3</a> Population studies have shown that FTD prevalence rates range between 2.7/100000 (with a peak of 9.4/100000 in subjects aged 60-69) in the Netherlands<a class="elsevierStyleCrossRef" href="#bib0015">3</a> and 15.1/100000 in adults younger than 65 in Cambridge (UK). In this last age group, AD prevalence was the same.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> Although it has traditionally been considered a rare cause of dementia in subjects over 65, it is probably more frequent than previously believed. Some authors identify FTD in 20-25% cases of dementia in patients older than 65 years.<a class="elsevierStyleCrossRefs" href="#bib0010">2,4,5</a> Onset normally takes place in the sixth decade of life although this may vary greatly and cases have been reported in patients aged between 30 and 90.<a class="elsevierStyleCrossRefs" href="#bib0010">2,4,5</a>Lack of homogeneity in terminology has added to the confusion for years. Frontotemporal dementia is a clinical term that refers to the group of syndromes characterised by progressive decline in behaviour or language and associated with focal atrophy of the frontal and temporal lobes. Predominant symptoms and their time of onset during the course of the disease define 3 main clinical syndromes: behavioural variant of FTD (bvFTD), semantic dementia (SD), and non-fluent primary progressive aphasia (nfPPA).<a class="elsevierStyleCrossRef" href="#bib0030">6</a> Patients in whom FTD is associated with signs of motor neuron disease are diagnosed with FTD/MND.<a class="elsevierStyleCrossRefs" href="#bib0035">7,8</a> Furthermore, another 2 syndromes are closely related to FTD: corticobasal syndrome and progressive supranuclear palsy. All 6 clinical syndromes are linked to a heterogeneous group of molecular disorders characterised by cortical neurodegeneration, neuronal loss, and microspongiosis of frontal and temporal lobes. These syndromes are classified as frontotemporal lobar degeneration (FTLD). The term FTD is therefore a clinical concept, while FTLD refers to a pathological concept. In this article, we will review clinical, diagnostic, and therapeutic aspects of bvFTD.Clinical considerations of behavioural variant frontotemporal dementiaThe most frequent clinical syndrome of FTD is bvFTD. It is characterised by the early onset (within the first 3 years) of insidious changes in personality and behaviour. There are 3 clinical subtypes corresponding to the affected prefrontal areas: dorsolateral (dysexecutive syndrome, pseudodepression, or frontal convexity syndromes), orbitomedial (disinhibition syndrome, pseudomania, or pseudopsychopathy), or medial frontal/cingulate gyrus (apathetic syndrome, akinetic syndrome).<a class="elsevierStyleCrossRefs" href="#bib0045">9,10</a> Onset of the disease usually occurs before the age of 65 and typical age of onset is about 58 years.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> Nevertheless, time of onset is frequently hard to determine since these patients present poor insight; detection of early symptoms will therefore depend on the powers of observation of their relatives and caregivers.As mentioned before, bvFTD is characterised by insidious changes in personality, interpersonal conduct, and emotional modulation. This is the result of progressive disintegration of the neuronal circuits involved in social cognition, emotional self-regulation, motivation and decision-making.<a class="elsevierStyleCrossRefs" href="#bib0055">11–15</a> Apathy is a very frequent symptom and manifests as loss of motivation and interest in personal activities, as well as progressive social isolation. Some authors point that apathy is more frequent in late onset bvFTD,<a class="elsevierStyleCrossRef" href="#bib0080">16</a> although there are contradictory results on this topic in the literature.<a class="elsevierStyleCrossRef" href="#bib0085">17</a>Disinhibition is predominant in other cases, which leads patients to commit impulsive acts, such as spending money in excess or behaving in an indiscreet or sexually inappropriate way. Compulsive gambling or, less commonly, hyper-religious ideation have been described as initial manifestations of bvFTD.<a class="elsevierStyleCrossRefs" href="#bib0090">18,19</a> Other studies have described patients with sociopathic and deviant behaviours such as violating traffic regulations or assaulting others physically.<a class="elsevierStyleCrossRefs" href="#bib0100">20,21</a>Perseveration, with repetitive and stereotyped behaviours (tendency to repeat movements, sentences, stories, or jokes), is another characteristic finding. These patients usually present rigidity and limited mental flexibility, therefore lack of adaptation to new situations or routines is frequent. Affective disorders range from affective flattening and emotional coldness to expansive affect with signs of hypomania. Eating disorders, including hyperphagia, lack of satiety, cravings for sweet food, loss of appetite, and hyporexia, are frequently observed.<a class="elsevierStyleCrossRef" href="#bib0110">22</a> Although the exact mechanisms remain unknown, these changes may be related to hypothalamic dysfunction.<a class="elsevierStyleCrossRef" href="#bib0115">23</a> Psychotic symptoms are very rare and they have been associated with dementia with motor neuron diseases, or early-onset FTLD cases with fused in sarcoma protein (FTLD-FUS), in which they manifest in up to 50%.<a class="elsevierStyleCrossRefs" href="#bib0120">24–27</a>Out of all the behavioural manifestations listed above, social disinhibition, euphoria, stereotyped motor behaviours, and changes in eating behaviour are the most useful for distinguishing between bvFTD and other degenerative disorders such as AD.<a class="elsevierStyleCrossRefs" href="#bib0140">28,29</a> Therefore, a detailed behavioural evaluation is crucial for diagnosing bvFTD.In early stages, despite the presence of severe behavioural and personality changes, neuropsychological tests may yield normal results<a class="elsevierStyleCrossRef" href="#bib0150">30</a> since they reflect dorsolateral frontal lobe dysfunction rather than ventromedial dysfunction. For this reason, adding neuropsychological tests to the evaluation could be useful.<a class="elsevierStyleCrossRef" href="#bib0155">31</a>The Mini Mental State Examination is not sufficiently sensitive to identify bvFTD. Addenbrooke's cognitive examination shows changes in 90% of cases at onset.<a class="elsevierStyleCrossRef" href="#bib0160">32</a> The Spanish version of this test has recently been validated. It shows 92% sensitivity for detecting dementia and has been proved useful for discriminating between AD and bvFTD.<a class="elsevierStyleCrossRefs" href="#bib0165">33,34</a> It may therefore be considered a good screening tool. These patients are usually oriented, unlike patients with AD.<a class="elsevierStyleCrossRef" href="#bib0175">35</a> Neuropsychological evaluation should include an executive function assessment, as well as evaluation of other cognitive domains that will be useful in differential diagnosis. Examples include memory, language, and visuospatial functions.<a class="elsevierStyleCrossRef" href="#bib0180">36</a> In Spain, these aspects can be evaluated using the different subtests included in the Barcelona Test,<a class="elsevierStyleCrossRef" href="#bib0185">37</a> as well as the different standardised neuropsychological tests within the NEURONORMA project.<a class="elsevierStyleCrossRefs" href="#bib0190">38,39</a> Verbal span (digits), Corsi Block-Tapping Test, Trail Making Test,<a class="elsevierStyleCrossRefs" href="#bib0200">40,41</a> Verbal Fluency Tests,<a class="elsevierStyleCrossRefs" href="#bib0210">42,43</a> Stroop Colour-Word Interference Test, and the Tower of London Test<a class="elsevierStyleCrossRefs" href="#bib0220">44,45</a> are some of the main tests used to evaluate the different domains of executive function. Presence of perseverance and confabulation during the testing process is very typical and can help physicians differentiate bvFTD from other disorders.<a class="elsevierStyleCrossRefs" href="#bib0230">46,47</a>It was traditionally believed that the early stages of bvFTD were characterised by impaired attention, altered working memory, and executive dysfunction with relatively unaffected language, episodic memory, and visuospatial functions. Altered episodic memory was in fact considered a criterion for exclusion.<a class="elsevierStyleCrossRef" href="#bib0240">48</a> Recent studies have suggested that episodic memory deficits are more frequent than was once thought.<a class="elsevierStyleCrossRefs" href="#bib0245">49,50</a> Some studies including histologically confirmed FTLD series have shown that up to 10%-15% of patients present acute memory changes at onset.<a class="elsevierStyleCrossRefs" href="#bib0255">51,52</a> This may call into question the requirement, included in the currently applicable criteria, of “relatively intact episodic memory in comparison with executive functions”.Over the past few years, researchers have described patients who initially present clinical signs of bvFTD but whose condition does not progress to dementia.<a class="elsevierStyleCrossRef" href="#bib0265">53</a> These patients, termed ‘phenocopies’, are generally men and their condition may remain stable, or even improve, over the course of many years.<a class="elsevierStyleCrossRefs" href="#bib0270">54,55</a> Absence of executive dysfunction in neurological tests, preserved memory and social cognition, and absence of atrophy (magnetic resonance imaging), or hypometabolism (positron emission tomography) in neuroimaging tests differentiate these cases from true bvFTD.<a class="elsevierStyleCrossRefs" href="#bib0115">23,54–56</a>Patients’ recognition of emotions, especially the negative emotions of fear, sadness, or anger, is impaired from early stages.<a class="elsevierStyleCrossRefs" href="#bib0285">57,58</a> However, physiological responses to emotional stimuli (such as skin conductance response) may be preserved.<a class="elsevierStyleCrossRef" href="#bib0295">59</a> Difficulty recognising more complex emotions, such as embarrassment, may also be present.<a class="elsevierStyleCrossRef" href="#bib0300">60</a> These changes are not specific to bvFTD and can also be observed in other FTD subtypes, such as SD.Patients with bvFTD also present changes in different aspects of social cognition. Lack of empathy and emotional coldness are frequent and can be evidenced by specific tests.<a class="elsevierStyleCrossRef" href="#bib0305">61</a> These patients normally present difficulty inferring other people's intentions, understanding other people's points of view, identifying sarcasm, or understanding situations that require moral judgement.<a class="elsevierStyleCrossRefs" href="#bib0310">62–64</a>Activities of daily life (ADL) are affected by more severe, earlier-onset changes than in AD or variants in which language is affected,<a class="elsevierStyleCrossRefs" href="#bib0160">32,65,66</a> regardless of length of symptoms or results on neuropsychological tests.<a class="elsevierStyleCrossRefs" href="#bib0160">32,65</a> Many patients may present changes in ADL from early stages.Diagnostic criteria for behavioural variant frontotemporal dementiaBehavioural variant FTD may present a diagnostic challenge, especially during its early stages, since many of its symptoms are identical to those found in psychiatric disorders or other types of dementia.<a class="elsevierStyleCrossRef" href="#bib0125">25</a> New diagnostic criteria (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>) have been suggested in a recent attempt to improve diagnostic accuracy for bvFTD.<a class="elsevierStyleCrossRef" href="#bib0335">67</a> These more flexible and less restrictive criteria demonstrate higher sensitivity than the previous ones.<a class="elsevierStyleCrossRefs" href="#bib0240">48,68</a> Nevertheless, sensitivity seems to decrease in patients aged 65 and older.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Course of the disease and outcomeMedian survival of FTD patients has been estimated at 6-11 years from symptom onset, and 3-4 years from diagnosis.<a class="elsevierStyleCrossRefs" href="#bib0345">69–71</a> Most studies suggest that survival rates are lower and cognitive and functional impairment progresses faster in DFT than in AD.<a class="elsevierStyleCrossRefs" href="#bib0350">70,71</a> However, other studies suggest the opposite.<a class="elsevierStyleCrossRef" href="#bib0360">72</a> Association with MND (survival of 2.4-4.9 years from onset and 1.2-1.4 years from diagnosis)<a class="elsevierStyleCrossRef" href="#bib0355">71</a> and presence of language impairment at diagnosis have been proposed as factors reducing survival in bvFTD.<a class="elsevierStyleCrossRef" href="#bib0365">73</a>Although it has been used in most studies, the clinical dementia rating (CDR) score,<a class="elsevierStyleCrossRef" href="#bib0370">74</a> was initially designed for AD and mainly assesses memory alteration. It tends to underestimate dementia severity in bvFTD.<a class="elsevierStyleCrossRef" href="#bib0375">75</a> An adapted version including language and behaviour domains (fCDR) is sensitive enough to detect changes in most FTD patients.<a class="elsevierStyleCrossRef" href="#bib0375">75</a> A recently-developed FTD-specific scale (FRS) also includes behavioural and ADL changes.<a class="elsevierStyleCrossRef" href="#bib0380">76</a> According to this scale, bvFTD patients tend to present more severity and faster progression than patients with semantic dementia, regardless of length of symptoms.<a class="elsevierStyleCrossRef" href="#bib0380">76</a>Josephs et al.<a class="elsevierStyleCrossRef" href="#bib0385">77</a> studied 86 patients with bvFTD and analysed possible predictor variables for disease progression. They found that anatomical subtype was the most powerful predictor variable for the course of the disease. Thus, patients who presented faster progression according to the CDR-SB scale showed a predominantly frontal and frontotemporal pattern of atrophy with less pronounced temporal pole volume loss. Other predictors of rapid progression were older age at onset; poorer executive, language and visuospatial function; less disinhibition, agitation/aggression, and night-time behaviours at onset; and mutations in the microtubule associated protein tau (MAPT) gene.<a class="elsevierStyleCrossRef" href="#bib0385">77</a>More than clinical symptomsClinical symptoms are essential, but not sufficient, to diagnose bvFTD. First, assigning an early diagnosis of bvFTD may be difficult: changes in patient's social cognition may go unnoticed until they interfere with the caregiver's duties. Also, the patient's cognitive performance may be normal during the first stages, and neuropsychiatric symptoms can sometimes be erroneously attributed to a primary psychiatric disorder. As we have already mentioned, there are also patients with symptoms compatible with bvFTD whose condition does not finally progress to dementia (phenocopies), and others who fulfil clinical criteria for bvFTD but whose autopsies reveal diseases other than FTLD.<a class="elsevierStyleCrossRef" href="#bib0390">78</a> Second, the new drugs being developed to treat these diseases are agents aimed at specific molecular targets, and therefore in vivo assessment of disease pathology and molecular biology is especially important. Some clinical phenotypes show a strong association with specific histopathological subtypes, but in the case of bvFTD we found no clear correlations with any particular subtypes.<a class="elsevierStyleCrossRefs" href="#bib0390">78,79</a> Therefore, while some clinical signs suggesting specific molecular subtypes have been identified (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>),<a class="elsevierStyleCrossRef" href="#bib0395">79</a> it is also possible that a correlation between different subtypes and certain anatomical and biochemical features may exist.<a class="elsevierStyleCrossRef" href="#bib0390">78</a><elsevierMultimedia ident="tbl0010"></elsevierMultimedia>TreatmentNo specific treatment approaches for FTD are currently available in clinical practice. Treatment is basically symptomatic or supportive and its main objective is to alleviate symptoms and improve the patient's quality of life, especially when behavioural changes are so pronounced that they interfere with patient care.<a class="elsevierStyleCrossRef" href="#bib0400">80</a> Since no effective treatments are available, physicians often use psychoactive drugs off-label to alleviate symptoms.<a class="elsevierStyleCrossRefs" href="#bib0405">81,82</a> The most commonly used drugs are selective serotonin reuptake inhibitors (SSRI) and antipsychotics, which indicates that serotonergic and dopaminergic changes are associated with FTD.<a class="elsevierStyleCrossRefs" href="#bib0415">83–85</a>SSRIs have been used to treat behavioural symptoms, impulsiveness-disinhibition, and eating disorders in patients with FTD, with mixed results.<a class="elsevierStyleCrossRefs" href="#bib0430">86–89</a> Despite the lack of scientific evidence, atypical antipsychotics have also been used to treat FTD symptoms, especially agitation and disinhibition. The literature describes one case treated with risperidone<a class="elsevierStyleCrossRef" href="#bib0450">90</a> and an open trial with olanzapine that favours use of the drug.<a class="elsevierStyleCrossRef" href="#bib0455">91</a> Other dopaminergic agents, such as selegiline (IMAO-B),<a class="elsevierStyleCrossRef" href="#bib0460">92</a> have been used successfully to reduce neuropsychiatric symptoms. Methylphenidate has also been tested in patients with bvFTD with satisfactory results.<a class="elsevierStyleCrossRef" href="#bib0465">93</a>Cholinesterase inhibitors and memantine are also frequently used for FTD<a class="elsevierStyleCrossRefs" href="#bib0470">94,95</a> because of their effect in AD and based on data from open uncontrolled clinical trials with low patient numbers. However, the poor results obtained with donepezil, together with the controversial results for galantamine and rivastigmine,<a class="elsevierStyleCrossRefs" href="#bib0480">96–100</a> have given rise to a general recommendation that cholinesterase inhibitors should be avoided as treatment for FTD.<a class="elsevierStyleCrossRefs" href="#bib0400">80–82</a> Identification of 3 bvFTD cases<a class="elsevierStyleCrossRef" href="#bib0505">101</a> that showed an improved score on the neuropsychiatric inventory (NPI) after treatment with memantine encouraged researchers to conduct clinical trials. Two open uncontrolled clinical trials with memantine have been completed. One included a series of 16 patients with bvFTD<a class="elsevierStyleCrossRef" href="#bib0510">102</a> whose behavioural symptoms did not improve with memantine dosed at 20mg/kg/day. In the other study, the same dose of memantine was administered to 21 patients with bvFTD, 13 patients with SD, and 9 with nfPPA.<a class="elsevierStyleCrossRef" href="#bib0515">103</a> Patients with bvFTD demonstrated a temporary initial improvement on the NPI score, but subsequent follow-up did not show any other benefits. Two multicentre, prospective and randomised double-blind placebo-controlled trials are currently being performed (a phase VI trial in the USA and a phase II trial in France).Disease-modifying treatmentThe most promising line of action focuses on developing drugs that bind to a specific molecular target. In the case of FTLD, the main therapeutic targets are Tau protein, TAR DNA-binding protein 43 (TDP-43), and to a lesser extent, FUS protein. Tau protein participates in the pathogenesis of AD, as well as in a large percentage of all FTLD cases. Therefore, these new Tau aggregation inhibitors being developed for AD may be also useful for treating Tau-FTLD.<a class="elsevierStyleCrossRefs" href="#bib0400">80,82,104</a>Progranulin (PGRN) mutations cause haploinsufficiency due to loss of protein function and they are associated with some cases of FTLD, mainly FTLD-TDP.<a class="elsevierStyleCrossRef" href="#bib0525">105</a> Plasma PGRN levels are low in these cases,<a class="elsevierStyleCrossRefs" href="#bib0525">105–107</a> so normalising these levels could constitute an interesting therapeutic strategy. Researchers have recently managed to use micro-ARN-29b to increase PGRN levels in vitro.<a class="elsevierStyleCrossRef" href="#bib0540">108</a> Other possible therapeutic targets include inhibition of hyperphosphorylation, ubiquitination, cleavage, and TDP-43 translocation from the cytoplasm to the nucleus.<a class="elsevierStyleCrossRef" href="#bib0545">109</a>ConclusionsFTLDs are frequent causes of dementia. Over the past 20 years, knowledge of this group of diseases has increased considerably thanks to advances in molecular biology and genetics. Behavioural variant FTD, characterised by insidious changes in personality and behaviour, is the most frequent clinical syndrome in this group. This devastating condition typically manifests in middle-aged subjects and affects individuals with active family, social, and professional lives. Assigning an early clinical diagnosis is often difficult and since the patient may show poor insight, his or her medical history as described by relatives is a crucial resource. From a histopathological and biomolecular point of view, bvFTD is a heterogeneous condition and predicting the underlying pathology in vivo is still difficult. The definition of the syndrome describes too broad of a concept. Therefore, identifying differential characteristics that help define ‘clinical subtypes’ may be useful for improving the clinical-pathological correlation. The identification of biomarkers and development of drugs aimed at specific molecular targets are essential strategies that will usher in new treatment approaches.Conflicts of interestThe authors have no conflicts of interest to declare." "textoCompletoSecciones" => array:1 [ "secciones" => array:14 [ 0 => array:2 [ "identificador" => "xres372893" "titulo" => array:4 [ 0 => "Abstract" 1 => "Introduction" 2 => "Development" 3 => "Conclusions" ] ] 1 => array:2 [ "identificador" => "xpalclavsec351930" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres372894" "titulo" => array:4 [ 0 => "Resumen" 1 => "Introducción" 2 => "Desarrollo" 3 => "Conclusiones" ] ] 3 => array:2 [ "identificador" => "xpalclavsec351931" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction and concepts" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Clinical considerations of behavioural variant frontotemporal dementia" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Diagnostic criteria for behavioural variant frontotemporal dementia" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Course of the disease and outcome" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "More than clinical symptoms" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Treatment" ] 10 => array:2 [ "identificador" => "sec0035" "titulo" => "Disease-modifying treatment" ] 11 => array:2 [ "identificador" => "sec0040" "titulo" => "Conclusions" ] 12 => array:2 [ "identificador" => "sec0045" "titulo" => "Conflicts of interest" ] 13 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2013-02-27" "fechaAceptado" => "2013-03-16" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec351930" "palabras" => array:6 [ 0 => "Behavioural variant frontotemporal dementia" 1 => "Frontotemporal lobar degeneration" 2 => "Clinical aspects" 3 => "Diagnosis" 4 => "Diagnostic criteria" 5 => "Treatment" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec351931" "palabras" => array:6 [ 0 => "Demencia frontotemporal variante conductual" 1 => "Degeneración lobar frontotemporal" 2 => "Clínica" 3 => "Diagnóstico" 4 => "Criterios diagnósticos" 5 => "Tratamiento" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "IntroductionBehavioural variant frontotemporal dementia (bvFTD) is the most frequent presentation in the clinical spectrum of frontotemporal dementia (FTD) and it is characterised by progressive changes in personality and conduct. Major breakthroughs in molecular biology and genetics made during the last two decades have lent us a better understanding of this syndrome, which may be the first manifestation in many different neurodegenerative diseases. DevelopmentWe reviewed the main epidemiological, clinical, diagnostic and therapeutic aspects of bvFTD. Most cases manifest sporadically and the average age of onset is 58 years. Current criteria for bvFTD propose three levels of diagnostic certainty: possible, probable, and definite. Clinical diagnosis is based on a detailed medical history provided by family members and caregivers, in conjunction with neuropsychological testing. Treatments which have been used in bvFDT to date are all symptomatic and their effectiveness is debatable. New drugs designed for specific molecular targets that are implicated in frontotemporal lobar degeneration are being developed. ConclusionsBvFDT is a frequent cause of dementia. It is a non-specific syndrome associated with heterogeneous histopathological and biomolecular findings. The definition of clinical subtypes complemented by biomarker identification may help predict the underlying pathology. This knowledge, along with the development of drugs designed for molecular targets, will offer new treatment possibilities." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "IntroducciónLa variante conductual de la demencia frontotemporal (DFT vc) es el síndrome clínico más frecuente de las demencias frontotemporales (DFT) y se caracteriza por una alteración progresiva de la personalidad y la conducta. En las últimas 2 décadas, los avances en biología molecular y genética han contribuido a un mayor conocimiento de esta entidad, que puede ser el modo de presentación de diferentes enfermedades neurodegenerativas. DesarrolloSe revisan los principales aspectos epidemiológicos, clínicos, diagnósticos y terapéuticos de la DFT vc. La mayoría de los casos son esporádicos, iniciándose en torno a los 58 años de media. Los criterios diagnósticos vigentes establecen 3 niveles de certeza diagnóstica: posible, probable y definitivo. El diagnóstico clínico se basa en la anamnesis detallada de familiares, complementada con la realización de test neuropsicológicos dirigidos. Hasta la fecha, los tratamientos empleados son solo sintomáticos y de eficacia controvertida. Se están diseñando fármacos dirigidos contra dianas moleculares específicas implicadas en la patogenia de las degeneraciones lobares frontotemporales. ConclusionesLa DFT vc es una causa frecuente de demencia. Se trata de un síndrome amplio, heterogéneo desde el punto de vista histopatológico y biomolecular. La definición de subtipos clínicos y la identificación de biomarcadores podrían ayudar a predecir la afección subyacente, lo que junto con el desarrollo de fármacos dirigidos contra dianas moleculares ofrece nuevas posibilidades terapéuticas." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Fernández-Matarrubia M, Matías-Guiu JA, Moreno-Ramos T, Matías-Guiu J. Demencia frontotemporal variante conductual: aproximación clínica y terapéutica. Neurología. 2014;29:464‐472." ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "bvFTD: behavioural variant frontotemporal dementia; FTLD: frontotemporal lobar degeneration; PET: positron emission tomography; MRI: magnetic resonance imaging; SPECT: single photon emission computed tomography; CT: computed tomography." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neurodegenerative disease \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Progressive deterioration of behaviour and/or cognition evidenced by observation or medical history \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Possible bvFTD \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">At least 3 of the following cognitive or behavioural symptoms are present, persistently or recurrently (A–F): \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">A. Early behavioural disinhibition (3 years) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">B. Early apathy or inertia (3 years) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C. Early loss of empathy (3 years) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">D. Perseverative, stereotyped, or compulsive/ritualistic behaviour \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">E. Hyperorality and dietary changes \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">F. Neuropsychological profile: executive function deficits with relative sparing of memory and visuospatial functions \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Probable bvFTD \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">All following conditions should be met: \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">A. Fulfils criteria for possible bvFTD \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">B. Exhibits significant functional decline \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C. Neuroimaging findings compatible with frontal and/or anterior temporal atrophy (CT or MRI) or hypoperfusion (SPECT) or hypometabolism (PET) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Definitive bvFTD \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Criterion A plus B or C must be met: \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">A. Meets criteria for possible or probable bvFTD \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">B. Histopathological evidence of FTLD in biopsy or at post-mortem \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C. Presence of a known pathogenic mutation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Exclusion Criteria for bvFTD \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">A. Pattern of deficits is better accounted for by a different non-degenerative neurological or other medical disorder \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">B. Behavioural disturbance is better accounted for by a psychiatric disorder \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C. Biomarkers strongly indicative of Alzheimer disease or another neurodegenerative process<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab563802.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "Criterion C does not rule out diagnosis of possible bvFTD but effectively rules out probable bvFTD." ] ] ] "descripcion" => array:1 [ "en" => "Consensus criteria for clinical diagnosis of behavioural variant of FTD (Rascovsky, 2007).<a class="elsevierStyleCrossRef" href="#bib0335">67</a>" ] ] 1 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "FTLD-TDP subtypes 1 and 3 have been designated according to Mackenzie classification.Taken from data by Josephs et al. (2007).<a class="elsevierStyleCrossRef" href="#bib0395">79</a>aFTLD-U: atypical frontotemporal lobar degeneration with ubiquitin-immunoreactive inclusions; CBD: corticobasal inclusion; FTLD-FUS: frontotemporal lobar degeneration associated with fused in sarcoma protein; FTLD-Tau: frontotemporal lobar degeneration with tau inclusions; FTLD-TDP: frontotemporal lobar degeneration associated with TAR DNA-binding protein 43; MAPT: microtubule-associated protein tau; PGRN: progranulin; PSP: progressive supranuclear palsy." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Clinical signs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Molecular pathology</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Subtype \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Type \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pronounced apathy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Type 1 associated with PGRN gene mutation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">FTLD-TDP \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Signs of motor neuron diseases \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Type 3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Psychotic symptoms \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Type 3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Disinhibition and altered semantic features of language \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Associated with MAPT gene mutation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tau-FTLD \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Vertical supranuclear gaze palsy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CBD>PSP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Early onset, hypersexuality, hyperphagia, obsessions, stereotypy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">aFTLD-U \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">FTLD-FUS \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab563801.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Clinical signs indicative of certain biomolecular subtypes in bvFTD." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:109 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical and biomolecular classification of the frontotemporal dementias. 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Review article

Demencia frontotemporal variante conductual: aproximación clínica y terapéutica

M. Fernández-Matarrubia

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martafmatarrubia@gmail.com
marta_fm1@hotmail.com

Corresponding author.

, J.A. Matías-Guiu, T. Moreno-Ramos, J. Matías-Guiu

Servicio de Neurología, Hospital Clínico San Carlos, Madrid, Spain

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    "titulosAlternativos" => array:1 [
      "es" => array:1 [
        "titulo" => "Demencia frontotemporal variante conductual&#58; aproximaci&#243;n cl&#237;nica y terap&#233;utica"
      ]
    ]
    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Introduction and concepts</span><p id="par0005" class="elsevierStylePara elsevierViewall">Since Pick described the first case in 1892&#44; it has taken nearly a century for neurology to renew its interest in frontotemporal dementia &#40;FTD&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> In the past 20 years&#44; developments in molecular biology and genetics have produced an undeniable revolution in our knowledge of different types of FTDs&#46; This has enabled researchers to make significant progress in understanding their causal mechanisms&#46; As a result&#44; new diagnostic criteria and classifications that give shape to the current FTD classification scheme have been drafted&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">FTDs are listed as the third most common cause of degenerative dementia after Alzheimer disease &#40;AD&#41; and dementia with Lewy bodies&#46; In patients younger than 65&#44; they represent the second most common cause&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;3</span></a> Population studies have shown that FTD prevalence rates range between 2&#46;7&#47;100<span class="elsevierStyleHsp" style=""></span>000 &#40;with a peak of 9&#46;4&#47;100<span class="elsevierStyleHsp" style=""></span>000 in subjects aged 60-69&#41; in the Netherlands<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> and 15&#46;1&#47;100<span class="elsevierStyleHsp" style=""></span>000 in adults younger than 65 in Cambridge &#40;UK&#41;&#46; In this last age group&#44; AD prevalence was the same&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Although it has traditionally been considered a rare cause of dementia in subjects over 65&#44; it is probably more frequent than previously believed&#46; Some authors identify FTD in 20-25&#37; cases of dementia in patients older than 65 years&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;4&#44;5</span></a> Onset normally takes place in the sixth decade of life although this may vary greatly and cases have been reported in patients aged between 30 and 90&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;4&#44;5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Lack of homogeneity in terminology has added to the confusion for years&#46; Frontotemporal dementia is a clinical term that refers to the group of syndromes characterised by progressive decline in behaviour or language and associated with focal atrophy of the frontal and temporal lobes&#46; Predominant symptoms and their time of onset during the course of the disease define 3 main clinical syndromes&#58; behavioural variant of FTD &#40;bvFTD&#41;&#44; semantic dementia &#40;SD&#41;&#44; and non-fluent primary progressive aphasia &#40;nfPPA&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Patients in whom FTD is associated with signs of motor neuron disease are diagnosed with FTD&#47;MND&#46;<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#44;8</span></a> Furthermore&#44; another 2 syndromes are closely related to FTD&#58; corticobasal syndrome and progressive supranuclear palsy&#46; All 6 clinical syndromes are linked to a heterogeneous group of molecular disorders characterised by cortical neurodegeneration&#44; neuronal loss&#44; and microspongiosis of frontal and temporal lobes&#46; These syndromes are classified as frontotemporal lobar degeneration &#40;FTLD&#41;&#46; The term FTD is therefore a clinical concept&#44; while FTLD refers to a pathological concept&#46; In this article&#44; we will review clinical&#44; diagnostic&#44; and therapeutic aspects of bvFTD&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Clinical considerations of behavioural variant frontotemporal dementia</span><p id="par0020" class="elsevierStylePara elsevierViewall">The most frequent clinical syndrome of FTD is bvFTD&#46; It is characterised by the early onset &#40;within the first 3 years&#41; of insidious changes in personality and behaviour&#46; There are 3 clinical subtypes corresponding to the affected prefrontal areas&#58; dorsolateral &#40;dysexecutive syndrome&#44; pseudodepression&#44; or frontal convexity syndromes&#41;&#44; orbitomedial &#40;disinhibition syndrome&#44; pseudomania&#44; or pseudopsychopathy&#41;&#44; or medial frontal&#47;cingulate gyrus &#40;apathetic syndrome&#44; akinetic syndrome&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;10</span></a> Onset of the disease usually occurs before the age of 65 and typical age of onset is about 58 years&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Nevertheless&#44; time of onset is frequently hard to determine since these patients present poor insight&#59; detection of early symptoms will therefore depend on the powers of observation of their relatives and caregivers&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">As mentioned before&#44; bvFTD is characterised by insidious changes in personality&#44; interpersonal conduct&#44; and emotional modulation&#46; This is the result of progressive disintegration of the neuronal circuits involved in social cognition&#44; emotional self-regulation&#44; motivation and decision-making&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#8211;15</span></a> Apathy is a very frequent symptom and manifests as loss of motivation and interest in personal activities&#44; as well as progressive social isolation&#46; Some authors point that apathy is more frequent in late onset bvFTD&#44;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> although there are contradictory results on this topic in the literature&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Disinhibition is predominant in other cases&#44; which leads patients to commit impulsive acts&#44; such as spending money in excess or behaving in an indiscreet or sexually inappropriate way&#46; Compulsive gambling or&#44; less commonly&#44; hyper-religious ideation have been described as initial manifestations of bvFTD&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">18&#44;19</span></a> Other studies have described patients with sociopathic and deviant behaviours such as violating traffic regulations or assaulting others physically&#46;<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20&#44;21</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Perseveration&#44; with repetitive and stereotyped behaviours &#40;tendency to repeat movements&#44; sentences&#44; stories&#44; or jokes&#41;&#44; is another characteristic finding&#46; These patients usually present rigidity and limited mental flexibility&#44; therefore lack of adaptation to new situations or routines is frequent&#46; Affective disorders range from affective flattening and emotional coldness to expansive affect with signs of hypomania&#46; Eating disorders&#44; including hyperphagia&#44; lack of satiety&#44; cravings for sweet food&#44; loss of appetite&#44; and hyporexia&#44; are frequently observed&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> Although the exact mechanisms remain unknown&#44; these changes may be related to hypothalamic dysfunction&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> Psychotic symptoms are very rare and they have been associated with dementia with motor neuron diseases&#44; or early-onset FTLD cases with fused in sarcoma protein &#40;FTLD-FUS&#41;&#44; in which they manifest in up to 50&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">24&#8211;27</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Out of all the behavioural manifestations listed above&#44; social disinhibition&#44; euphoria&#44; stereotyped motor behaviours&#44; and changes in eating behaviour are the most useful for distinguishing between bvFTD and other degenerative disorders such as AD&#46;<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">28&#44;29</span></a> Therefore&#44; a detailed behavioural evaluation is crucial for diagnosing bvFTD&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">In early stages&#44; despite the presence of severe behavioural and personality changes&#44; neuropsychological tests may yield normal results<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> since they reflect dorsolateral frontal lobe dysfunction rather than ventromedial dysfunction&#46; For this reason&#44; adding neuropsychological tests to the evaluation could be useful&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">The Mini Mental State Examination is not sufficiently sensitive to identify bvFTD&#46; Addenbrooke&#39;s cognitive examination shows changes in 90&#37; of cases at onset&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> The Spanish version of this test has recently been validated&#46; It shows 92&#37; sensitivity for detecting dementia and has been proved useful for discriminating between AD and bvFTD&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">33&#44;34</span></a> It may therefore be considered a good screening tool&#46; These patients are usually oriented&#44; unlike patients with AD&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> Neuropsychological evaluation should include an executive function assessment&#44; as well as evaluation of other cognitive domains that will be useful in differential diagnosis&#46; Examples include memory&#44; language&#44; and visuospatial functions&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> In Spain&#44; these aspects can be evaluated using the different subtests included in the Barcelona Test&#44;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> as well as the different standardised neuropsychological tests within the NEURONORMA project&#46;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">38&#44;39</span></a> Verbal span &#40;digits&#41;&#44; Corsi Block-Tapping Test&#44; Trail Making Test&#44;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">40&#44;41</span></a> Verbal Fluency Tests&#44;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">42&#44;43</span></a> Stroop Colour-Word Interference Test&#44; and the Tower of London Test<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">44&#44;45</span></a> are some of the main tests used to evaluate the different domains of executive function&#46; Presence of perseverance and confabulation during the testing process is very typical and can help physicians differentiate bvFTD from other disorders&#46;<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">46&#44;47</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">It was traditionally believed that the early stages of bvFTD were characterised by impaired attention&#44; altered working memory&#44; and executive dysfunction with relatively unaffected language&#44; episodic memory&#44; and visuospatial functions&#46; Altered episodic memory was in fact considered a criterion for exclusion&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> Recent studies have suggested that episodic memory deficits are more frequent than was once thought&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">49&#44;50</span></a> Some studies including histologically confirmed FTLD series have shown that up to 10&#37;-15&#37; of patients present acute memory changes at onset&#46;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">51&#44;52</span></a> This may call into question the requirement&#44; included in the currently applicable criteria&#44; of &#8220;relatively intact episodic memory in comparison with executive functions&#8221;&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Over the past few years&#44; researchers have described patients who initially present clinical signs of bvFTD but whose condition does not progress to dementia&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a> These patients&#44; termed &#8216;phenocopies&#8217;&#44; are generally men and their condition may remain stable&#44; or even improve&#44; over the course of many years&#46;<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">54&#44;55</span></a> Absence of executive dysfunction in neurological tests&#44; preserved memory and social cognition&#44; and absence of atrophy &#40;magnetic resonance imaging&#41;&#44; or hypometabolism &#40;positron emission tomography&#41; in neuroimaging tests differentiate these cases from true bvFTD&#46;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#44;54&#8211;56</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Patients&#8217; recognition of emotions&#44; especially the negative emotions of fear&#44; sadness&#44; or anger&#44; is impaired from early stages&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">57&#44;58</span></a> However&#44; physiological responses to emotional stimuli &#40;such as skin conductance response&#41; may be preserved&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a> Difficulty recognising more complex emotions&#44; such as embarrassment&#44; may also be present&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a> These changes are not specific to bvFTD and can also be observed in other FTD subtypes&#44; such as SD&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Patients with bvFTD also present changes in different aspects of social cognition&#46; Lack of empathy and emotional coldness are frequent and can be evidenced by specific tests&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">61</span></a> These patients normally present difficulty inferring other people&#39;s intentions&#44; understanding other people&#39;s points of view&#44; identifying sarcasm&#44; or understanding situations that require moral judgement&#46;<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">62&#8211;64</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Activities of daily life &#40;ADL&#41; are affected by more severe&#44; earlier-onset changes than in AD or variants in which language is affected&#44;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32&#44;65&#44;66</span></a> regardless of length of symptoms or results on neuropsychological tests&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32&#44;65</span></a> Many patients may present changes in ADL from early stages&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Diagnostic criteria for behavioural variant frontotemporal dementia</span><p id="par0080" class="elsevierStylePara elsevierViewall">Behavioural variant FTD may present a diagnostic challenge&#44; especially during its early stages&#44; since many of its symptoms are identical to those found in psychiatric disorders or other types of dementia&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> New diagnostic criteria &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41; have been suggested in a recent attempt to improve diagnostic accuracy for bvFTD&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">67</span></a> These more flexible and less restrictive criteria demonstrate higher sensitivity than the previous ones&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">48&#44;68</span></a> Nevertheless&#44; sensitivity seems to decrease in patients aged 65 and older&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Course of the disease and outcome</span><p id="par0085" class="elsevierStylePara elsevierViewall">Median survival of FTD patients has been estimated at 6-11 years from symptom onset&#44; and 3-4 years from diagnosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">69&#8211;71</span></a> Most studies suggest that survival rates are lower and cognitive and functional impairment progresses faster in DFT than in AD&#46;<a class="elsevierStyleCrossRefs" href="#bib0350"><span class="elsevierStyleSup">70&#44;71</span></a> However&#44; other studies suggest the opposite&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">72</span></a> Association with MND &#40;survival of 2&#46;4-4&#46;9 years from onset and 1&#46;2-1&#46;4 years from diagnosis&#41;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">71</span></a> and presence of language impairment at diagnosis have been proposed as factors reducing survival in bvFTD&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">73</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Although it has been used in most studies&#44; the clinical dementia rating &#40;CDR&#41; score&#44;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">74</span></a> was initially designed for AD and mainly assesses memory alteration&#46; It tends to underestimate dementia severity in bvFTD&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">75</span></a> An adapted version including language and behaviour domains &#40;fCDR&#41; is sensitive enough to detect changes in most FTD patients&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">75</span></a> A recently-developed FTD-specific scale &#40;FRS&#41; also includes behavioural and ADL changes&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">76</span></a> According to this scale&#44; bvFTD patients tend to present more severity and faster progression than patients with semantic dementia&#44; regardless of length of symptoms&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">76</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Josephs et al&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">77</span></a> studied 86 patients with bvFTD and analysed possible predictor variables for disease progression&#46; They found that anatomical subtype was the most powerful predictor variable for the course of the disease&#46; Thus&#44; patients who presented faster progression according to the CDR-SB scale showed a predominantly frontal and frontotemporal pattern of atrophy with less pronounced temporal pole volume loss&#46; Other predictors of rapid progression were older age at onset&#59; poorer executive&#44; language and visuospatial function&#59; less disinhibition&#44; agitation&#47;aggression&#44; and night-time behaviours at onset&#59; and mutations in the microtubule associated protein tau &#40;<span class="elsevierStyleItalic">MAPT</span>&#41; gene&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">77</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">More than clinical symptoms</span><p id="par0100" class="elsevierStylePara elsevierViewall">Clinical symptoms are essential&#44; but not sufficient&#44; to diagnose bvFTD&#46; First&#44; assigning an early diagnosis of bvFTD may be difficult&#58; changes in patient&#39;s social cognition may go unnoticed until they interfere with the caregiver&#39;s duties&#46; Also&#44; the patient&#39;s cognitive performance may be normal during the first stages&#44; and neuropsychiatric symptoms can sometimes be erroneously attributed to a primary psychiatric disorder&#46; As we have already mentioned&#44; there are also patients with symptoms compatible with bvFTD whose condition does not finally progress to dementia &#40;phenocopies&#41;&#44; and others who fulfil clinical criteria for bvFTD but whose autopsies reveal diseases other than FTLD&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">78</span></a> Second&#44; the new drugs being developed to treat these diseases are agents aimed at specific molecular targets&#44; and therefore in vivo assessment of disease pathology and molecular biology is especially important&#46; Some clinical phenotypes show a strong association with specific histopathological subtypes&#44; but in the case of bvFTD we found no clear correlations with any particular subtypes&#46;<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">78&#44;79</span></a> Therefore&#44; while some clinical signs suggesting specific molecular subtypes have been identified &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">79</span></a> it is also possible that a correlation between different subtypes and certain anatomical and biochemical features may exist&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">78</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Treatment</span><p id="par0105" class="elsevierStylePara elsevierViewall">No specific treatment approaches for FTD are currently available in clinical practice&#46; Treatment is basically symptomatic or supportive and its main objective is to alleviate symptoms and improve the patient&#39;s quality of life&#44; especially when behavioural changes are so pronounced that they interfere with patient care&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">80</span></a> Since no effective treatments are available&#44; physicians often use psychoactive drugs off-label to alleviate symptoms&#46;<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">81&#44;82</span></a> The most commonly used drugs are selective serotonin reuptake inhibitors &#40;SSRI&#41; and antipsychotics&#44; which indicates that serotonergic and dopaminergic changes are associated with FTD&#46;<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">83&#8211;85</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">SSRIs have been used to treat behavioural symptoms&#44; impulsiveness-disinhibition&#44; and eating disorders in patients with FTD&#44; with mixed results&#46;<a class="elsevierStyleCrossRefs" href="#bib0430"><span class="elsevierStyleSup">86&#8211;89</span></a> Despite the lack of scientific evidence&#44; atypical antipsychotics have also been used to treat FTD symptoms&#44; especially agitation and disinhibition&#46; The literature describes one case treated with risperidone<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">90</span></a> and an open trial with olanzapine that favours use of the drug&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">91</span></a> Other dopaminergic agents&#44; such as selegiline &#40;IMAO-B&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">92</span></a> have been used successfully to reduce neuropsychiatric symptoms&#46; Methylphenidate has also been tested in patients with bvFTD with satisfactory results&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">93</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Cholinesterase inhibitors and memantine are also frequently used for FTD<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">94&#44;95</span></a> because of their effect in AD and based on data from open uncontrolled clinical trials with low patient numbers&#46; However&#44; the poor results obtained with donepezil&#44; together with the controversial results for galantamine and rivastigmine&#44;<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">96&#8211;100</span></a> have given rise to a general recommendation that cholinesterase inhibitors should be avoided as treatment for FTD&#46;<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">80&#8211;82</span></a> Identification of 3 bvFTD cases<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">101</span></a> that showed an improved score on the neuropsychiatric inventory &#40;NPI&#41; after treatment with memantine encouraged researchers to conduct clinical trials&#46; Two open uncontrolled clinical trials with memantine have been completed&#46; One included a series of 16 patients with bvFTD<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">102</span></a> whose behavioural symptoms did not improve with memantine dosed at 20<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day&#46; In the other study&#44; the same dose of memantine was administered to 21 patients with bvFTD&#44; 13 patients with SD&#44; and 9 with nfPPA&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">103</span></a> Patients with bvFTD demonstrated a temporary initial improvement on the NPI score&#44; but subsequent follow-up did not show any other benefits&#46; Two multicentre&#44; prospective and randomised double-blind placebo-controlled trials are currently being performed &#40;a phase VI trial in the USA and a phase II trial in France&#41;&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Disease-modifying treatment</span><p id="par0120" class="elsevierStylePara elsevierViewall">The most promising line of action focuses on developing drugs that bind to a specific molecular target&#46; In the case of FTLD&#44; the main therapeutic targets are Tau protein&#44; TAR DNA-binding protein 43 &#40;TDP-43&#41;&#44; and to a lesser extent&#44; FUS protein&#46; Tau protein participates in the pathogenesis of AD&#44; as well as in a large percentage of all FTLD cases&#46; Therefore&#44; these new Tau aggregation inhibitors being developed for AD may be also useful for treating Tau-FTLD&#46;<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">80&#44;82&#44;104</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Progranulin &#40;PGRN&#41; mutations cause haploinsufficiency due to loss of protein function and they are associated with some cases of FTLD&#44; mainly FTLD-TDP&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">105</span></a> Plasma PGRN levels are low in these cases&#44;<a class="elsevierStyleCrossRefs" href="#bib0525"><span class="elsevierStyleSup">105&#8211;107</span></a> so normalising these levels could constitute an interesting therapeutic strategy&#46; Researchers have recently managed to use micro-ARN-29b to increase PGRN levels in vitro&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">108</span></a> Other possible therapeutic targets include inhibition of hyperphosphorylation&#44; ubiquitination&#44; cleavage&#44; and TDP-43 translocation from the cytoplasm to the nucleus&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">109</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Conclusions</span><p id="par0130" class="elsevierStylePara elsevierViewall">FTLDs are frequent causes of dementia&#46; Over the past 20 years&#44; knowledge of this group of diseases has increased considerably thanks to advances in molecular biology and genetics&#46; Behavioural variant FTD&#44; characterised by insidious changes in personality and behaviour&#44; is the most frequent clinical syndrome in this group&#46; This devastating condition typically manifests in middle-aged subjects and affects individuals with active family&#44; social&#44; and professional lives&#46; Assigning an early clinical diagnosis is often difficult and since the patient may show poor insight&#44; his or her medical history as described by relatives is a crucial resource&#46; From a histopathological and biomolecular point of view&#44; bvFTD is a heterogeneous condition and predicting the underlying pathology in vivo is still difficult&#46; The definition of the syndrome describes too broad of a concept&#46; Therefore&#44; identifying differential characteristics that help define &#8216;clinical subtypes&#8217; may be useful for improving the clinical-pathological correlation&#46; The identification of biomarkers and development of drugs aimed at specific molecular targets are essential strategies that will usher in new treatment approaches&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Conflicts of interest</span><p id="par0135" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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          "identificador" => "xres372893"
          "titulo" => array:4 [
            0 => "Abstract"
            1 => "Introduction"
            2 => "Development"
            3 => "Conclusions"
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        1 => array:2 [
          "identificador" => "xpalclavsec351930"
          "titulo" => "Keywords"
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        2 => array:2 [
          "identificador" => "xres372894"
          "titulo" => array:4 [
            0 => "Resumen"
            1 => "Introducci&#243;n"
            2 => "Desarrollo"
            3 => "Conclusiones"
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        ]
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          "identificador" => "xpalclavsec351931"
          "titulo" => "Palabras clave"
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        4 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction and concepts"
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        5 => array:2 [
          "identificador" => "sec0010"
          "titulo" => "Clinical considerations of behavioural variant frontotemporal dementia"
        ]
        6 => array:2 [
          "identificador" => "sec0015"
          "titulo" => "Diagnostic criteria for behavioural variant frontotemporal dementia"
        ]
        7 => array:2 [
          "identificador" => "sec0020"
          "titulo" => "Course of the disease and outcome"
        ]
        8 => array:2 [
          "identificador" => "sec0025"
          "titulo" => "More than clinical symptoms"
        ]
        9 => array:2 [
          "identificador" => "sec0030"
          "titulo" => "Treatment"
        ]
        10 => array:2 [
          "identificador" => "sec0035"
          "titulo" => "Disease-modifying treatment"
        ]
        11 => array:2 [
          "identificador" => "sec0040"
          "titulo" => "Conclusions"
        ]
        12 => array:2 [
          "identificador" => "sec0045"
          "titulo" => "Conflicts of interest"
        ]
        13 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2013-02-27"
    "fechaAceptado" => "2013-03-16"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec351930"
          "palabras" => array:6 [
            0 => "Behavioural variant frontotemporal dementia"
            1 => "Frontotemporal lobar degeneration"
            2 => "Clinical aspects"
            3 => "Diagnosis"
            4 => "Diagnostic criteria"
            5 => "Treatment"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec351931"
          "palabras" => array:6 [
            0 => "Demencia frontotemporal variante conductual"
            1 => "Degeneraci&#243;n lobar frontotemporal"
            2 => "Cl&#237;nica"
            3 => "Diagn&#243;stico"
            4 => "Criterios diagn&#243;sticos"
            5 => "Tratamiento"
          ]
        ]
      ]
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    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Behavioural variant frontotemporal dementia &#40;bvFTD&#41; is the most frequent presentation in the clinical spectrum of frontotemporal dementia &#40;FTD&#41; and it is characterised by progressive changes in personality and conduct&#46; Major breakthroughs in molecular biology and genetics made during the last two decades have lent us a better understanding of this syndrome&#44; which may be the first manifestation in many different neurodegenerative diseases&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0015">Development</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">We reviewed the main epidemiological&#44; clinical&#44; diagnostic and therapeutic aspects of bvFTD&#46; Most cases manifest sporadically and the average age of onset is 58 years&#46; Current criteria for bvFTD propose three levels of diagnostic certainty&#58; possible&#44; probable&#44; and definite&#46; Clinical diagnosis is based on a detailed medical history provided by family members and caregivers&#44; in conjunction with neuropsychological testing&#46; Treatments which have been used in bvFDT to date are all symptomatic and their effectiveness is debatable&#46; New drugs designed for specific molecular targets that are implicated in frontotemporal lobar degeneration are being developed&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0020">Conclusions</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">BvFDT is a frequent cause of dementia&#46; It is a non-specific syndrome associated with heterogeneous histopathological and biomolecular findings&#46; The definition of clinical subtypes complemented by biomarker identification may help predict the underlying pathology&#46; This knowledge&#44; along with the development of drugs designed for molecular targets&#44; will offer new treatment possibilities&#46;</p>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0030">Introducci&#243;n</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">La variante conductual de la demencia frontotemporal &#40;DFT vc&#41; es el s&#237;ndrome cl&#237;nico m&#225;s frecuente de las demencias frontotemporales &#40;DFT&#41; y se caracteriza por una alteraci&#243;n progresiva de la personalidad y la conducta&#46; En las &#250;ltimas 2 d&#233;cadas&#44; los avances en biolog&#237;a molecular y gen&#233;tica han contribuido a un mayor conocimiento de esta entidad&#44; que puede ser el modo de presentaci&#243;n de diferentes enfermedades neurodegenerativas&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0035">Desarrollo</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Se revisan los principales aspectos epidemiol&#243;gicos&#44; cl&#237;nicos&#44; diagn&#243;sticos y terap&#233;uticos de la DFT vc&#46; La mayor&#237;a de los casos son espor&#225;dicos&#44; inici&#225;ndose en torno a los 58 a&#241;os de media&#46; Los criterios diagn&#243;sticos vigentes establecen 3 niveles de certeza diagn&#243;stica&#58; posible&#44; probable y definitivo&#46; El diagn&#243;stico cl&#237;nico se basa en la anamnesis detallada de familiares&#44; complementada con la realizaci&#243;n de test neuropsicol&#243;gicos dirigidos&#46; Hasta la fecha&#44; los tratamientos empleados son solo sintom&#225;ticos y de eficacia controvertida&#46; Se est&#225;n dise&#241;ando f&#225;rmacos dirigidos contra dianas moleculares espec&#237;ficas implicadas en la patogenia de las degeneraciones lobares frontotemporales&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0040">Conclusiones</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">La DFT vc es una causa frecuente de demencia&#46; Se trata de un s&#237;ndrome amplio&#44; heterog&#233;neo desde el punto de vista histopatol&#243;gico y biomolecular&#46; La definici&#243;n de subtipos cl&#237;nicos y la identificaci&#243;n de biomarcadores podr&#237;an ayudar a predecir la afecci&#243;n subyacente&#44; lo que junto con el desarrollo de f&#225;rmacos dirigidos contra dianas moleculares ofrece nuevas posibilidades terap&#233;uticas&#46;</p>"
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Please cite this article as&#58; Fern&#225;ndez-Matarrubia M&#44; Mat&#237;as-Guiu JA&#44; Moreno-Ramos T&#44; Mat&#237;as-Guiu J&#46; Demencia frontotemporal variante conductual&#58; aproximaci&#243;n cl&#237;nica y terap&#233;utica&#46; Neurolog&#237;a&#46; 2014&#59;29&#58;464&#8208;472&#46;</p>"
      ]
    ]
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        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
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        "tabla" => array:3 [
          "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">bvFTD&#58; behavioural variant frontotemporal dementia&#59; FTLD&#58; frontotemporal lobar degeneration&#59; PET&#58; positron emission tomography&#59; MRI&#58; magnetic resonance imaging&#59; SPECT&#58; single photon emission computed tomography&#59; CT&#58; computed tomography&#46;</p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Neurodegenerative disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Progressive deterioration of behaviour and&#47;or cognition evidenced by observation or medical history</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Possible bvFTD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">At least 3 of the following cognitive or behavioural symptoms are present&#44; persistently or recurrently &#40;A&#8211;F&#41;&#58;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>A&#46; Early behavioural disinhibition &#40;3 years&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>B&#46; Early apathy or inertia &#40;3 years&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>C&#46; Early loss of empathy &#40;3 years&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>D&#46; Perseverative&#44; stereotyped&#44; or compulsive&#47;ritualistic behaviour&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>E&#46; Hyperorality and dietary changes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>F&#46; Neuropsychological profile&#58; executive function deficits with relative sparing of memory and visuospatial functions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Probable bvFTD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">All following conditions should be met&#58;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>A&#46; Fulfils criteria for possible bvFTD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>B&#46; Exhibits significant functional decline&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>C&#46; Neuroimaging findings compatible with frontal and&#47;or anterior temporal atrophy &#40;CT or MRI&#41; or hypoperfusion &#40;SPECT&#41; or hypometabolism &#40;PET&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Definitive bvFTD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Criterion A plus B or C must be met&#58;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>A&#46; Meets criteria for possible or probable bvFTD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>B&#46; Histopathological evidence of FTLD in biopsy or at post-mortem&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>C&#46; Presence of a known pathogenic mutation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Exclusion Criteria for bvFTD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>A&#46; Pattern of deficits is better accounted for by a different non-degenerative neurological or other medical disorder&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>B&#46; Behavioural disturbance is better accounted for by a psychiatric disorder&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>C&#46; Biomarkers strongly indicative of Alzheimer disease or another neurodegenerative process<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Criterion C does not rule out diagnosis of possible bvFTD but effectively rules out probable bvFTD&#46;</p>"
            ]
          ]
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          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Consensus criteria for clinical diagnosis of behavioural variant of FTD &#40;Rascovsky&#44; 2007&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">67</span></a></p>"
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                  \t\t\t\t">Clinical signs&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Type 3&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Psychotic symptoms&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Type 3&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Disinhibition and altered semantic features of language&nbsp;\t\t\t\t\t\t\n
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                    0 => array:2 [
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                      "autores" => array:1 [
                        0 => array:2 [ …2]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Frontotemporal lobar degeneration&#58; demographic characteristics of 353 patients"
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Article information

ISSN: 21735808
Original language: English

DOI:10.1016/j.nrleng.2013.03.004

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Year/Month	Html	Pdf	Total

2024 November	9	1	10
2024 October	97	13	110
2024 September	65	5	70
2024 August	63	11	74
2024 July	36	8	44
2024 June	37	4	41
2024 May	29	11	40
2024 April	39	6	45
2024 March	35	7	42
2024 February	50	14	64
2024 January	89	8	97
2023 December	43	20	63
2023 November	44	17	61
2023 October	54	6	60
2023 September	36	11	47
2023 August	47	15	62
2023 July	28	8	36
2023 June	33	6	39
2023 May	37	15	52
2023 April	29	10	39
2023 March	22	5	27
2023 February	24	10	34
2023 January	42	21	63
2022 December	32	14	46
2022 November	35	13	48
2022 October	38	23	61
2022 September	36	16	52
2022 August	36	15	51
2022 July	21	12	33
2022 June	20	14	34
2022 May	31	19	50
2022 April	42	21	63
2022 March	64	39	103
2022 February	40	14	54
2022 January	78	21	99
2021 December	52	14	66
2021 November	49	23	72
2021 October	36	19	55
2021 September	47	31	78
2021 August	76	15	91
2021 July	31	17	48
2021 June	21	17	38
2021 May	41	19	60
2021 April	141	69	210
2021 March	55	15	70
2021 February	64	16	80
2021 January	58	21	79
2020 December	48	15	63
2020 November	48	8	56
2020 October	34	6	40
2020 September	47	14	61
2020 August	50	7	57
2020 July	27	6	33
2020 June	32	14	46
2020 May	44	14	58
2020 April	52	7	59
2020 March	29	5	34
2020 February	28	18	46
2020 January	48	16	64
2019 December	61	6	67
2019 November	56	14	70
2019 October	46	9	55
2019 September	50	15	65
2019 August	33	9	42
2019 July	41	11	52
2019 June	118	27	145
2019 May	220	25	245
2019 April	108	42	150
2019 March	48	19	67
2019 February	55	7	62
2019 January	40	16	56
2018 December	37	6	43
2018 November	52	9	61
2018 October	44	7	51
2018 September	49	19	68
2018 August	74	9	83
2018 July	23	2	25
2018 June	21	13	34
2018 May	17	5	22
2018 April	23	1	24
2018 March	22	2	24
2018 February	14	4	18
2018 January	18	6	24
2017 December	26	4	30
2017 November	25	2	27
2017 October	25	6	31
2017 September	24	8	32
2017 August	24	5	29
2017 July	27	1	28
2017 June	40	16	56
2017 May	37	7	44
2017 April	53	10	63
2017 March	31	57	88
2017 February	24	7	31
2017 January	24	6	30
2016 December	37	15	52
2016 November	33	11	44
2016 October	36	3	39
2016 September	46	9	55
2016 August	67	6	73
2016 July	28	6	34
2016 June	37	17	54
2016 May	32	8	40
2016 April	24	27	51
2016 March	42	38	80
2016 February	35	16	51
2016 January	27	10	37
2015 December	24	9	33
2015 November	35	9	44
2015 October	42	10	52
2015 September	49	8	57
2015 August	48	9	57
2015 July	75	6	81
2015 June	40	9	49
2015 May	94	7	101
2015 April	56	14	70
2015 March	50	10	60
2015 February	32	8	40
2015 January	37	13	50
2014 December	56	21	77
2014 November	54	24	78
2014 October	101	48	149

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