Special Topics final

Frontotemporal Dementia

Group of disorders that cause
progressive cell loss in frontal and
temporal lobes of the brain
• Nerve cell damage leads to loss of function
in these brain regions

FTD prevalence

Accounts for around 5% of dementia
cases
• 1.2-1.8 million worldwide
• Most common form of dementia for
people under the age of 60
• Onset
• 20-80s
• Most present in their 50/60s

Symptoms of FTD

A APATHY
• B BEHAVIORAL DISINHIBITION
• C COMPULSIVE BEHAVIORS
• D DIETARY EATING HABITS
• E EMPATHY/EMOTIONS
• F FUNCTIONING (EXEC)

APATHY

Lack of motivation or interest in previously meaningful activities, like work or hobbies

BEHAVIORAL DISINHIBITION

Lack of restrain in social situations, making inappropriate or rude comments or actions, ignoring
personal space, shoplifting or other reckless behavior

COMPULSIVE BEHAVIORS

Performing single actions over & over, repeating words, reading, or watching same things,
hoarding

DIETARY EATING HABITS

Excessive or binge eating, new sweet tooth, only wanting to eat certain foods

EMPATHY/EMOTIONS

Loss of empathy or concern for others, inability to recognize other’s emotions, frequent mood
swings & irritability

Diagnostic Criteria

Must have 3 clear changes in behavior or executive function
• Early Apathy or inertia
• Early Behavioral disinhibition
• Compulsive/stereotyped/ritualized behavior
• Dietary changes/hyperorality
• Early loss of Empathy
• Loss of executive Function

Behavioral Variant FTD (bvFTD)

Most common recognized FTD syndrome
• More than 50% of cases
• Genetic or sporadic
• Primary sx= progressive behavioral
disturbances with executive dysfunction

Semantic Variant Primary Progressive Aphasia
(SvPPA)

Semantic=how we understand word and objective meaning
• Primary=not caused by non-degenerative process (e.g., stroke)
• Progressive=gradually worsens over time
• Aphasia=problems with language
• SvPPA causes early and progressive loss of word meaning
& conceptual knowledge involving the temporal lobes (left but sometimes right)
• Using the wrong words or non-specific words
• Difficulty reading unusually spelled words
• Difficulty recalling use or meaning of objects
• Difficulty with naming and understanding meaning of words

Nonfluent/Agrammatic Variant Primary
Progressive Aphasia (nfaPPA)

Fluency= easy and quick production of speech sounds & words
• Agrammatism= problems with grammar in speech & writing

Symptoms of nonfluent/agrammatic PPA:
• Slow labored speech with trouble articulating sounds (called apraxia of speech)– needing to repeat sounds over again to make them clear
• Pauses or hesitation in speech, or using uncharacteristically shorter sentences
• Difficulty with forming and understanding complex grammar
• Leaving out nouns or connecting words
• Improper word order
• Using wrong verb tenses

Sporadic FTD

Most occurs sporadically
• Large minority can be linked to genetic mutations/passed through
families
• bvFTD higher proportion of genetic changes (20-40% cases)
• FTD with ALS higher proportion of genetic changes

Genetics of FTD

Three major genetic mutations
• C9ORF72- 10-15% of f-FTD
• Most common cause of familial FTD/ALS
• Progranulin (GRN)- 10-15% of f-FTD
• Tau (MAPT)- 5-10% of f-FTD

What causes FTD

Frontotemporal lobar degeneration or FTLD
• Consists of buildup of certain proteins in the brain cells and eventual death of brain cells

Tau,TDP-43,FUS

Parkinson’s Disease

caused by low level
of dopamine in brain
• Most common neurodegenerative
movement disorder
• Over 1 million Americans Average age of dx 60

Early-onset/young onset
If dx before 50

Pathological Hallmarks

Death of neurons in substantia nigra
• Loss of dopamine-producing cells
• At time of diagnosis, approx 80% of dopamine cells have died
• Results in disruption of motor functioning
• Lewy bodies (clumps of abnormal
alpha-synuclein proteins)

Testing

DaTscan
• Noninvasive brain scan that helps evaluate
dopamine system in the brain
• Can help determine if someone has
Parkinsonian syndrome
Alpha-synuclein test
• Spinal fluid
• Skin test
• Small biopsy from neck, knee, ankle

Risk of PD

Age
• Sex (males > females)
• Genetic mutations
• Certain environmental factors

Protective Factors

Lower Risk
• Coffee consumption
• Smoking

Sporadic/idiopathic PD

(90-95% cases)
• Can’t attribute it to anything
• Most common

inherited/Familial

(5-10%)
• >Dozen genes identified
• LRRK2 & GBA
• Common in Ashkenazi Jewish population

Group A: significant risk of PD
• Group B: includes more frequent variants that are
associated with moderately high risk of PD. This
group currently includes GBA1 and
LRRK2 variants.
• Group C: variants associated with low risk of PD,
but which are observed in a high percentage of
patients with the disease.
• Size of each bubble population frequency of each allele
• Colors indicate the form of inheritance: dominant
(red), recessive (yellow), and risk loci (green)

Environmental Exposure

Herbicides/Pesticides (farming communities)

Solvents
MPTP-Synthetic neurotoxin
Heavy metals (Iron workers/welders)
Organic pollutants
Polychlorinated biphenyls (PCBs)
Banned in 70s
High concentrations of PCBs in brain of ppl with PD

Cardinal Motor Symptoms of PD

Bradykinesia :Slowness of movement or speed

Tremor: Often first sx of PD Usually asymmetric, especially in early stages Usually occurs at rest and lessens during sleep and when body part is actively in use Usually hands, but can appear in jaw, or leg

Rigidity:Stiffness in arms, legs, trunk, facial
muscles

Postural instability: Problems maintaining balance
while standing or walking increases risk of falls to right side

Non-Motor Symptoms of PD

• Depression
• Anxiety
• Fatigue
• Urinary problems
• Sexual dysfunction
• Constipation
• Sleep disturbances
• Loss of sense of smell

Prognosis

Usually very slow
• Usually over years or even decades
• Mild changes over long period (generally)
• Rate of progression varies by person
• Depends on age at dx, other health factors, family
history (e.g., certain types of abnormalities may indicate quicker progression)
• Symptomatic therapies are effective

Medication PD

Carbidopa-Levodopa (Sinemet, Rytary)
• Levodopa is converted into dopamine in brain
• Improves PD symptoms
• Side effects: nausea, lightheadedness, sleepiness
• Long-term use of CL= Dyskinesia
(involuntary twisting turning movements)

Deep Brain Stimulation

implanted electrodes and electrical stimulation to treat movement disorders

Lewy Body Dementia

Problem
• Under recognized by medical community
• Poorly understood by direct care providers
• On average, takes 18mo and 3 doctors to receive correct dx
• Outcome
• Delayed diagnosis is common
• Patients often don’t get effective medications & may be prescribed harmful
meds

Two Main Subtypes

Parkinson’s Disease Dementia (PDD)
• Classic PD (usually for many years)
• Later develop dementia sx

Dementia with Lewy Bodies
• Thinking, movement, psychiatric symptoms
all about same time
• Dementia first followed by movement
problems

One Year Rule

if movement only for 1 year=
PDD
• If dementia first or within 1
year of PD sx/dx= DLB

Regions in Brain

Basal Ganglia-here lewy bodies produce
PD or Parkinsonian sx
• Motor Symptoms
• Tremor, stiffness, slowness,

Cerebral Cortex
• Lobes involved with different
areas of thinking

Core Features PD

Fluctuating cognition
• Recurrent well-formed
visual hallucinations
• Spontaneous fts of PD

Suggestive Features

REM sleep behavior
disorder
• Neuroleptic sensitivity
• Low dopamine tran. Uptake

Supportive Features PD

Falls, autonomic dysfunction, delusions, depression, Visual-spatial problems

Clinical Criteria

Probable DLB
• 1.)Dementia plus two core features
• 2.)Positive biomarker plus one core feature
• Low dopamine transporter uptake in basal ganglia
• SPECT or PET
• Abnormal (low uptake) I-MIBG myocardial scintigraphy
• Polysomnographic confirmation of REM sleep
Possible DLB
• One core feature
• One or more indicative biomarker, but no core feature

Sex Differences x Symptoms

Hallucinations F
RBD M
Parkinsonism M
Fluctuations M/F

Treatment of Lewy Body Dementia

No cure but Treatments help with symptoms

Carbidopa/levodopa Cholinesterase inhibitors

AVOID anti-cholinergic medications

Amyotrophic Lateral Sclerosis

ALS Lou Gehrig’s disease

Pathophysiology

Progressive degeneration of upper & lower motor
neurons

LMN Loss

Weakness
• Muscle atrophy
• Twitching (fasciculations)
• Muscle cramps

UPM Loss

Weakness
• Spasticity
• Increased tone seen with damage to
UMN
• Patients describe as stiffness/ &
slowness
• Hyperreflexia
• Overactive/exaggerated reflexes

Symptoms PD

70-75% of cases are limb-onset
• Asymmetric weakness in either one arm/leg
• 25-30% are bulbar onset
• Initial symptoms are dysarthria (motor speech disorder difficult to form/pronounce words)
and dysphagia (difficulty swallowing)
• Approx 50% have varying degrees of cognitive/behavioral impairment

Diagnosis

Rule out other causes
• If other causes ruled out,
• UMN dysfunction
• Neuroimaging of brain/spine to
exclude structural abnormalities as
cause of dysfunction
• LMN dysfunction
• Electrophysiology

Definite and probable ALS

Definite :presence of upper and lower motor neurons in three anatomical regions

Probable :Prescence of upper and lower motor neurons in at least two regions with upper motor sign rostral to lower motor signs

Genetics of ALS

90% sporadic
• 10% familial
• >40 genes identified
• C9orf72 (most common)
• SOD1 (second common)
• TARDBP
• FUS
Account for 70% of familial ALS

Epidemiology of ALS

worldwide prevalence
• 4.42 per 100,000
• Worldwide incidence
• 1.59 per 100,00
• Highest-Western Europe
• Lowest-South Asia

More common-Whites& Non-Hispanics
• Impacts all ages age 60-69& Male

Mortality

80% of cases die within 2-5 years
• Heterogeneity of speed of progression
• COD often respiratory failure

Stephen Hawking-Renowned physicist Origins and structure of the universe Dx at age 21 Died at 71

technological Advances

Eye/Gaze, Blinking-switch control
• Voicebanking
• Cheek-switch control
AAC devices

Vascular Dementia

second most common cause of dementia

Men
• African Americans & Asians
• Evidence common type of dementia in Japan

VaD: Overview

Brain damage due to lack of blood supply from bleeding, clotting, or narrowing of arteries

VaD: Criteria

First effort to define VaD Hachinski
• Numerical nature
• Ease of use
• Clinical efficiency
Negative
• Oversimplifies
• Does not include modern markers (e.g., MRI)

Criteria met for major or mild neurocognitive disorder
• Clinical features are consistent with vascular etiology
• Evidence considered sufficient to account for neurocognitive deficits

VaD: Presentation

Varies
• Depends on area(s) of brain impacted
• Frequently within 3 months of vascular events (not always)

Symptoms VaD

Abrupt onset
• Stepwise decline
• Gait disturbance
• Motor impairment
• Urinary incontinence
• Emotional/emotional changes

Complexity of Vascular Diseases

Large Vessel Ischemia (top)
• Major deficits
• More step-wise

Small vessel Ischemia (middle)
• Minor deficits
• Insidious

Hemorrhage (bottom)
• Spectrum

Large Vessel Ischemia

KA large vessel occlusion (LVO)
• Blood supply to major cerebral
artery blocked

Most common cause of acute
ischemic stroke

Cerebral Small Vessel Disease

Small blood vessels in the brain are damaged/narrowed
• Often due to inflammation or buildup of plaques
• Impaired blood flow to the brain
• MRI= white matter hyperintensities

CADASIL

Most common inherited form of VD
• Heterogeneity of expression (even within family some individuals with same mutation
may have different course
• Excellerated dementia
• Cognitively normal

Hemorrhage

vessel leak blood or bursts
• Can occur between brain and skull (epidural, subdural, subarachnoid) or inside brain
tissue (intracerebral, intraventricular)
• Causes pressure against brain &prevents oxygen & nutrients

Creutzfeldt-Jakob

both neurodegenerative & transmissible (infectious)
• Caused by a transmissible protein (prion)
• the infectious prion triggers a neurodegenerative process in the brain

CJD: Epidemiology

RARE!
• 1 in a million individuals
• About 300 cases dx annually in US
• On the rise

Whites
• Surveillance data (28 years)
97% white &3% non-white (Asian/Asian British, Black/African/Caribbean)
• Age Risk factor, risk increase with age
• Age onset 4 years lower for nonwhite pts

Sporadic CJD

Misfolding of normal PrP isoforms with no apparent triggers (cause unknown)
• Majority of cases (>85 %)

Non-specific symptoms: vertigo, headache, fatigue, sleep disorders

55-75 years old Die within a year of onset (median duration=4-5 months)
• Median age at death =68

Hereditary/Inherited

Mutation in the prion gene (PRNP) on chromosome 20

Autosomal Dominat

onset 40-50s

Always fatal

Acquired

iatrogenic (e.g., med proceed)

age onset depends on age at exposure and incubation period 15 months to decades

Variant CJD (e.g., infected beef)
• Early presentation
• Psychiatric symptoms/behavioral changes and painful dysesthesias
• Movement disorders can occur early too
• As advances- Dementia (usually late sign)
• Symptoms occur? Depends on exposure Typically younger than patients with sporadic
• Mortality 13-14 months Median age at death is 28

Can I get it from?

Normal contact (e.g., touching, ,kissing, utensil sharing)
• No (living individuals)
• Yes (deceased individual)
• If body has been autopsied, family should avoid touching/kissing the individual
• High risk exposures
• Contaminated brain or nervous tissue
• ***Contaminated transfusions/blood (some mixed literature)4 known cases
• Contaminated meat

CJD: Diagnosis

Brain biopsy
• Not current preferred method

• Cerebral spinal fluid
• 14-3-3 protein
• Help dx, but not specific to condition

• MRI/Diffusion-weighted imaging (DWI)
• Abnormalities in cortical gray matter (cortical
ribboning)