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 An Overview of Frontotemporal Dementia and Non-Alzheimer’s Dementias

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 B12)  toxin exposure  infection  neurodegeneration

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

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

Neurodegenerative Diseases  Alzheimer’s disease  frontotemporal dementia (FTD)  behavioral variant (“Pick’s disease”)  primary progressive aphasias  posterior cortical atrophy (PCA)  progressive supranuclear palsy (PSP)  corticobasal degeneration (CBD)  dementia with Lewy bodies (DLB)  Huntington’s disease  Parkinson’s disease  ALS (Lou Gehrig’s disease) predominantly cognitive symptoms predominantly motor symptoms cognitive & 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 20s)  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 FRONTAL PARIETAL TEMPORAL

LobeFunction frontalrestraint, planning, initiative empathy language production (left) temporalmemory face and object identification language comprehension (left) parietalspatial processing occipitalvisual processing Brain Anatomy

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  2000s: more new discoveries than in past 100 years  2011: new international consensus diagnostic criteria

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

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 (bvFTD)  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 *

bvFTD: Structural Imaging Findings MRI: atrophy of frontal and temporal lobes normal bvFTD

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

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 McMonagle & Kertesz Neurology 2006 normalPCA

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 Kato et al J Neurol Sci 2003 “hummingbird sign” normal

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 bvFTDDLB

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 >> bvFTD  Case 3: 53 ♀  problems with spatial relationships >> PCA  Case 4: 68 ♂  visual hallucinations, sleep abnormalities >> DLB

Why Bother?  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 “This is dementia. There is no cure.”