Cognitive and Behavioral Issues in PSP, CBD, FTD, and PPA · PSP, CBD, FTD, and PPA Future Directions •Increase awareness among the public and health care professions that PSP,

Bradley F. Boeve, M.D.

Division of Behavioral Neurology

Department of Neurology

Mayo Clinic

Rochester, Minnesota

Alzheimer’s Disease Research Center

Mayo Foundation

Bradley F. Boeve, M.D.Bradley F. Boeve, M.D.

Division of Behavioral NeurologyDivision of Behavioral Neurology

Department of Neurology Department of Neurology

Mayo ClinicMayo Clinic

Rochester, MinnesotaRochester, Minnesota

AlzheimerAlzheimer’’s Disease Research Centers Disease Research Center

Mayo FoundationMayo Foundation

Cognitive and Behavioral Issues in

PSP, CBD, FTD, and PPA

Cognitive and Behavioral Issues in Cognitive and Behavioral Issues in

PSP, CBD, FTD, and PPAPSP, CBD, FTD, and PPA

Cognitive and Behavioral Issues in

PSP, CBD, FTD, and PPAOutline

Cognitive and Behavioral Issues in Cognitive and Behavioral Issues in

PSP, CBD, FTD, and PPAPSP, CBD, FTD, and PPAOutlineOutline

• History

• Brain-Behavior Correlations

• The Syndromes/Disorders

• Management

• Resources

• Questions

• History

• Brain-Behavior Correlations

• The Syndromes/Disorders

• Management

• Resources

• Questions

HistoryHistoryHistory

PSP, CBD, FTD, and PPAHistory

PSP, CBD, FTD, and PPAPSP, CBD, FTD, and PPAHistoryHistory

• PSP – initially characterized in the 1960s

• CBD – initially characterized in the late 1960s

• PPA – initially characterized in 1982

– nonfluent variant

– semantic variant

• FTD – initially characterized in 1994

• PSP – initially characterized in the 1960s

• CBD – initially characterized in the late 1960s

• PPA – initially characterized in 1982

– nonfluent variant

– semantic variant

• FTD – initially characterized in 1994

PSP, CBD, FTD, and PPAHistory

PSP, CBD, FTD, and PPAPSP, CBD, FTD, and PPAHistoryHistory

• The 4 different disorders have been classically

considered to be distinct and separate

• Growing evidence that these are strikingly

similar, with one of the primary distinctions

being what parts of the brain are maximally

affected

• The 4 different disorders have been classically

considered to be distinct and separate

• Growing evidence that these are strikingly

similar, with one of the primary distinctions

being what parts of the brain are maximally

affected

Brain-Behavior CorrelationsBrainBrain--Behavior CorrelationsBehavior Correlations

PSP, CBD, FTD, and PPA Brain-Behavior Correlations

PSP, CBD, FTD, and PPA PSP, CBD, FTD, and PPA BrainBrain--Behavior CorrelationsBehavior Correlations

Templates

A B C

A

B

C

Thinking/Cognitive

A B C

A

B

C

Behavior

Language



Memory - hippocampi

A B C

A

B

C



“Emotional valence”

- amygdala

A B C

A

B

C



Problem-solving,

reasoning, complex

decision-making -

dorsolateral frontal regions

A B C

A

B

C



Socially appropriate

behavior, “theory of

mind” - ventromedial

frontal regions

A B C

A

B

C



Motivation, spontaneous

actions - anterior cingulate

region

A B C

A

B

C



A B C

A

B

C

Language - left frontal,

temporal, parietal regions

NamingNaming

““SpeechSpeech””

““SpeechSpeech””, ,

naming, naming,

comprecompre--

hensionhension

CompreCompre--

hensionhension, ,

namingnaming



C B A

A

B

C

Prosody - right frontal,

temporal, parietal regions



C B A

A

B

C

Visual recognition - right >

left temporal and occipital

regions



Social disinhibition

Loss of empathy and insight

Change in food preferences

Hoarding of food

Utilization behavior

A B C

A

B

C



Memory loss

A B C

A

B

C



Executive dysfunction

Poor planning and judgement

Inability to multitask

A B C

A

B

C



Loss of motivation

Tendency to sit, not initiative

conversations or actions

A B C

A

B

C



A B C

A

B

C

Poor verbal expression

NamingNaming

““SpeechSpeech””Poor naming of objects

and people



C B A

A

B

C

Aprosodia

Monotone voice

Unable to interpret inflections in

voice another person’s voice



C B A

A

B

C

Visual agnosia

Unable to recognize objects and

people



The Syndromes/DisordersThe Syndromes/DisordersThe Syndromes/Disorders

Progressive Supranuclear PalsyProgressive Supranuclear Palsy

Clinical Features Clinical Features

• symmetric rigidity and bradykinesia– axial > appendicular– levodopa unresponsive

• postural/gait instability– frequent falls

• extraocular movement dysfunction– saccadic pursuits– delayed, slowed saccades– supranuclear gaze palsy, particularly downgaze

• apathy, bradyphrenia

• symmetric rigidity and bradykinesia– axial > appendicular– levodopa unresponsive

• postural/gait instability– frequent falls

• extraocular movement dysfunction– saccadic pursuits– delayed, slowed saccades– supranuclear gaze palsy, particularly downgaze

• apathy, bradyphrenia

Corticobasal Syndrome/Corticobasal DegenerationCorticobasal Syndrome/Corticobasal Degeneration


• Progressive course

• Asymmetric findings

• Limb rigidity

• Limb apraxia

•• Progressive courseProgressive course

•• Asymmetric findingsAsymmetric findings

•• Limb rigidityLimb rigidity

•• Limb apraxiaLimb apraxia

Progressive asymmetric rigidity and apraxiaProgressive asymmetric rigidity and apraxiaProgressive asymmetric rigidity and apraxia

Behavioral Variant Frontotemporal DementiaBehavioral Variant Frontotemporal Dementia


• personality/behavioral changes• loss of empathy/sympathy

• loss of insight• apathy• social disinhibition• change in food preferences• poor judgement and planning

• personality/behavioral changes• loss of empathy/sympathy

• loss of insight• apathy• social disinhibition• change in food preferences• poor judgement and planning

Primary Progressive AphasiaPrimary Progressive Aphasia


• Nonfluent– changes in speech/language

production

• Semantic

– loss of nouns and word meaning

• Nonfluent– changes in speech/language

production

• Semantic

– loss of nouns and word meaning

Frontotemporal Lobar DegenerationsFrontotemporal Lobar Degenerations

PSPPSP CBDCBD FTDFTD PPAPPA

ManagementManagementManagement

PSP, CBD, FTD, and PPA Management

PSP, CBD, FTD, and PPA PSP, CBD, FTD, and PPA ManagementManagement

Pharmacotherapy

Improve symptoms

Manage behaviors

Decrease injury risk

PharmacotherapyPharmacotherapy

Improve symptoms

Manage behaviors


Non-Pharmacotherapy

Improve symptoms

Manage behaviors


Improve caregiving strategies

NonNon--PharmacotherapyPharmacotherapy

Improve symptoms

Manage behaviors


Improve caregiving strategies

Improve QOL for all involvedImprove QOL for all involved



• Approach – ask patients and caregivers to list and then rank which symptoms/problems are most bothersome,

which allows the clinicians to tailor the management plan

• Problem list:

– Cognitive

– Neuropsychiatric

– Motor

– Speech/swallowing

– Sleep

•• Approach Approach –– ask patients and caregivers to list and then ask patients and caregivers to list and then

rank which symptoms/problems are most bothersome, rank which symptoms/problems are most bothersome,

which allows the clinicians to tailor the management planwhich allows the clinicians to tailor the management plan

•• Problem list:Problem list:

–– CognitiveCognitive

–– NeuropsychiatricNeuropsychiatric

–– MotorMotor

–– Speech/swallowingSpeech/swallowing

–– SleepSleep



• There are no FTD-approved medications specifically

developed to impact PPA, CBD, FTD, and PPA

• There are few well-designed studies that have shown that any medication improves symptoms in any of these

disorders

• There is considerable debate among clinicians whether

any medications are worth using in patients with any of

these disorders

• Almost all medications to be discussed are expensive

and are associated with mild to severe side-effects

•• There are no FTDThere are no FTD--approved medications specifically approved medications specifically

developed to impact PPA, CBD, FTD, and PPAdeveloped to impact PPA, CBD, FTD, and PPA

•• There are few wellThere are few well--designed studies that have shown designed studies that have shown

that any medication improves symptoms in any of these that any medication improves symptoms in any of these

disordersdisorders

•• There is considerable debate among clinicians whether There is considerable debate among clinicians whether

any medications are worth using in patients with any of any medications are worth using in patients with any of

these disordersthese disorders

•• Almost all medications to be discussed are expensive Almost all medications to be discussed are expensive

and are associated with mild to severe sideand are associated with mild to severe side--effectseffects

Cognitive

Education/Counseling/Behavioral Management:

Stay physically, mentally, and socially active

Establish and maintain a daily routine

Religious use of a daily planner

CognitiveCognitive


Stay physically, mentally, and socially active

Establish and maintain a daily routine

Religious use of a daily planner



Cognitive (cont.)

Executive dysfunction, memory impairment:

? Carbidopa/levodopa, dopamine agonists

Sinemet®, Mirapex®, Requip®

? Cholinesterase inhibitorsAricept®, Exelon®, Razadyne®

? PsychostimulantsProvigil®, Nuvigil®, Ritalin®, Adderall®, Desoxyn®

? NMDA antagonistsNamenda®

Cognitive (cont.)Cognitive (cont.)

Executive dysfunction, memory impairment:

? Carbidopa/levodopa, dopamine agonists

Sinemet®, Mirapex®, Requip®



? NMDA antagonistsNamenda®



Neuropsychiatric


Develop tolerance and choose your battles!

Acknowledge and redirect; refrain from arguing

“Employ therapeutic fibs”

Support group involvement

Work with local psychologists and psychiatrists

NeuropsychiatricNeuropsychiatric


Develop tolerance and choose your battles!

Acknowledge and redirect; refrain from arguing

“Employ therapeutic fibs”

Support group involvement

Work with local psychologists and psychiatrists



Neuropsychiatric (cont.)

Disinhibition, socially inappropriate behavior, delusions:

? Selective serotonin reuptake inhibitorsCelexa®, Lexapro®, Paxil®, Prozac®, Remeron®, Zoloft®

? Atypical neurolepticsSeroquel®, Respirdal®, Zyprexa®

? AnticonvulsantsDepakote®, Neuronin®, Tegretol®

? Beta-blockersInderal®

Neuropsychiatric (cont.)Neuropsychiatric (cont.)

Disinhibition, socially inappropriate behavior, delusions:

? Selective serotonin reuptake inhibitorsCelexa®, Lexapro®, Paxil®, Prozac®, Remeron®, Zoloft®

? Atypical neurolepticsSeroquel®, Respirdal®, Zyprexa®

? AnticonvulsantsDepakote®, Neuronin®, Tegretol®

? Beta-blockersInderal®



Neuropsychiatric (cont)

Apathy:

? Selective serotonin reuptake inhibitorsCelexa®, Lexapro®, Paxil®, Prozac®, Zoloft®


? Carbidopa/levodopa, dopamine agonistsSinemet®, Mirapex®, Requip®


Neuropsychiatric (cont)Neuropsychiatric (cont)

Apathy:

? Selective serotonin reuptake inhibitorsCelexa®, Lexapro®, Paxil®, Prozac®, Zoloft®






Motor

Parkinsonism:


Deep brain stimulation (experimental)

Gait impairment/falls:

Gait assistance devices and PT

Power operated vehicle (POV)

MotorMotor

Parkinsonism:


Deep brain stimulation (experimental)

Gait impairment/falls:

Gait assistance devices and PT

Power operated vehicle (POV)



Speech/Swallowing

Dysarthria/nonfluent aphasia/apraxia of speech:

Speech therapy


Dysphagia:

Swallowing study

Thick-It, pureed food, PEG tube

Speech/SwallowingSpeech/Swallowing

Dysarthria/nonfluent aphasia/apraxia of speech:

Speech therapy


Dysphagia:

Swallowing study

Thick-It, pureed food, PEG tube



Sleep Disorders

Insomnia

Daytime hypersomnia

Obstructive sleep apnea

Central sleep apnea

Restless legs syndrome

Periodic limb movements during sleep

* Discuss with primary MD, and in select cases, consider a formal sleep medicine evaluation and sleep study

Sleep DisordersSleep Disorders

Insomnia

Daytime hypersomnia

Obstructive sleep apnea

Central sleep apnea

Restless legs syndrome

Periodic limb movements during sleep

* Discuss with primary MD, and in select cases, consider a formal sleep medicine evaluation and sleep study



Pathophysiology and

Implications for Future Therapies

Pathophysiology and Pathophysiology and

Implications for Future TherapiesImplications for Future Therapies

PSP, CBD, FTD, and PPA Pathophysiology and Implications for Future Therapies

PSP, CBD, FTD, and PPA PSP, CBD, FTD, and PPA Pathophysiology and Implications for Future TherapiesPathophysiology and Implications for Future Therapies

Tauopathies• Pick’s disease • Corticobasal degeneration• Progressive supranuclear palsy• Argyrophilic grain disease• Frontotemporal dementia with Parkinsonism associated with

mutations in microtubule associated protein tau on chromosome 17 (FTDP-17MAPT)

TDP-43opathies• Frontotemporal lobar degeneration (FTLD) with motor neuron

disease (MND)• Frontotemporal lobar degeneration (FTLD) with

ubiquitin/TDP-43-positive inclusions• Frontotemporal dementia with Parkinsonism associated with

mutations in progranulin on chromosome 17 (FTDP-17PGRN)

Tauopathies• Pick’s disease • Corticobasal degeneration• Progressive supranuclear palsy• Argyrophilic grain disease• Frontotemporal dementia with Parkinsonism associated with

mutations in microtubule associated protein tau on chromosome 17 (FTDP-17MAPT)

TDP-43opathies• Frontotemporal lobar degeneration (FTLD) with motor neuron

disease (MND)• Frontotemporal lobar degeneration (FTLD) with

ubiquitin/TDP-43-positive inclusions• Frontotemporal dementia with Parkinsonism associated with

mutations in progranulin on chromosome 17 (FTDP-17PGRN)



PSPPSP

FTDFTD

CBDCBD

PPAPPA

tautau TDPTDP--4343 amyloidamyloid

Dickey & Petrucelli, Expert Opin Ther Targets 2006

? ? TauopathyTauopathy therapiestherapies

•• Microtubule stabilizersMicrotubule stabilizers

•• tau kinase inhibitorstau kinase inhibitors

•• Hsp90 inhibitorsHsp90 inhibitors

•• tau aggregation inhibitorstau aggregation inhibitors

•• davunetidedavunetide

•• remberrember



Normal neuronNormal neuron Abnormal neuronAbnormal neuron

UbiquitinUbiquitin++

TDPTDP--43+43+

degradeddegradedproteinsproteins

progranulinprogranulin

wastewasteproteinsproteins

clumpedclumpedproteinsproteins

progranulinprogranulin

wastewasteproteinsproteins





Eval #1 Eval #2 Eval #3 Eval #4 Eval #5

worsening

Theoretical considerations for future experimental drug trialsTheoretical considerations for future experimental drug trials



Tx


worsening

Slowed progression with diseaseSlowed progression with disease--altering therapyaltering therapy




Tx


improvem

ent

Improvement with diseaseImprovement with disease--altering therapyaltering therapy


PSP, CBD, FTD, and PPA Research Protocol Participation

PSP, CBD, FTD, and PPA PSP, CBD, FTD, and PPA Research Protocol ParticipationResearch Protocol Participation

Consider participating in research studies!!Consider participating in research studies!!

Thank you!!Thank you!!

PSP, CBD, FTD, and PPA Future Directions

PSP, CBD, FTD, and PPA PSP, CBD, FTD, and PPA Future DirectionsFuture Directions

• Increase awareness among the public and health care professions that PSP, CBD, FTD, and PPA exist, are recognizable disorders, and can be diagnosed and managed

• Develop networks of patients, families, friends, and health careprofessionals to improve managing the day-to-day aspects of the disorders

• Increase federal and private funding for research, education, and counseling

This is where you can help!

•• Increase awareness among the public and health care professions Increase awareness among the public and health care professions that PSP, CBD, FTD, and PPA exist, are recognizable disorders, that PSP, CBD, FTD, and PPA exist, are recognizable disorders, and can be diagnosed and managedand can be diagnosed and managed

•• Develop networks of patients, families, friends, and health careDevelop networks of patients, families, friends, and health careprofessionals to improve managing the dayprofessionals to improve managing the day--toto--day aspects of the day aspects of the disordersdisorders

•• Increase federal and private funding for research, education, anIncrease federal and private funding for research, education, and d counselingcounseling

This is where you can help!This is where you can help!

PSP, CBD, FTD, and PPA Future Directions

PSP, CBD, FTD, and PPA PSP, CBD, FTD, and PPA Future DirectionsFuture Directions

• Refine the clinical, genetic, neuropsychological, radiologic, and pathologic characterization of the disorders that cause these disorders

• Improve our understanding of tau and TDP-43 protein physiology and pathophysiology so promising therapies can be developed and tested

• Identify and develop clinical, laboratory, neuropsychological, and radiologic measures for future therapeutic drug trials

Ultimately prevent, delay the onset, and slow the progression of the disorders that cause PSP, CBD, FTD, and PPA

•• Refine the clinical, genetic, neuropsychological, radiologic, anRefine the clinical, genetic, neuropsychological, radiologic, and d pathologic characterization of the disorders that cause these pathologic characterization of the disorders that cause these disordersdisorders

•• Improve our understanding of tau and TDPImprove our understanding of tau and TDP--43 protein physiology 43 protein physiology and pathophysiology so promising therapies can be developed and and pathophysiology so promising therapies can be developed and testedtested

•• Identify and develop clinical, laboratory, neuropsychological, aIdentify and develop clinical, laboratory, neuropsychological, and nd radiologic measures for future therapeutic drug trialsradiologic measures for future therapeutic drug trials

Ultimately prevent, delay the onset, and slow the progression ofUltimately prevent, delay the onset, and slow the progression of the the

disorders that cause PSP, CBD, FTD, and PPAdisorders that cause PSP, CBD, FTD, and PPA

Resources

(some of many excellent resources)

ResourcesResources

(some of many excellent resources)(some of many excellent resources)

FTD and PPA Resources - Websites

FTD and PPA FTD and PPA Resources Resources -- WebsitesWebsites

http://www.ftdhttp://www.ftd--picks.orgpicks.org

http://www.brain.northwestern.edu/ppa/index.htmlhttp://www.brain.northwestern.edu/ppa/index.html

PSP and CBD Resources - Websites

PSP and CBD PSP and CBD Resources Resources -- WebsitesWebsites

http://www.ftdhttp://www.ftd--picks.orgpicks.org

http://curepsp.orghttp://curepsp.org

Questions?Questions?Questions?

Documents

Cognitive and Behavioral Issues in PSP, CBD, FTD, and PPA · PSP, CBD, FTD, and PPA Future Directions •Increase awareness among the public and health care professions that PSP,