An Overview of Frontotemporal Dementia and Non-Alzheimer s Dementias

An Overview of Frontotemporal Dementia and Non-Alzheimer’s Dementias Kimiko Domoto-Reilly, MD 1, 2, 5 Daisy Sapolsky, MS, CCC-SLP 1, 3, 4 Aly Negreira, BA 1, 3 1 Frontotemporal Disorders Unit, Departments of 2 Neurology, 3 Psychiatry, 4 Speech and Language Pathology, Massachusetts General Hospital, 5 Brigham Behavioral Neurology Group, Boston, MA

Outline dementia overview FTD and related dementias brain anatomy / pathology clinical signs / symptoms and progression treatment research multidisciplinary care team communication support resources

Dementia: Definition acquired loss of multiple cognitive abilities significant enough to interfere with typical daily activities multiple potential causes stroke amyloid angiopathy traumatic brain injury normal pressure hydrocephalus other medical conditions (e. g. , thyroid disorder, low vit B 12) toxin exposure infection neurodegeneration

Progression of Neurodegenerative Diseases Presymptomatic Prodromal Dementia Cognitive / Behavioral / Motor Function ~5 -20? years ~1 -10? years ~2 -20 years Years

Progression of Neurodegenerative Diseases Presymptomatic Prodromal Dementia Cognitive / Behavioral / Motor Function gradual accumulation of neuropathology Years

Neurodegenerative Diseases Alzheimer’s disease frontotemporal dementia (FTD) behavioral variant (“Pick’s disease”) primary progressive aphasias predominantly cognitive symptoms posterior cortical atrophy (PCA) progressive supranuclear palsy (PSP) corticobasal degeneration (CBD) dementia with Lewy bodies (DLB) cognitive & motor symptoms Huntington’s disease Parkinson’s disease ALS (Lou Gehrig’s disease) predominantly motor symptoms

Case 1: Alzheimer’s Disease 71 ♂: 2 year history of cognitive/behavioral changes difficulty coming up with people’s names left the keys in the front door several times while vacationing, got lost coming back from the store continues to play tennis, but loses track of the score gets confused about checking versus savings account no longer cooking the elaborate meals he was known for less patient with the grandchildren

Case 2: Non-Alzheimer’s dementia 60♀: 2 year history of cognitive/behavioral changes no longer called children “just to check in” family: “She has no filter! Don’t ask her a question you don’t want answered” continues to perform chores around the house, but insists on a specific routine started smoking, including around the grandchildren (had quit in her 20 s) drives through stop signs and red lights needs to be reminded to change her clothes

Case 3: Non-Alzheimer’s dementia 53♀: 2 year history of cognitive/behavioral changes several “dings” while parking the car trouble keeping eyes on page while reading difficulty pouring liquids into measuring cups significant difficulty adjusting to house renovations occasionally wear shirts inside out

Case 4: Non-Alzheimer’s dementia 68♂: 2 year history of cognitive/behavioral changes left hand tremor quieter at family gatherings, speech softer and slower drifts off to sleep during the day wife often woken up at night when he seems to be acting out his dreams asked family, “Whose dog is that? ”

Brain Anatomy PARIETAL FRONTAL OCCIPITAL TEMPORAL

Brain Anatomy Lobe Function temporal memory face and object identification language comprehension (left) parietal spatial processing occipital visual processing frontal restraint, planning, initiative empathy language production (left)

FTD: Brief History 1892: case descriptions by Arnold Pick 71♀ with gradual behavioral decline followed by speech and language deterioration brain with frontal and temporal lobar atrophy 1911: pathologic description by Alois Alzheimer 1982: “PPA” coined by Marsel Mesulam 1998: first “consensus” diagnostic criteria for FTD 2000 s: more new discoveries than in past 100 years 2011: new international consensus diagnostic criteria

FTD: Demographics 3 rd most common neurodegenerative dementia 15% of all dementias most common early onset dementia (50 s-60 s) estimated to affect 250, 000 Americans typically more rapid decline than AD 10% inherited, ~60% sporadic

FTD: Brain Anatomy

FTD: Brain Anatomy

FTD: Brain Pathology normal proteins in brain cells → twisted & tangled clump within cells → clog machinery → damage cell disease focality: specific cells types in certain brain regions FTD proteins: tau, TDP-43, FUS, amyloid

FTD: Clinical Findings behavioral variant (bv. FTD) disinhibition socially inappropriate behavior impulsivity apathy loss of interest, drive, motivation loss of sympathy / empathy repetitive / compulsive / ritualistic behavior language variants (3 subtypes) progressive nonfluent aphasia (PNFA) logopenic progressive aphasia (LPA) semantic dementia (SD)

FTD: Diagnosis history from patient and family review possible alternative diagnoses medication side effects primary psychiatric / seizure / sleep disorder brain tumor additional tests neuropsychology testing brain scans: structural (MRI), functional (PET) lumbar puncture * continued follow up *

bv. FTD: Structural Imaging Findings MRI: atrophy of frontal and temporal lobes normal bv. FTD

bv. FTD: Functional Imaging Findings PET: hypometabolism of frontal and temporal lobes

FTD: Clinical Course starts out distinctly as one variant, indicating brain region initially involved often progresses to involve other domains language variants may include behavioral changes behavioral variants may include language changes in movement may also occur coordination problems, slowing, stiffness, falls changes in eye movements impaired swallowing survival is 2 – 20+ years after onset of symptoms

FTD: Treatment disease modifying medication (slow / stop / reverse) none currently symptomatic medications nothing is yet proven Alzheimer’s medications: Aricept (donepezil), Namenda (memantine) antidepressants / mood stabilizers: SSRIs, valproate stimulants?

FTD: Research Presymptomatic Prodromal Dementia Cognitive / Behavioral / Motor Function Presymptomatic / Prodromal gradual decrease accumulation of neuropathology Years understand natural history of FTD “calibrate” tools for monitoring risk factors genetics treatment disease modifying

Non-Alzheimer’s Dementias posterior cortical atrophy (PCA) brain anatomy: parietal lobes protein: often amyloid symptoms: difficulties with spatial relationships clinical course: functionally blind treatment: Alzheimer’s medication; antidepressants normal PCA Mc. Monagle & Kertesz Neurology 2006

Non-Alzheimer’s Dementias progressive supranuclear palsy (PSP) brain anatomy: deep structures of brain protein: tau symptoms: vertical eye movement abnormalities, slowed thinking / movements, axial rigidity, postural instability with falls backwards, abnormal displays of emotional clinical course: wheelchair bound treatment (supportive): prism glasses, support stockings for blood pressure drops, change diet for swallowing difficulties normal “hummingbird sign” Kato et al J Neurol Sci 2003

Non-Alzheimer’s Dementias corticobasal degeneration (CBD) brain anatomy: asymmetric, frontoparietal protein: mixed symptoms: asymmetric limb stiffness, alien limb, myoclonic jerks, apraxia clinical course: may overlap with PNFA treatment: limited

Non-Alzheimer’s Dementias dementia with Lewy bodies (DLB) brain anatomy: occipital lobe protein: amyloid, α-synuclein (Lewy bodies) symptoms: visual hallucinations, fluctuating alertness, sleep disorder, Parkinsonian features clinical course: may develop delusions treatment: Parkinson’s medications, Alzheimer’s medications; sensitivity to antipsychotics bv. FTD DLB

Non-Alzheimer’s Dementias Huntington’s disease brain anatomy: deep structures (basal ganglia) protein: huntingtin symptoms: fidgity → chorea clinical course: impulsivity, poor judgment, suicidality treatment: tetrabenazine if movements become problematic; feeding tube genetics: autosomal dominant

Non-Alzheimer’s Dementias FTD-ALS brain anatomy: motor system protein: TDP-43 symptoms: muscle weakness, muscle twitching, muscle wasting, nasal voice, behavioral changes clinical course: weakness ↔ disinhibition; rapid decline treatment: riluzole; motorized wheelchair, feeding tube

Case Review Case 1: 71♂ prominent memory problems, but also difficulty with navigation, multistep tasks >> AD Case 2: 60♀ lack of empathy, poor decisions and insight, rigid routine >> bv. FTD Case 3: 53♀ problems with spatial relationships >> PCA Case 4: 68♂ visual hallucinations, sleep abnormalities >> DLB

Why Bother? “This is dementia. There is no cure. ” importance of diagnosis ensure diagnosis is correct which symptoms are part of the disease, which aren’t plan appropriately for future potential genetic implications multidisciplinary team appropriate monitoring provide support and education for patient and caregivers receive treatment as soon as it becomes available