FRONTO TEMPORAL DEMENTIA

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1 FRONTO TEMPORAL DEMENTIA Dr. Diana Paleacu Kertesz Neurology Service and Memory Clinic Abarbanel Mental Health Center Department of Neurology, Tel Aviv University Fronto-Temporal Lobe Dementia (FTLD) DAT: 55-60% VD: 15-20% DLBD: 15-20% FTD: 10-15% A. PICK- (1892): clinical significance of selective frontal and/or frontotemporal cortical degeneration in dem. (6 pts.) PICK BODY Pick s disease Ballooned neurons argyrophillic round large inclusions weakly basophilic on H&E stain best demonstrated w/silver stain made up of TAU isoforms Lateral view Coronal view

2 End stage FTLD with striking atrophy of frontal and temporal lobes. No artophy of parietal and occipital lobes. Courtesy Webpath SCHEMATIC ORGANIZATION OF THE FRONTAL LOBES BRAIN REGION HYPOTHESIZED DYS FUNCTION FUNCTION ORBITOBASAL inhibition disinhibited, social control Impulsive antisocial confabulates DORSOLATERAL attention poor focus, working memory (area 46)alternate programs generate words, designs ideas self awareness & generation of affect (Rt>Lt) W.M. deficits poor organization poor planning expression of affect MEDIAL FRONTAL energy, motivation, drive apathy, abulia, depression? Adapted from Benson and Stuss (1986) PIRAMIDAL CELL CELL SPINDLE Location: Anterior cingulate cortex and Fronto-insular cortex and dorsolateral prefrontal cortex. Function: Global firing rate regulation and regulation of emotional state Morphology:Unique spindle-shaped projection neuron Presynaptic connections Local input to ACC and FI Postsynaptic connections Frontal and temporal cortex

3 WORKING MEMORY Working memory Working memory, is sometimes thought of as a synonym for SHORT TERM MEMORY (or STM). However the two terms have slightly different values, since the term working memory emphasised the active, taskbased nature of the store. The working memory is implicated particularly in carrying out complex cognitive tasks. The classic example is complicated mental arithmetic, in which a person must hold the results of previous calculations in working memory while they work on the next stage. The working memory contains two complementary systems for storing information the ARTICULATORY LOOP the visuospatial scratchpad. Both systems are linked to the so-called central executive, a more active system which actually performs the shortterm memory task under discussion. concept of working memory - Alan Badeley Working memory is where the brain stores information used to make immediate calculations, similar to the random access memory (RAM) in a computer. Like RAM, the information stored in working memory is dumped when it is no longer needed. Working memory allows the brain to take in information and create planned responses using ABSTRACT thought. Without it, human behavior would consist mostly of reflexive actions, and humans would not have been able to develop higher mental abilities. In a group of 20 healthy 8- to 30-year-olds, Dr. Luna and her colleagues used a test called an oculomotor delayed response task to track memory-guided saccades (eye movements) while imaging their brains using functional magnetic resonance imaging (fmri). Study participants briefly were shown a pinpoint of light and asked to remember where the light appeared. Ten seconds later, they were asked to look at the location where the light had been using just their memory. The 10-second time lapse was chosen because it would force the subjects to use their working memory and not short- or longterm memory. RESULTS OF THE IMAGING STUDY SHOWED THAT PRE- ADOLESCENT CHILDREN RELIED MOST HEAVILY ON THE PREFRONTAL AND PARIETAL REGIONS OF THE BRAIN DURING THE TASK; ADOLESCENTS USED THOSE REGIONS PLUS THE ANTERIOR CINGULATE; AND IN ADULTS, A THIRD AREA OF THE BRAIN, THE MEDIAL TEMPORAL LOBE, WAS BROUGHT IN TO SUPPORT THE FUNCTIONS OF THE OTHER AREAS. Frontotemporal lobar degeneration ADULTS DID BEST WITH THE SACCADE TEST PROBABLY BECAUSE THE MEDIAL TEMPORAL LOBE HELPS REFINE ENCODING OF INFORMATION INTO WORKING MEMORY. IN PRACTICAL SITUATIONS, INTRODUCTION OF THE MEDIAL TEMPORAL LOBE INTO THE WORKING MEMORY PROCESS LIKELY PROVIDES THE KICK NEEDED TO KEEP INFORMATION AROUND LONG ENOUGH AND CLEARLY ENOUGH FOR THE BRAIN TO MULL IT OVER AND MAKE A RATIONAL, INFORMED DECISION RATHER THAN AN IMPULSIVE, REFLEXIVE ACTION.

4 FTLD Dementia Initial clinical stages: Insidious onset, slow progression Marked personality changes Loss of personal and social awareness and judgement Hyperorality and perseverations Stereotyped and perseverative behavior, OCD Utilisation behavior Progressive diminution of speech W/ relative preservation of spatial orientation and memory and calculation intact PRIMARY PROGRESSIVE APHASIA Mesulam, % of dementia present w/aphasia word finding difficulty or anomia + well preserved memory and non-verbal cognition first two years are critical for Dg. Atypical: stuttering or phonological paraphasias or verbal apraxia w/writing and comprehension preserved (DD: functional) Then, non fluent aphasia => mutism SEMANTIC DEMENTIA Snowden, 1989 This begins with loss of knowledge about the world, which often presents as problems with language. Although people can still speak fluently they lose the words for certain items and also lose the knowledge of the meaning of the word. For example, someone may not only forget the word "hippopotamus" when shown a picture, but also loses all the knowledge they once had about this (e.g. that it is an African animal that lives in rivers). However, unlike in DAT, memory for day to day events (episodic) and autobiographic may be good. later stages, personality is often affected

5 AFFECTIVE SYMPTOMS IN FTD Depression, anxiety, excessive sentimentality Hypochondriasis and bizzare somatic activities Bizzare thought content (religiosity) Emotional unconcern amimia (aspontaneity, inertia, apathy) PHYSICAL SIGNS IN FTD Early primitive reflexes Early incontinence Late akinesia, rigidity, tremor Low and labile BP UMN + LMN signs in the presence of ALS INVESTIGATIONS Normal EEG despite clinical dementia Brain imaging (CT/MRI/SPECT) frontal and/or anterior temporal atrophy Neuropsychological tests - failure on frontal lobe tests despite absence of severe amnesia, aphasia or perceptual spatial disorders FAB SUPPORTIVE DIAGNOSTIC FEATURES Onset before age 65 positive family history of similar disorder in first degree relatives bulbar palsy, muscular wasting, fasciculations (MND)

6 DD WITH ALZHEIMER S DISEASE Mendez and co-workers (1993) found, even in the absence of temporal or frontal lobe atrophy on CT brain scans, that Pick's disease can be distinguished from Alzheimer's disease if 3 of the following 5 characteristics are present early in the disease: presenile onset (under 65 years old); initial personality change; hyperorality (loss of normal controls, e.g. excessive eating, indiscriminate putting things in one's mouth); disinhibition; and DD WITH ALZHEIMER S DISEASE seizures are uncommon delusions and hallucinations are rare and apraxia (inability to perform, command, or imitate a familiar action) and agnosia (inability to recognise objects) are less common. gait and muscle tone are affected (PD/MND). In the late stages EP symptoms, immobility, incontinence and mutism occur. In the terminal stage, the different dementias are clinically indistinguishable. roaming behaviour. DD WITH ALZHEIMER S DISEASE CLUES ON NEUROPSYCHOLOGICAL DG. Sparing of pentagon drawing on MMSE with scores below 20 better on visual recall, verbal and visual recognition more perseveration on WCS and Stroop specific disturbed behaviors:early loss of personal or social awareness, hyperorality, stereotyped or perseverative behaviors Imaging of frontotemporal dementia (FTD) subtypes. Seelaar H et al. J Neurol Neurosurg Psychiatry doi: /jnnp Imaging of frontotemporal dementia (FTD) subtypes. (A) Frontal atrophy on axial fluid attenuated inversion recovery MRI of a patient with behavioural variant of FTD (bvftd). (B) Axial T1-weighted image with left temporal lobe atrophy in a patient with semantic dementia (SD). (C) Coronal T1-weighted MR image of a patient with progressive nonfluent aphasia (PNFA) and left inferior frontal and superior temporal atrophy. (D) Axial T1- weighted MR image in a patient with predominant right temporal lobe atrophy by BMJ Publishing Group Ltd

7 MRI T2 FTLD This 59 year old woman had a three year history of a progressive alteration in social behavior which included apathy and occasional disinhibition. Images reveal severe focal shrinkage of temporal and frontal lobes bilaterally On the left a patient with progressive aphasia. The most prominent finding is the striking asymmetric atrophy of the temporal lobe on the left side with not only atrophy of the hippocampus, but also the temporal poles. The atrophy has resulted in gyri that appear as sharp as knives ('knife blade atrophy'). There is also some increased signal intensity seen on the FLAIR image probably due to gliosis. These findings are very typical for the diagnosis of FTLD HMPAO-SPECT PERFUSION IMAGES IN RED AND GREEN SCALE (PICK S DISEASE) Transaxial Sagital Coronal DDPAC (DISINHIBITION-DEMENTIA-PARKINSONISM-AMYOTROPHY COMPLEX) Subtype of FTD linked to cr. 17q21-22 mutations in the microtubule associated τ protein most mutations are in the 9-13 exons (10!) linkage analysis suggests that mutations in this region are implicated in other diseases as well: CBGD - ALS PSG - PSP

8 CORTICOBASAL GANGLIONIC DEGENERATION.Chronic progressive course.asymmetric at onset (includes dysphasia).presence of both: Higher Cortical Dysfunction Movement Disorders a. apraxia a. akinetic-rigid sd. unresponsive and/ or to L-dopa b. cortical sensory loss b. dystonic limb posturingh c. alien limb c. myoclonus late dementia OTHER MUTATIONS IN FTLD sporadic cases of FTD -(FTD-CHMP2B): several genes and a locus on chromosome 9p have been linked to familial FTLD with ubiquitinimmunoreactive, tau-negative inclusions (FTLD- U): genetic defects include mutations in the chromatin modifying protein 2B (CHMP2B gene), the cause of chromosome 3-linked FTLD Frontotemporal dementia with inclusion body myopathy and Paget disease of bone is a rare, autosomal-dominant disorder caused by mutations in the gene valosin-containing protein (VCP): mutations in the valosin-containing protein (VCP) gene, a cause of chromosome 9- linked FTLD

9 Neuropathologic diagnostic criteria for FTLD 1. Tauopathy (with associated neuron loss and gliosis) and insoluble tau with a predominance of 3R tau, the most likely diagnoses are: 2. FTLD with Pick bodies FTLD with MAPT mutation 1. Tauopathy (with associated neuron loss and gliosis) and insoluble tau with a predominance of 4R tau, the most likely diagnoses are 2. : Corticobasal degeneration Progressive supranuclear palsy Argyrophilic grain disease Sporadic multiple system tauopathy with dementia FTLD with MAPT mutation 1. Tauopathy (with associated neuron loss and gliosis) and insoluble tau with a predominance of 3R and 4R tau, the most likely diagnoses are: Neurofibrillary tangle dementia FTLD with MAPT mutation Frontotemporal neuronal loss and gliosis without tau- or ubiquitin/p62- positive inclusions, the most likely diagnoses is: FTLD (also known as dementia lacking distinctive histologic features) CONT 1. TDP-43 proteinopathy with associated neuronal loss and ubiquitinpositive/p62-positive, tau-negative inclusions, with MND or without MND but with MND-type inclusions, the most likely diagnoses are: FTLD-U with MND (FTLD-U types 1 3) FTLD-U but without MND (FTLD-U types 1 3) FTLD-U with GRN mutation (FTLD-U type 3) FTLD-U with VCP mutation (FTLD-U type 4) FTLD-U linked to chromosome 9p (FTLD-U type 2) Other as yet unidentified TDP-43 proteinopathies 1. Frontotemporal neuronal loss and gliosis with ubiquitin-positive/p62- positive, TDP-43- and tau-negative inclusions, the most likely diagnoses are: FTLD-U with CHMP2B mutation 2. Basophilic inclusion body disease (BIBD) Other as yet unidentified FTLD-U, non-tdp-43 proteinopathies Frontotemporal neuronal loss and gliosis with ubiquitin/p62 and α- internexin-positive inclusions, the most likely diagnosis is: Neuronal intermediate filament inclusion disease (NIFID) Behavioral variant of frontotemporal dementia (FTD-bv). Clinical diagnostic features: Early progressive decline in social interpersonal conduct Emotional blunting Loss of insight Supportive features: Mental rigidity Inflexibility Distractibility Hyperorality Decline in personal grooming and hygiene Primary progressive aphasia (PPA; also known as progressive nonfluent aphasia, or PNFA). Clinical diagnostic features: Gradual decline in spontaneous speech associated with: Anomia Agrammatism Phonemic paraphasias Loss of verbal fluency Parkinsonism. Clinical diagnostic features: Bradykinesia Rigidity Gait instability Resting tremor Corticobasal syndrome Clinical diagnostic features [Boeve et al 2003]: Progressive asymmetric rigidity Apraxia Alien-limb phenomenon Cortical sensory loss Focal dystonia Myoclonus Dementia Frontotemporal dementia associated with GRN (also known as PGRN) mutations Clinical, genetic and pathological spectrum of frontotemporal lobar degeneration. Seelaar H et al. J Neurol Neurosurg Psychiatry doi: /jnnp by BMJ Publishing Group Ltd

10 TDP-43 TAR DNA-binding protein 43 (TDP-43), encoded by the TARDBP gene, has been identified as the major pathological protein of FTLD with ubiquitin-immunoreactive (ub-ir) inclusions (FTLD-U) with or without amyotrophic lateral sclerosis (ALS) and sporadic ALS. Recently, mutations in the TARDBP gene in familial and sporadic ALS have been reported which demonstrate that abnormal TDP-43 alone is sufficient to cause neurodegeneration. TREATMENT No available treatment for FTD diminished brain serotonin => SSRI s (A. Kertesz) dopaminergic pathology => dopa replacement (bromocriptine for PPA) symptomatic (atypical) neuroleptics for behavioral disturbances

11 ENHANCED ARTISTIC CREATIVITY IN FTD PATIENTS The emergence of new skills in the setting of dementia suggests that loss of function in one brain area can release new functions elsewhere. painting Maurice Ravel and FTD References Subjects Medication Study Type Duration Main Findings Limitations Diehl-Schmid et al. [21] Kertesz et al. [22*] 16 (bvftd and tvftd) 36 (bvftd and PPA) Memantine 20mg/day Galantamine mg/day Cruz et al. [23] 1 (bvftd) Topiramate 100mg b.i.d. All participants given open-label treatment All participants given open-label treatment, followed by 8-week, doublelind,placebocontrolled, randomized withdrawal 6 months 18 weeks Case report 6 months No improvement in behavior; worsening of cognitive function No improvement in bvftd, trend of efficacy in PPA Reduction of alcohol abuse but not other compulsive behaviors Small sample size, no control group Possible admixture of AD patients in PPA group Case report, alcoholism uncommon in FTD Anneser et al. [24] 1 (FTD- MND) Sertraline 50 mg b.i.d. Case report n/a Successful treatment of inappropriate sexual behavior Case report Swanberg et al. [25] 3 (bvftd) Memantine 10 mg b.i.d. Case series, all patients given tx for 3 mo 3 months All 3 patients had improved NPI score, specifically apathy, agitation, and anxiety Sample size CLINICAL IMPLICATIONS Selective degeneration of the left anterior temporal lobe is often accompanied by loss of semantic knowledge, but preservation or enhancement of visual and musical abilities. Visual and musical abilities should be encouraged in the setting of left anterior temporal injury or dysfunction. Dementia is not invariably associated with relentless loss of all intellectual abilities. PROGNOSIS compared data from 70 autopsy-confirmed FTLD cases and 70 confirmed AD cases, matched to FTLD cases by demographic and cognitive status at initial evaluation. Overall, the FTLD group had a less favorable survival rate than the AD group (median survival after initial evaluation, 4.2 years vs. 6.0 years). Compared to FTLD patients with tau-positive pathology, FTLD patients with tau-negative pathology had a worse survival rate. The survival rate in tau-positive patients was similar to that in AD patients.

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