Various clinical syndromes were described explaining. Frontotemporal Dementia and Psychiatric Symptoms. Reviews. Elif Onur 1, Pınar Dikmen Yalınay 2 - PDF

Düşünen Adam The Journal of Psychiatry and Neurological Sciences 2011;24: DOI: /DAJPN Reviews Frontotemporal Dementia and Psychiatric Symptoms Elif Onur 1, Pınar Dikmen Yalınay

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Düşünen Adam The Journal of Psychiatry and Neurological Sciences 2011;24: DOI: /DAJPN Reviews Frontotemporal Dementia and Psychiatric Symptoms Elif Onur 1, Pınar Dikmen Yalınay 2 1 Assoc. Prof. Dr., Dokuz Eylül University Medical School, Department of Psychiatry, İzmir - Turkey 2 Neurologist, Acıbadem University Medical School, Department of Neurology, İstanbul - Turkey ABSTRACT Frontotemporal dementia and psychiatric symptoms Frontotemporal dementia (FTD) is the second most common cause of early onset dementia and is clinically characterized by progressive behavioural change, executive dysfunctions, and language difficulties. FTD is frequently confused with Alzheimer s disease and psychiatric disorders. Clinical features of FTD include changes of personality, restlessness, loss of inhibition, apathy, social withdrawal and impulsiveness. Most patients with FTD display socially inappropriate behaviours, compulsive-like acts, poor insight and psychiatric features including hallucinations and paranoid delusions. These symptoms can lead to misdiagnosing FTD as a psychiatric disorder. The etiology of sporadic FTD is unknown. In hereditary FTD, a causative mutation in the tau gene has been identified. Three clinical FTD syndromes has been described; a behavioural variant of FTD, semantic dementia and progressive non-fluent aphasia. At the present time the term FTD is used to define clinical syndromes while frontotemporal lobar degeneration refers to underlying pathologies. A detailed history and psychiatric and neurologic examination with the usage of magnetic resonance imaging can help to distinguish FTD from other common forms of dementia and psychiatric disorders. Although no effective treatment for FTD exists, serotonin reuptake inhibitor drugs have been shown to improve behavioural symptoms. Key words: Frontotemporal dementia, neuropsychiatric symptoms, treatment ÖZET Frontotemporal demans ve psikiyatrik belirtiler Frontotemporal demans (FTD), erken başlangıçlı demanslar içinde ikinci sıklıkta görülmektedir; ilerleyici davranış değişiklikleri, yürütücü işlevlerdeki bozukluklar ve lisan problemleri ile karakterizedir. FTD, sıklıkla Alzheimer hastalığı ve psikiyatrik hastalıklarla karışır. Klinik olarak, kişilik değişiklikleri, huzursuzluk, inhibisyon kaybı, apati, sosyal geri çekilme ve impuls kontrolünde bozukluk görülür. Frontotemporal demanslı birçok hastada uygunsuz sosyal davranışlar, kompulsiyon benzeri hareketler, içgörü kaybı ve psikiyatrik hastalıklarda görülebilen varsanılar ve paranoid sanrılar gibi belirtiler nedeniyle hastalar sıklıkla psikiyatrik bozukluk tanısı alırlar. Sporadik FTD nin etiyolojisi bilinmemektedir. Herediter FTD de 17. kromozomda, tau geninde mutasyonlar olduğu saptanmıştır. Üç klinik FTD sendromu tanımlanmıştır: Davranış varyantı, semantik demans ve ilerleyici tutuk afazi. Günümüzde FTD terimi klinik sendromları kapsarken, frontotemporal lob dejenerasyonu ise altta yatan patolojiyi tanımlamak için kullanılır. Ayrıntılı öykü, psikiyatrik ve nörolojik muayene, manyetik rezonans görüntüleme FTD yi diğer sık görülen demanslardan ve psikiyatrik bozukluklardan ayırt etmeye yardım eder. Frontotemporal demansın etkin bir tedavisi olmamasına karşın, serotonin geri alım inhibitörlerinin davranışsal belirtilerin kontrolünde yararlı olduğu gösterilmiştir. Anahtar kelimeler: Frontotemporal demans, nöropsikiyatrik belirtiler, tedavi Address reprint requests to: Assoc. Prof. Dr. Elif Onur, Dokuz Eylül Üniversitesi Sağlık Yerleşkesi. Psikiyatri Anabilim Dalı. İnciraltı 35340, İzmir - Turkey Phone: address: Date of receipt: February 28, 2011 Date of acceptance: March 21, 2011 INTRODUCTION Various clinical syndromes were described explaining primary degenerative processes related with frontal and/or temporal lobes: Pick s Disease, frontotemporal dementia (FTD) related with chromosome 17 and Parkinsonism, Frontotemporal lobar degeneration (FTLD) with motor Neuron Disease (MND). In recent years, FTD has been used to define clinical syndromes and FTLD is used to define pathological processes (1). EPIDEMIOLOGY Studies about epidemiology of FTD is limited although it makes up % of degenerative dementias (2). In postmortem studies, prevalence among all types of dementia was found 3-10% (3). In population-based studies, prevalence of FTD was found / in Zuid-Holland study and 7.8/ in North London study (5). Gender distribution is equal in frontotemporal 228 Düşünen Adam Psikiyatri ve Nörolojik Bilimler Dergisi, Cilt 24, Sayı 3, Eylül 2011 / Düşünen Adam The Journal of Psychiatry and Neurological Sciences, Volume 24, Number 3, September 2011 E. Onur, P. D. Yalınay dementia. Its onset is between 45 and 65 years of age and mean survey is 6-9 years (3,6). PATHOPHYSIOLOGY Although it was focused on genetic mutations to bring out pathophysiology of frontotemporal dementia and important findings were achieved, pathophysiology of the disease has not been understood yet. Genetics of FTD is complicated with multiple genetic factors and more than 40% of cases are genetically inherited with 10% of them being autosomal dominant (7). Microtubule-related protein (MAPT), valosinecontaining protein (VCP), chromatin-modifying protein 2 (CHMP2B) and TDP-43 (TARDP) are previously described mutations (8). After the role of tau protein gene mutations inherited at chromosome 17 in FTD cases were understood, more than 35 tau mutations were detected in familial FTD cases (5,9). Proportion of tau mutations in familial cases is around 30% (5). Tau is a microtubule-related protein with low molecular weight coded by a gene at Chromosome 17. Mutations in tau protein alter the structure of microtubules and affect neuronal transport and may even cause neuronal death. Cases of FTD without a mutation in tau protein lead to investigate different genetic mutations. Progranuline gene mutations at chromosome 17 were found to be related to FTD (5,6). Although there are FTD cases having presenilin gene mutations at chromosome 14, its direct relation to FTD is not clear (3,6,9). In frontotemporal dementia, macroscopically there is atrophy in frontal and temporal lobes and microscopically there is superficial cortical spongious changes and gliosis in grey and white matters (10,11). Recent tendency is to classify FTD based on neuroanatomical, biochemical and molecular genetic changes. FTLD is histopathologically classified into two groups according to presence or absence of specific inclusion bodies: containing tau positive inclusion bodies (Pick, chromosome 17-related FTLD and Parkinsonism) and containing ubiquitine positive, tau negative inclusion bodies (6,7,12). It was also proposed that autoimmunity has a role in ethiopathogenesis of FTLD. However, it is not clear whether processes are primary or secondary (3). Frontotemporal Dementia and Neurotransmitter Changes It was suggested that alterations in serotonergic, cholinergic, dopaminergic, glutamatergic and noradrenergic systems have roles in neuropathology of the disease especially in behavioral variant (13). Serotonin: Impulsivity, depressive symptoms, change in eating habits and compulsive behaviors support presence of serotonergic dysfunction seen in frontotemporal dementia (13,14). Brain imaging and autopsy studies following decrease in number of serotonin receptors in temporal and frontal cortices shown by Procter et al. (15) showed anomalies of serotonin receptors. Yang et al. (16) showed decrease in raphe nucleus neurons in FTD patients and reported that seroteonergic tracts ascending to forebrain may be affected. Decrease in 5-HT2A (17) and 5-HT1A receptors (18) were detected in orbitofrontal, medial frontal and cingulate cortices. These findings explain efficacy of selective serotonin reuptake inhibitors (SSRI) in FTD. Acetylcholine: Neurons of Meynert s basal nucleus was found preserved (19), cortical acetylcholine transferase levels were found normal (15,19) and postsynaptic muscarinic receptor binding was found to be normal (15) in the studies. These findings and inefficacy of acetylcholine esterase enzyme inhibitors suggest that there is not an evident pathology in the cholinergic system. Dopamine: Levels of homovalinic acid (HVA) which is a dopamine metabolite in cerebrospinal fluid were reported to be low in patients with FTD (20). It was shown that presynaptic dopamine transporters in putamen caudate nucleus are decreased (21) and severity of extrapyramidal symptoms are related with secretase in striatal dopamine transport (22). HVA/5- hydroxyindolacetic acid (5-HIAA) ratios in cerebrospinal fluid were detected higher than other dementias (Alzheimer dementia (AD), mixed dementia, Lewy body dementia) and were found to be related with Düşünen Adam Psikiyatri ve Nörolojik Bilimler Dergisi, Cilt 24, Sayı 3, Eylül 2011 / Düşünen Adam The Journal of Psychiatry and Neurological Sciences, Volume 24, Number 3, September Frontotemporal dementia and psychiatric symptoms aggressive behaviors in sub-group of FTD patients not receiving psychotropic drugs (23). Noradrenaline: Studies which evaluated both number of noradrenergic neurons in locus ceruleus and levels of noradrenalin metabolite methoxy-hydroxyphenyl-glycol (MHFG) did not find clear results (13). Glutamate: Findings suggest that alterations in glutamtergic system may have roles in FTD. Studies showed that there is a decrease in the number of N-methyl-D-aspartate (NMDA) and α-amino-3- hydroxy-5-methyl-4-isoxasole proprionic acid (AMPA) receptors (23) at cortical pyramidal cells of frontal and temporal cortex (24). There is need for further studies on the role of glutamatergic system. CLINICAL MANIFESTATIONS Frontotemporal dementia is classified into 3 subtypes according to clinical and neuroanatomical localizations as Behavioral variant (FTDbv), Semantic variant (SD) and Progressive Non-Fluent Aphasia (PNA) (25). Behavioral Variant Neuropsychiatric symptoms are more prevalent. Personality and social behavioral changes seen in initial period of the disease were described in Clinical Consensus Criteria (25) (Table 1). These criteria may be inadequate especially at the early period due to a group of patients called phenocopy which carry clinical characteristics of behavioral FTD but symptoms do not substantially progress over time. Criteria were revised (26,27). In newly formed criteria, behavioral variant were evaluated in 3 diagnostic accuracy level as possible, probable and definite. In the possible category, presence of three of basic behavioral or cognitive symptoms is mandatory; in probable category, these symptoms should substantially progress and supported by brain imaging findings and in definite category presence of neuropathological findings or genetic mutations is mandatory (Table 2) (26). Loss of empathy, inappropriate affection, behavioral disinhibition, loss of social awareness, apathy/ aspontaneity, stereotypical behaviors and alterations in eating habits (addiction to food with a high carbohydrate content) can be seen. Slight cognitive changes and predominant psychiatric symptoms cause difficulties in differential diagnosis at early period. In this period, while clinical tests (working memory, planning, mental flexibility, response inhibition, concept formation) are within normal limits, it will be useful to evaluate neuropsychological functions related with ventromedial prefrontal cortex (28,29). Sub-types were defined according to assessment of grey matter and neuroanatomical features (predominantly frontal, frontotemporal, temporofrontoparietal, predominantly temporal) or behavioral characteristics and involvement of related neural tracts (apathetic type, disinhibited type, stereotypical) (30). Table 1: Neary Consensus Criteria in Diagnosis of Frontotemporal Dementia Neary et al. (25), Consensus Criteria: Behavioral Variant of Frontotemporal Dementia (bvftd) Basic Diagnostic Characteristics Insidious onset and slow progression Impairment of interpersonal social relations in early period Impairment in personal attitude in early period Emotional blunting in early period Loss of insight in early period Neary et al. (25), Consensus Criteria: Behavioral Variant of Frontotemporal Dementia (bvftd) Supportive Diagnostic Characteristics Behavioral Characteristics Language and Speech Characteristics Physical Characteristics Insidious onset and slow progression Economical or suppressive speech Primitive reflexes Impairment of interpersonal social relations in early period Stereotypical speech Incontinence Impairment in self-hygiene in early period Echolalia Akinesia, rigidity and tremor Emotional blunting in early period Perseveration Low or labile blood pressure Mutism 230 Düşünen Adam Psikiyatri ve Nörolojik Bilimler Dergisi, Cilt 24, Sayı 3, Eylül 2011 / Düşünen Adam The Journal of Psychiatry and Neurological Sciences, Volume 24, Number 3, September 2011 E. Onur, P. D. Yalınay Table 2: Rascovsky et al. (26) Behavioral Variant Revised Criteria Possible Behavioral Variant. Repetitive presence of at least 3 criteria. A Early (3 years) behavioral inhibition B Early (3 years) apathy or dullness C Early (3 years) loss of empathy or sympathy D Early (3 years) perseverative, stereotypical or compulsive /ritualistic behaviors E Hyperorality and alterations in eating habits F Neuropsychological profile: Memory and visuspatial -and to a minor extent- executive dysfunction Most Probable Behavioral Variant. All criteria should be met. A Meeting possible behavioral variant criteria B Significant functional impairment C Brain imaging findings consistent with behavioral variant (frontal and/or temporal atrophy in computed tomography or magnetic resonance or hypoperfusion in SPECT or PET imaging) Definite Behavioral Variant. Presence of B or C with criterion A. A Meeting possible or probable diagnostic criteria of behavioral variant B Histopathological diagnosis by post-mortem biopsy C Presence of pathogenic mutations Exclusion Criteria of Behavioral Variant. A and B criteria negative, C criterion can be positive in possible behavioral variant but it should highly probably be negative in behavioral variant. A Pattern of deficits can be explained by other neurodegenerative dementia or medical conditions better. B Behavioral characteristics can be explained better by psychiatric disorders. C Biomarkers point out Alzheimer dementia or other neurodegenerative dementias. Additional Characteristics A Presence of motor neuron findings lead to motor neuron disease. B Motor manifestations and findings point out corticobasal degeneration and progressive supranucelar palsy. C Word and object naming impairment D Motor speech defects E Significant grammar deficits Semantic Dementia: Anterior temporal area is predominantly affected. When right temporal lobe is predominantly affected then problems in emotional perception and expression are seen and when left temporal lobe is affected, language impairment is predominant. There is insidious and slowly progressive language impairment (fluent aphasia) is present when left side is affected. Speech is fluent, empty and spontaneous. Place orientation and memory is relatively preserved in these patients different from AD. Behavioral symptoms can be seen in moderate-to-severe phases in patients with semantic dementia and obsessivecompulsive features are predominant (10,31). Progressive non-fluent aphasia: This is an insidious, slowly progressive clinical picture with left frontal atrophy. Language disorder is predominant and non-fluent speech accompanied by at least one of the features such as anomia, agrammatism or paraphasia. Behavioral symptoms occur late in the course (10,32). PSYCHIATRIC SYMPTOMS Different psychiatric symptoms are seen according to affected neuroanatomical areas. Brain imaging studies showed that decrease in emotional processing, remoteness in interpersonal relations, hypomania-like behaviors are predominant when temporal areas are affected and apathy, and decrease in social activities are predominant when frontal areas are affected (33). Personality and behavioral changes, apathy, repetitive compulsive behaviors and lack of insight cause problems mainly in behavioral variant and especially at early periods and cause FTD cases misdiagnosed such as psychosis, schizophrenia, depression and late-onset Düşünen Adam Psikiyatri ve Nörolojik Bilimler Dergisi, Cilt 24, Sayı 3, Eylül 2011 / Düşünen Adam The Journal of Psychiatry and Neurological Sciences, Volume 24, Number 3, September Frontotemporal dementia and psychiatric symptoms bipolar disorder (34-37). Although psychiatric symptoms are prevalent, number of studies investigating prevalence of psychiatric disorders in FTD is limited. Mild Behavioral Impairment (MBI) is the clinical syndrome in which disinhibition is the predominant symptom, and which does not meet dementia or major psychiatric disorder diagnoses according to DSM-IV diagnostic criteria and does have behavioral and psychiatric symptoms (38). This definition also covers lack of severe cognitive disorder and maintenance of daily activities (38) and has risk of dementia, especially FTD. Taragano et al. (39) evaluated 119 MBI and 239 mild cognitive impairment (MCI) cases about development of dementia in their 5 year follow-up study. Dementia developed in 30% of patients with MCI and 70% of patients with MBI. However, FTD developed more in patients with MBI. It should be kept in mind that psychiatric-behavioral symptoms without cognitive impairment can be the prodromal phase of FTD. Psychiatric symptoms in frontotemporal dementia can be evaluated under 3 main topics: Personality and behavioral changes, affective symptoms and psychotic symptoms. Personality and Behavioral Changes Personality changes of insidious onset and impairment in interpersonal relations and mood are primary characteristics of behavioral variant. Brain imaging studies showed that especially right temporal involvement is related with personality changes (33,40). Socially inappropriate behaviors such as childishness, inappropriate jokes and sexual statements are present among behavioral symptoms. Impairment in emotional processing may cause not performing socially appropriate behaviors (41,42). Neglecting self-hygiene, collecting weird objects, alterations in eating habits, compulsions about punctuality, late-onset gambling and rarely excessive religious involvement can be seen in behavioral variant (43-45). In semantic dementia, there are compulsive symptoms such as oversensitivity for timing and excessive dependence on daily routine (46). When left frontal hypoperfusion is evident, aggression, criminal behaviors, going away from friends, insensitivity to financial issues, pervert sexual behaviors are seen; when right frontal hypoperfusion is evident, political or religious ideologies and inconsistency in dressing and behaviors are seen (47). Behavioral symptoms and severity of the disease is correlated and agitation, disinhibition and irritability are mainly seen in late stages (45). Presence of typical or atypical behavioral symptoms, lack of evaluating social clues during interview of FTD patients, limited eye contact and lack of interest on whether their responses are correct may help in differential diagnosis (48). Detailed interviews with patients relatives and administering scales such as Neuropsychiatric Inventory, Frontal Behavior Questionnaire and Cambridge Behavioral Questionairre are recommended to evaluate behavioral symptoms (45). Affective Symptoms: Depression, apathy, irritability, anxiety and euphoria can be seen. Apathy has an important role among affective symptoms due to both its prevalence and importance in differential diagnosis of depression (45). FTD cases can be misdiagnosed as depression due to mental dullness, lack of motivation, l
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