Frontotemporal Dementia (FTD)

Frontotemporal Dementia (FTD)
Monica K. Crane, MD Associate Director Cole Neuroscience Center, UTMCK Clinical Assistant Professor, Dept. of Medicine

Frontotemporal dementia (FTD) Overview
Background and clinical definition Prevalence Anatomy FTD clinical subtypes Neuropathology and genetics of Frontotemporal lobe dementia (FTLD) Historical cases

FTD = a clinical neurodegenerative disease affecting frontal & temporal lobes
Personality changes Loss of socially acceptable behavior & emotions Bizarre and compulsive behaviors Language dysfunction Movement disorder Some of the features that I find in in the clinic include lack of concern for other’s – particularly if a loved one is sick – FTD patients lack any kind of response They can be socially inappropriate – ie loss of the filter and frequent use of explicit language. Persons can have other socially unacceptable behaviors – ie picking, fecal perseverating, hoarding unusual items. The most alienating behaviors are driven by specific anatomy – thus Right Anterior temporal damage causes persons to be unable to express emtions In additional persons can be hyperoral secondary to R insular and R ventral medial frontal cortex. I give the examples of persons gaining pounds from carbohydrate overeating. I had one patient who would eat everything to the point of eating condiments after her husband locked the refrigerator. Another patient with FTD0MND also have a specific behavior where he would only early pimento sandwiches and would chew 30+ packs of gum daily.

FTD International Research Criteria:
Three of the following: Either #7 or #8 one symptom from #1-6 OR Early disinhibition Early apathy, loss of motivation Loss of emotional recognition Perseverative, compulsive, ritualistic behavior Hyperorality/ dietary changes FTD neuropsychological profile 7. Frontal and/or anterior temporal atrophy; other radiologic findings 8. Presence of a known mutation TO meet criteria you need three of the top three symptoms. However if you the radiological or mutation findings you only need one other criteria. B. L. Miller, C. Ikonte, M. Ponton, et al. Neurology 1997;48;937

“Dementia That's Neither Alzheimer's Nor Easy”
Frontotemporal dementia is a very focal disorder. This slide represents fluorodeoxyglucose (18F), commonly abbreviated 18F-FDG or FDG, is radiotracer used in PET positron emission tomography. In Alzheimer’s disease, the posterior cingulate cortex, medial-posterior temporal lobe and medical-posterior parietal lobe, namely precuneus. In FTD, the prefrontal cortex and inferior frontal cortex, and anterior temporal lobe and anterior cingulate cortex are highly affected. In a 2010 study by Agosta at UCSF, she reported that if the posterior networks are affected it is likely AD but if anterior networks are affected that it in NOT AD – or it would be very rare to be AD And if the termporal poles are affected – highly likely that it is FTD not AD Language networks in semantic dementia Brain January; 133(1): 286–299. Federica Agosta,1,2 Roland G. Henry,3 Raffaella Migliaccio,1,4 John Neuhaus,5 Bruce L. Miller,1 Nina F. Dronkers,6,7 Simona M. Brambati,1,8 Massimo Filippi,2 Jennifer M. Ogar,1 Stephen M. Wilson,1 and Maria Luisa Gorno-Tempini1,9 Normal Alzheimer's FTD FDG-PET images of metabolic activity: healthy controls, AD, and FTD. Scale red (high FDG uptake)-yellow-green-blue (low FDG uptake). Photo Credit: Dr. Janet Miller, Dr. Suzanna Lee, MGH/ Harvard, Radiology Rounds April 2006

Dementia Prevalence (% of each type seen in US)
FTD syndromes~10-15% Alzheimer’s Disease (AD) ~ 50-70% Vascular dementia ~ 5-10% Dementia with Lewy Bodies & Parkinson’s disease dementia ~10% Boxer AL, Miller BL. Alzheimer Dis Assoc Disord. 2005;19 S1:S3-6

FTD Prevalence FTD: Alzheimer’s disease (AD) ratio is 1:1 in those aged Ratnavalli et al, Neurology 2002. FTD is more common that AD below age 60. Knopman et al, Neurology 2004. FTD spectrum comprises near 15% or more of the total FTD dementia cases. Boxer AL, Miller BL. Alzheimer Dis Assoc Disord. 2005. FTD is actually quite common. Among younger patients (<65) the prevalence is greater than that of Alzheimer disease… so at least 50% of the cases are FTD Boxer AL, Miller BL. Clinical features of frontotemporal dementia. Alzheimer Dis Assoc Disord. Oct-Dec 2005;19 Suppl 1:S3-6 Cruts M, Gijselinck I, van den Zee J, et al. Null mutations in progranulin cause ubiquitin positive frontotemporal dementia linked to chromosome 17q21. Nature. 2006;442: Among younger patients (<65) the prevalence is greater than that of Alzheimer disease… so at least 50% of the cases are FTD! Accurate prevalence information comes from a Dutch study (Stevens et al)  74 cases in a population of 15 million (i.e. 5 cases per 1,000,000  Among those aged years, 28 cases per 100,000

Pick’s disease ≠ FTD Pick’s is an autopsy finding only so do not use this term. The clinical disease is FTD. In 1892, Dr. Pick reported a case of a 71 year-old man with focal atrophy and aphasia, & concluded that “progressive brain atrophy can lead to symptoms of local disturbance through local accentuation of the diffuse process.” History of Psychiatry v (1994), GE Berrios and DM Girling. Classic Text No 20. Cambridge. The emphasis of Dr. Pick’s report was frontotemporal deficit not histopathology. The term is historically incorrectr as Dr. Pick described cases with focal cortical deficit due to frontotemporal “circumscribed atrophy” Pick bodies are made of 3r TAU The great Prague neuropsychiatrist (Dr. Pick) reported a case of a 71 year-old man with focal senile atrophy and aphasia. This paper has been quoted by generations as the locus classicus for what is called Pick’s disease. He summarized the report with “simple His case study, "On the relationship between aphasia and senile atrophy of the brain", still serves as a frame of reference for apparently focal brain syndromes in diffuse or generalized degenerative diseases of the brain.1 As Pick stated, “simple progressive brain atrophy can lead to symptoms of local disturbance through local accentuation of the diffuse process.” Dr. Arnold Pick ( ) Prof. of Psychiatry, Prague History of Psychiatry v. 1994, GE Berrios , DM Girling. Classic Text No 20. Cambridge.

Pick’s is a small subset of FTLD
Frontotemporal lobar degeneration (FTLD) = Neuropathology of clinical FTD Pick’s is a small subset of FTLD Although most FTDs are tauopathies or associated with ubiquitin-positive, and tau- and -synuclein-negative inclusions, the neuropathology of other FTDs is heterogeneous and the clinical manifestations of FTDs do not indicate the underlying neuropathology. Therefore more informative biomarkers are needed to distinguish AD from the other disorders shown here and in Fig. 3. Note: some of the disorders listed here and in Fig. 3 are double or triple brain amyloidoses because inclusions formed by multiple amyloidogenic proteins (for example, senile plaques formed by fibrillar A , neurofibrillary tangles (NFTs) formed by phosphorylated forms of tau, and Lewy bodies formed by -synuclein filaments) occur in these diseases. 3R-tau, tau isoforms with three microtubule-binding repeats; 4R-tau, tau isoforms with four microtubule-binding repeats; AGD, agyrophilic grain disease; CBD, corticobasal degeneration; DLDH, dementia lacking distinctive histopathology; FTDP-17, FTD with Parkinsonism linked to chromosome 17; FTLD, frontotemporal lobar degeneration, an alternative term for DLDH; FTLD-U, FTD with ubiquitin-positive but tau- and -synuclein-negative inclusions; LBVAD, Lewy body variant of AD; NFID, neuronal intermediate filament disease; PiD, Pick's disease; PSP, progressive supranuclear palsy; TPSD, tangle predominant senile dementia. From: LM Shaw LM, Korecka M, Clark CM, Lee VMY, Troganowski. Biomarkers of neurodeneration for diagnosis and monitoring therapeutics Nature Reviews Drug Discovery. 2007;6:

Heterogeneity of FTD subtypes: Anatomy and Clinical presentation

What areas of the brain are affected in FTD?

FTD damages 3 major networks: Dorosolateral prefrontal cortex (DLPFC) Anterior cingulate cortex (ACC) Orbitofrontal cortex (OFC) In figure A, The dorsolateral prefrontal cortexof DLPFC is the important area of the brain for neuropsychological behavior The orbitofrontal cortex is important in inhibition of behaviors The ACC is important in the initiation of activity – this gives us drive.

Areas affected in FTD versus AD
Hagmann P, Cammoun L, Gigandet X, Meuli R, Honey CJ, et al. Entorhinal cortex 2009

Clinical Presentation: FTD Subtypes

Frontotemporal dementia subtypes
Behavior variant (bvFTD) Semantic dementia (SD) Progressive nonfluent aphasia (PNFA) Progressive Supranuclear Palsy (PSP) Corticobasal degeneration (CBD) FTD with motor neuron disease (FTD-MND) ALS/CTE (Chronic Traumatic Encephalopathy) FTD is not as rare as we had previously thought – in fact it is quite common Elevated levels of the TDP-43 protein have also been identified in individuals diagnosed with chronic traumatic encephalopathy, a condition that often mimics ALS and that has been associated with athletes who have experienced multiple concussions and other types of head injury. Boxer AL, Miller BL. Clinical features of frontotemporal dementia. Alzheimer Dis Assoc Disord. 2005;19 S1:S3-6

Behavioral variant (bvFTD)
Approximately 60% of patients with any form of FTD have bvFTD. Figure 1. Coronal pathology section showing asymmetric right-sided atrophy (R temporal cortices with widening of the inferior horn of the lateral ventral). This is an autopsy example of the asymmetric atrophy of this case of behavioral variant FTD In this coronal slice, the right side shows marked atrophy of the temporal cortices. Accompanying this atrophy is more severe involvement of the right orbitofrontal cortex and widening of the inferior horn of the lateral ventricle. R L

Clinical Features of bv-FTD
Gradual onset Impaired judgment and planning Apathy Impaired insight (anosognosia) Loss of empathy and emotion recognition (alexithymia) Disinhibition Abnormal eating behavior Stereotypical or ritualistic behavior Personal neglect

Cogn Behav Neurol. 2010 Sep;23(3):159-64.
The use of profanity during letter fluency tasks in frontotemporal dementia and Alzheimer disease. Ringman JM, Kwon E, Flores DL, Rotko C, Mendez MF, Lu P. Source UCLA Department of Neurology, Easton Center for Alzheimer's Disease Research at UCLA, Los Angeles, CA , USA. Abstract OBJECTIVE: To assess whether the production of profanity during letter fluency testing distinguishes frontotemporal dementia (FTD) and Alzheimer disease (AD) patients. BACKGROUND: Alterations in language and social behavior typify FTD spectrum disorders. Nonetheless, in can be difficult to distinguish pathologically defined frontotemporal lobar degeneration (FTLD) from AD clinically. Assessing verbal fluency by having patients generate words beginning with specific letters in a given period of time can yield diverse information of diagnostic use. METHOD: Words produced during FAS letter fluency testing were reviewed, and instances of the use of "f*ck," "*ss," and "sh*t" and other words felt to be inappropriate were sought. The frequency of these words was compared between clinically diagnosed FTD and AD patients using χ(2) tests. RESULTS: We found that 6/32 (18.8%) patients with FTD generated the word "f*ck" during the "F" trial as opposed to none of 38 patients with AD (P=0.007). Patients who said "f*ck" had diagnoses of either behavioral variant FTD (3/15), progressive nonfluent aphasia (2/8), or semantic dementia (1/3). CONCLUSIONS: Though the specific neuropathology in these cases is uncertain, generation of "f*ck" during letter fluency testing seems to have use in differentiating FTD from AD. Profanity use during letter fluency tasks can differentiate FTD from AD. Ringman JM et al. Cogn Behav Neurol 2010;23:159-64

Behavior & Social problems
Clinical Features FTD AD Age of onset Rarely >75 Increases w age Behavior & Social problems Early disinhibition, + socially inappropriate Moderate-severe, increases with severity Language Isolated language problem Language + memory Visuospatial deficit Rare in mild-moderate Common Motor signs Unusual Mood Alexithymia, withdrawal, verbal irritability, labile Sadness, anhedonia Psychotic features Somatic, religious, bizarre delusions Delusions increase with disease severity Appetite/ hunger/diet Overeating, weight ↑↑; carbohydrate craving Weight loss, anorexia; misses meals Alexithymia – difficulties in understanding processing, or describing emotionasl Muangpaisan W. Clinical Differences Among Four Common Dementia Syndromes. Geriat Aging. 2007;10: McKhann MG et al. Clinical and pathological diagnosis of frontotemporal dementia. Arch Neurol 2001;58: Muangpaisan W et al. Frontotemporal dementia. Neuro J Thai 2003;3:45-51. otions Muangpaisan W. Geriat Aging. 2007; McKhann MG et al. Arch Neurol 2001; Muangpaisan W et al. Neuro J Thai 2003

>50% of FTD subtypes misdiagnosed as primary psychiatric disease
Woolley et al. J Clin Psychiatry. 201; 72(2): 126–133. Fig. % of patients initially misdiagnosed prior to neurodegenerative disease diagnosis for symptoms that eventually led to a ND diagnosis separated by gender. ♂ denotes male while ♀ denotes female patients. (*=p<0.01; †=p<0.05) Behavioral variant bvFTD misdiagnosed often (52.2%) Semantic Dementia patients misdiagnosed (24.4%) PNFA patients misdiagnosed (11.8%) Most common in FTD is not as rare as we had previously thought – in fact it is quite common Boxer AL, Miller BL. Clinical features of frontotemporal dementia. Alzheimer Dis Assoc Disord. Oct-Dec 2005;19 Suppl 1:S3-6 Cruts M, Gijselinck I, van den Zee J, et al. Null mutations in progranulin cause ubiquitin positive frontotemporal dementia linked to chromosome 17q21. Nature. 2006;442: Among younger patients (<65) the prevalence is greater than that of Alzheimer disease… so at least 50% of the cases are FTD! .. Accurate prevalence information comes from a Dutch study (Stevens et al)  74 cases in a population of 15 million (i.e. 5 cases per 1,000,000  Among those aged years, 28 cases per 100,000 correct diagnoses included bipolar affective disorder, Figure. % of patients initially misdiagnosed prior to ND diagnosis

Computer Self-Test (CST) as a diagnostic tool
Dougherty JD et al. The computerized self test (CST): an interactive, internet accessible cognitive screening test for dementia. J Alzheimer's Dis 2010 Apr;20: Crane MK et al. Distinguishing Frontotemporal dementia from Alzheimer’s disease: A pilot study employing the Computer Self-Test (CST). Dementia Geriatr Cogn Disord 2010;30:62. However, overlap in clinical presentation can make FTD difficult to distinguish from AD. Furthermore, while FTD is the 3rd most common primary dementia, nearly 50% of FTD patients are misdiagnosed or go undiagnosed.6-8 The CST is a quick Internet-accessible self-administered cognitive battery that may be useful in screening among dementia subtypes.

CST Cognitive pattern differentiates AD from FTD
Of 399 subjects, 247 were healthy controls, and 152 were cognitively impaired (30 of the patients had FTD) The study consisted of 399 total subjects with seven subgroups: control (n=247), 33 MCI , Early AD 26, mild-moderate AD 33, moderate-severe 25, severe 5 and FTD 30. With the computer data we were able to plot the degree of difference from the control to form a cognitive pattern unique to FTD. FTD patients were statistically different than Alzheimer’s patients in the clock face, clock numbering, clock hands, total clock and attention tasks. Crane, MK et al.Neurology Suppl(March) 76;

VIDEO example of bvFTD alexithymia

VIDEO example of a bvFTD patient with a palmar grasp reflex
The palmar grasp reflex appears at birth and persists until five or six months of age. When an object is placed in the infant's hand and strokes their palm, the fingers will close and they will grasp it. The grip is strong but unpredictable; though it may be able to support the child's weight, they may also release their grip suddenly and without warning. The reverse motion can be induced by stroking the back or side of the hand.

Behavior variant (bvFTD) Semantic dementia (SD) Progressive nonfluent aphasia (PNFA) Progressive Supranuclear Palsy (PSP) Corticobasal degeneration (CBD) FTD with motor neuron disease (FTD-MND) ALS/CTE (Chronic Traumatic Encephalopathy) Semantic dementia Boxer AL, Miller BL. Alzheimer Dis Assoc Disord. 2005;19 S1:S3-6

Semantic dementia (SD) or temporal variant
LEFT predominance •Language features: fluent speech but loss of semantics (word choice) •Reading declines, numbers intact RIGHT predominance • Severe deficits in understanding emotions; loss of empathy • Difficulty recognizing faces and facial expression Eventually R-sided disease progresses to L with language features, and visa versa SD patients develop bvFTD behaviors Semantic dementia or temporal variant FTD accounts for approximately 20% of FTDs. Semantic dementia can be left or right predominant L predominant disease can appear to be superficially similar to Wernicke’s aphasia but persons have relative preservation of familiar semantic items whereas Wernicke’s aphasia patients tend to have global semantic deficits regardless of familiarity. Additionally semantic dementia patients have deficits in behavior and expression of emotion R predominant disease tends to affect emotions and ability to recognize emotions

VIDEO example of semantic deficits

with phonetic fluency deficits
VIDEO example of bvFTD with phonetic fluency deficits

Behavior variant (bvFTD) Semantic dementia (SD) Progressive nonfluent aphasia (PNFA) Progressive Supranuclear Palsy (PSP) Corticobasal degeneration (CBD) FTD with motor neuron disease (FTD-MND) ALS/CTE (Chronic Traumatic Encephalopathy) Boxer AL, Miller BL. Alzheimer Dis Assoc Disord. 2005;19 S1:S3-6

Progressive nonfluent aphasia (PNFA)
20% of FTD cases Hesitant, effortful speech; stutter or return of childhood stutter Anomia, agrammatism, sound errors (“gat” for “cat”) Eventually develop severe movement disorder that overlaps with PSP and CBD Marcel Ravel, ( ) French composer. - in the early stages of PNFA/FTD when composing the orchestral work Boléro (1928). Progressive nonfluent aphasia makes up approimately 20% of FTD cases. Persons have difficultly with naming and have very labored hard to produce speech thus patients tend to be extremely silent. The famous French composer, Marcel Ravel was in the early stages of frontotemporal dementia during 1928, and this might account for the repetitive nature of Boléro.

Progressive nonfluent aphasia (PNFA)
Case 1 Case 2 These are Coronal T1 weighted MRI images of patients with progressive nonfluent aphasia. Patient 1 has mild PNFA showing L sided atrophy affecting the temporal lobe and the frontal operculum (or pars triangularis or Broadmans area 45 – Broca’s area) Case 2 is moderate PNFA and the MRI shows a more generalized atrophy that is asymmetrical being more on the left and in the perisylvian region. Tau mutations have symmetric atrophy,Progranulin mutations have asymmetric atrophy Fig. Coronal T1 weighted MRI of mild and moderate PNFA Case 1: mild PNFA, atrophy of temporal lobe & pars triangularis. Case 2: moderate PNFA, global atrophy with L-sided and perisylvian predominance.

Progressive supranuclear palsy (PSP)
Dudley Moore Progressive supranuclear palsy Deterioration of cells in the brainstem, frontal cortex and basal ganglia

Progressive supranuclear palsy (PSP)
key features Postural instability and falls within first year of diagnosis Vertical supranuclear opthalmoparesis Upward gaze paresis with abnormal saccadic eye movements Axial rigidity Cognitive decline Early stage difficult to distinguish from multiple system atrophy, Parkinson disease, and small vessel diease. Most patients with PNFA have PSP or CBD postmortem PSP has been described as a movement disorder associated with falls, ophthalmoplegia, axial rigidity and a frontal dementia Many patients do not present with just falls – but when probed – the very first symptom was falling Upward or DOWNWARD Gaze paresis “doe in headlights” appearance with early abnormalities of saccadic eye movements Persons can Like CBD, tau inclusions are seen postmortem. Recently, it has become evident that most patients with PNFA show PSP or CBD postmortem.

PSP radiologic features
Hypometabolism on FDG-PET in basal ganglia, brainstem, and frontal lobes PSP is characterized pathologically by the presence of tau positive neurofibrillary tangles, astrocytes, and ballooned neurons with neuronal degeneration involving the basal ganglia, brainstem, and frontal lobes. Hypometabolism on FDG-PET in basal ganglia, brainstem, and frontal lobes

Midbrain atrophy in PSP
(A) Normal: convex upper border of the midbrain (B) Severe atrophy of the midbrain with (C) concave upper border of midbrain “humming bird sign”. B A PSP has been described as a movement disorder associated with falls, ophthalmoplegia, axial rigidity and a frontal dementia. Like CBD, tau inclusions are seen postmortem. Recently, it has become evident that most patients with PNFA show PSP or CBD postmortem. Pronounced atrophy of the midbrain (mesencephalon), which accounts for the typical upward gaze paralysis. Normally the upper border of the midbrain is convex. The atrophy of the midbrain in PSP results in a concave upper border of the midbrain with the typical 'humming bird There is cell loss and gliosis in the cerebellar dentate nucleus as well as atrophy and demyelination in the superior cerebellar peduncle (SCP) as well as pathologic involvement of the dentato- rubrothalamic tract, which makes up the bulk of the fibers in the SCP, has been well documented. Most recently, macroscopic atrophy of the SCP at postmortem has been compared in PSP and other neurodegenerative diseases, concluding that SCP atrophy reliably distinguishes PSP.11 Criteria used for the diagnosis of PSP included midbrain diameter on axial scans of less than 17 mm, signal increase in the midbrain, atrophy or signal increase of the red nucleus and signal increase in the globus pallidus. No PSP patient was misclassified. Other studies have also suggested that reduced midbrain diameter on routine MRI may be of value in discriminating PSP from PD and MSA-P, although values may overlap with MSA-P and do not clearly correlate with disease duration or severity.35 Atrophy or abnormal signal of the superior cerebellar peduncle on proton-density-weighted MRI, postulated to represent demyelination and gliosis, may help in differentiating PSP from PD. C

Corticobasal Degeneration (CBD) criteria
Core Features Supportive Features Lateralized cognitive dysfunction with preserved memory and learning MRI with asymmetric atrophy in parietal and frontal cortex FDG-PET decreased glucose uptake in parietal and frontal cortex, basal ganglia and thalamus. Cortical dysfunction Asymmetric ideomotor apraxia Alien limb phenomenon Visual or sensory hemineglect Focal or asymmetric myoclonus Non-fluent aphasia (overlap with PNFA) Extrapyramidal dysfunction Asymmetric rigidity lacking sustained levodopa response, and focal dystonia CBD patients have what we term as ideomotor apraxia (inability to perform previously learned movements in the absence of weakness or sensory deficits Traditionally, CBD was defined by asymmetric parkinsonism with dystonia, rigidity, limb apraxia and a “useless or alien” limb. The dystonia can cause a limb to be immmobile and persons can develop contractures.- flexion of arm at elbow adduction fo shoulder and flexion internal rotation of wrist Contructional apraxia: a form of apraxia characterized by the inability to copy drawings or to manipulate objects to form patterns or designs. It is caused by a right hemisphere lesion. The deficit is tested by asking the patient to copy two-dimensional geometric patterns, such as circles, squares, diamonds, and hexagons, and to copy three-dimensional structures constructed of 1-inch building blocks. Pathological examination demonstrates neuronal inclusions with tau present in astrocytes and neurons.

Examples of decrease in cerebral cortical metabolism associated with atrophy of the corpus callosum. The corpus callosum on T1-weighted MRI images (repetition time, 400 milliseconds; echo time, 15 milliseconds) is shown on the left, and FDG_PET on the right. Patient 1 has focal atrophy of the corpus callosum in the middle portion (arrow) with mild decrease in glucose metabolism in the L frontoparietal cortex (arrow) Patient 2 the MRI shows Moderate atrophy of the corpus callosum with more extensive decrease in glucose metabolism in the L frontoparietal cortex (arrows) Patient 3 has Severe, diffuse atrophy on MRI with a severe bilateral hypometabolism accentuated in the right frontoparietal cortex (arrows) Figure. CBD. Pt1: Mild, focal atrophy of corpus callosum with mild hypometabolism in L frontoparietal cortex (arrow). Pt2: Moderate atrophy of corpus callosum, moderate hypometabolism in L frontoparietal cortex (arrows) Pt3: Severe, diffuse atrophy with bilateral hypometabolism accentuated in the right frontoparietal cortex (arrows)

Behavior variant (bvFTD) Semantic dementia (SD) Progressive nonfluent aphasia (PNFA) Progressive Supranuclear Palsy (PSP) Corticobasal degeneration (CBD) FTD with motor neuron disease (FTD-MND) ALS/CTE (Chronic Traumatic Encephalopathy Elevated levels of the TDP-43 protein have been found in CTE, a also been identified in patients with CTE, a condition that often mimics ALS and that has been associated with athletes who have experienced multiple concussions and head injury. I won’t talk about ALS but I will note that there is a newly classified subtype of FTD coined ALS-chronic traumatic encephalopathy. Elevated levels of the TDP-43 protein have also been identified in patients with CTE, a condition that often mimics ALS and that has been associated with athletes who have experienced multiple concussions and head injury.

FTD with motor neuron disease (FTD-MND)
FTD-MND is a CLINICAL PHENOTYPE: 15% of FTD patients also have FTD-MND FTD-MND co-occurs in patients with bvFTD but rare in PNFA, CBD, PSP Early cognitive and behavioral changes with MND symptoms: slurring of speech, difficulty swallowing, choking Autonomic dysfunction limb weakness or muscle wasting Patients live ≈ 1.4 years after diagnosis (respiratory complications of bulbar symptoms as cause of death) Most common MND is amyotrophic lateral sclerosis (ALS); older ALS patients may also have behavioral or cognitive problems similar to those seen in FTD (FTD-ALS syndrome) FTD-MND is a CLINICAL PHENOTYPE: 15% of FTD patients also have FTD-MND FTD-MND co-occurs in patients with bvFTD but rare in PNFA, CBD, PSP Early cognitive and behavioral changes with typical motor neuron symptoms of slurring of speech, difficulty swallowing, choking Autonomic dysfunction limb weakness or muscle wasting MND affects motor nerve cells in the spinal cord, the brain stem (which sits on top of , and the cerebral cortex. Because the brainstem was once referred to as the “bulb”, you may hear some MND symptoms described as bulbar symptoms. Most common MND is amyotrophic lateral sclerosis (ALS); older ALS patients may also have behavioral or cognitive problems similar to those seen in FTD (FTD-ALS syndrome)

Results of MRI voxel-based morphometry analyses: behavior & language dominant FTD-MND analysis compared to control Results of voxel-based morphometry analyses (A) Patterns of gray matter loss in FTD with motor neuron disease as compared to controls. Both groups show gray matter loss in the frontal and temporal lobes. The MRI voxel-based morphology analyses allows us to highlight the between the 2 groups The behavioral-dominant group showed greater loss in the frontal lobes The language-dominant group showed greater loss in the left lateral inferior temporal lobe and right putamen Both with frontotemporal gray matter loss. Behavioral variant FTD-MND↓ ↓ in frontal lobes. Language variant FTD-MND ↓ ↓ in L lateral inferior temporal lobe and R putamen. Coon E et al. Neurology 2011;76:

Neuropathology and Genetics

FTD inheritance Genetic (40%) Sporadic (60%)
50-80% of individuals appear to be the first person with FTD in the family, also called sporadic or nonfamilial FTD (family not at risk). Approximately 20-50% of FTD patients have an affected 1st degree relative. Familial FTD is suspected when 2+ family members are affected in 2+ generations. Among individuals with FTD, approximately 10% have a single gene mutation (autosomal dominant inheritance). FTD iis much more of a genetic disease than that of AD. Approximately 20-50% of FTD patients have an affected 1st degree relative. Familial FTD is suspected when 2+ family members are affected in 2+ generations. Among individuals with FTD, approximately 10% have a single gene mutation (autosomal dominant inheritance). However most of the mutation are sporadic .

Frontotemporal Lobar Degeneration (FTLD) is the pathologic confirmation of clinical FTD
FTLDs are histopathologic diagnosis with neuronal loss & gliosis, spongiosis & ballooned neurons (image below). Abnormal protein inclusions in neurons & glial cells. Tauopathies: FTLD with tau+ inclusions TDP-43 proteinopathies: FTLD with tau-, alpha-synuclein- inclusions which contain the protein TDP-43 + conjugated with ubiquitin+ FUS: tau-, ubiquitin+, TDP-43-, with fused in sarcoma (FUS) inclusions Microscopic findings: neuronal loss and gliosis, vacuolization of the superficial cortex (spongiosis), and ballooned neurons.

FTD is a clinically and genetical heterogenous group of diseases
FTD is a clinically and genetical heterogenous group of diseases. Note the spectrum of disease starting from a pure motor neuron disease (at left to the right with cbd and psp. In familial FTD, mutations in two genes, microtubule associated protein tau and Progranulin (GRN), account for about half of these cases. Rare defects in VCP, CHMP2B, TARDP and FUS genes have been found in a small number of families The two major groups are those with tau-positive inclusions (FTLD-tau) and those with ubiquitin-positive and TAR DNA-binding protein of 43 kDa (TDP-43) positive inclusions (FTLD-TDP). Clinical, neuropsychological, imaging, genetic and pathological developments that have changed our understanding of FTD. AN early diagnosis with accurate prediction of underlying pathology during life will be required for disease-specific therapeutic trials in the future. Seelar H, Rohrer LD, Pijnenburg YAL, Fox NC, can Swieten JC. Clinical, genetic and pathological heterogeneity of frontotemporal dementia: A review. J Neurol Neurosurg Psychiatry 2010.

Tau immunopositive inclusions and neurofibrillary tangles (NFTs) in tauopathy family of FTLDs
Pick inclusion bodies: tau-positive spherical cytoplasmic neuronal inclusions, composed of straight filaments NFTs and neuritic threads (arrow) in the gray matter of the frontal cortex. Pick inclusion bodies: tau-positive spherical cytoplasmic neuronal inclusions, composed of straight filaments NFTs and neuritic threads (arrow) in the gray matter of the frontal cortex. Perinuclear inclusions of (asterisk) within the frontal cortex Perinuclear inclusions of (asterisk) within the frontal cortex Reynolds M R et al. J. Neurosci. 2006;26: 51

BIGGEST ADVANCE in ALS and FTD
Chromosome 9 open reading frame 72 (C9ORF72) gene mutation most common cause of familial ALS and FTD Toxic buildup of RNA Similar to other ALS genes but not SOD1 40% of familial ALS of European descent 15% of familiar ALS SOD1 mutation Same expansion in 12% familial FTDand 3% sporadic FTD, 4% in sporadic ALS! Mutation is an expanded hexanucleotide repeat in a noncoding region of C9ORF72 Normal gene has between 2-20 GGGGCC units while mutant has 300+ Repeat is transcribed into RNA and normal gene is edited out The expanded repeat folds up on itself, forming aggregates Focus on Finland – highest incidence of ALS Expanded repeat in 30% of paients Non Finnish European ancestry 46% of patinets Brain and spinal cord pathology found 25% of cells in frontal cortex and spinal cord of affected patients; found expanded repeat RNA aggregates Aggregates also linked to MD (RNA aggregates depleat the neuron’s stock of RNA binding protein, accouting for manifestations of myotonic dystrophy) SOD1 ALS dementia is rare and no apparent RNA metabolism problem Mutations TDP43, C9ORF72 cause RNA metabolism problems with TDP43 contaitning protein aggregates FUS causes FUS protein aggregates Renton A, Majounie E, Waite A, J S-S, Sara Rollinson S, Gibbs J, et al. A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD. Neuron. 2011;72(2):257. Dejesus-Hernandez M, Mackenzie I, Boeve B, Boxer A, Matt Baker, Rutherford N, et a Neuron. 2011;72(2):245.

FTD and creative bursts
Trained in mathematics, chemistry and biology, Anne Adams, PhD decided to leave her career in science (1986) to care for a family member and to take up art. In 1994, she became fascinated with the music of Ravel, and thus painted “Unravelling Boléro” a work that translated the famous musical score into visual form. Ironically, Ravel was in early PNFA when composing Boléro. Both Adams and Ravel died from complications of PNFA/FTD. Anne Adams, PhD Chemist ( ) Trained in mathematics, chemistry and biology, Anne Adams, PhD decided to leave her career in science and devoted the rest of er life to painting. She was fascinated by repetitive forms. In 1994, she became fascinated with the music of Ravel, and thus painted “Unravelling Boléro” a work that translated the famous musical score into visual form. This Ravel was in the early stages of frontotemporal dementia during 1928, and this might account for the repetitive nature of Boléro. Both Adams and Ravel died from complications of PNFA/FTD. Marcel Ravel French Composer ( )

Anne Adams, Unravelling Boléro, 1994
n 1994, Dr. Adams became fascinated with Ravel. At age 53, she painted “Unravelling Bolero” translating the work into visual art. Unbeknownst to Adams, Ravel also suffered from a brain disease whose symptoms were identical to those observed in Dr. Adams. Ravel was also 53 when he composed Bolero in Ravel was also showing signs of his illness with spelling errors in musical scores and letters. “Bolero” alternates between 2 main melodic themes, repeating the pair 8 over 340 bars with increasing volume and layers of instruments. At the same time, the score holds methodically to two simple, alternating staccato bass lines. It iis an exercise in compulsivity, structure and perseveration. It builds without a key change until the 326th bar. Then it accelerates into a collapsing finale\ . Dr. Adams, who was also drawn to themes of repetition, painted one upright rectangular figure for each bar of “Bolero.” Height corresponds to volume, shape to note quality and color to pitch. The colors remain unified until the surprise key change in bar 326 that is marked with a run of orange and pink figures that herald the conclusion. Anne Adams, Unravelling Boléro, 1994 Each vertical figure represents a bar of music, with height corresponding to volume. The theme repeats & builds until a change to orange/pink, representing the key change preceding the dramatic conclusion.

Dr. Anne Adams, ‘Amsterdam’ (2004)
At the time of this painting, Adams was nearly mute taking seconds to initiate a word and was formally diagnosed with PNFA. Adams then developed a shuffling gait, R limb apraxia and dystonia, and stopped all verbal communication. She died in 2007 from advanced FTD with motor and respiratory symptoms. In 2004, AA painted ‘Amsterdam’ shortly before her diagnostic evaluation at UCSF. ‘Amsterdam’ was one of many paintings from this period that focused on buildings, with a particular emphasis on facades and surrounding surfaces. She was nearly mute taking 10-15s to initiate a word. Shortly after this painting she had a rapid limb apraxia and R upper extremity dystonia that impeded painting. Her gait became shuffling and she stopped all verbal communication. She died at age 67 from advanced FTD with motor and respiratory symptoms. Seeley W W et al. Brain 2008;131:39-49

Questions? Special thanks to the Cole Family Foundation for their ongoing support of the Cole Neuroscience Center at UTMCK, and to the Bagby family for their willingness to share and educate others Special recognition goes to my clinical mentor, Dr. John Dougherty, as well as to the neurologists and clinical team at Cole Neuroscience Center. In 1994, Dr. Adams became fascinated with the music of the composer Maurice Ravel, her husband recalled. At age 53, she painted “Unravelling Bolero” a work that translated the famous musical score into visual form. Unbeknown to her, Ravel also suffered from a brain disease whose symptoms were identical to those observed in Dr. Adams, said Dr. Bruce Miller, a neurologist and the director of the Memory and Aging Center at the University of California, San Francisco. Ravel composed “Bolero” in 1928, when he was 53 and began showing signs of his illness with spelling errors in musical scores and letters. “Bolero” alternates between two main melodic themes, repeating the pair eight times over 340 bars with increasing volume and layers of instruments. At the same time, the score holds methodically to two simple, alternating staccato bass lines. “ ‘Bolero’ is an exercise in compulsivity, structure and perseveration,” Dr. Miller said. It builds without a key change until the 326th bar. Then it accelerates into a collapsing finale. Dr. Adams, who was also drawn to themes of repetition, painted one upright rectangular figure for each bar of “Bolero.” The figures are arranged in an orderly manner like the music, countered by a zigzag winding scheme, Dr. Miller said. The transformation of sound to visual form is clear and structured. Height corresponds to volume, shape to note quality and color to pitch. The colors remain unified until the surprise key change in bar 326 that is marked with a run of orange and pink figures that herald the conclusion. Ravel and Dr. Adams were in the early stages of FTD when they were working, Ravel on “Bolero” and Dr. Adams on her painting of “Bolero,” Dr. Miller said. The disease apparently altered circuits in their brains, changing the connections between the front and back parts and resulting in a torrent of creativity.

Frontotemporal Dementia (FTD)

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Frontotemporal Dementia (FTD)

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