Behavioral Neurology

Question 1

Types of Intelligence

Answer 1

Used to define age-related neurocognitive changes:

• Crystalized intelligence
  
  • Refers to skills, ability and knowledge that is overlearned, well-practiced
  • Examples – vocabulary, general knowledge
• Fluid intelligence
  
  • The innate ability to process and deal with new information
  • Examples – executive function, memory, processing speed

Question 2

Age-Related

Neurocognitive Changes

Answer 2

Processing speed starts declining early

Other areas begin to decline ~ age 55

• Stable Cognitive Areas
  
  • Autobiographical memory
  • Recall of well-learned information
  • Semantic knowledge (knowledge of meanings)
  • Emotional processing
• Areas of Improvement
  
  • Vocabulary
• Areas of Decline
  
  • Encoding of new memories
  • Working memory
  • Processing speed

Question 3

Age-Related

Brain Changes

Answer 3

• Decrease in gray matter volume
  
  • Primarily dependent on diminishing connections among neurons
  • Partially due to death of neurons
  • Some volume decline starts after age 20
• Decrease in white matter volume
  
  • Primarily due to decline in number of axons

Question 4

Cognition Evaluation

Answer 4

Neuropsychological Testing

Objective cognition evaluation

• Compare vs normative values based on education level and age
• Evaluates attention, executive function, memory, neurovisual function, language and other aspects of cognition
• Will determine whether persons cognition is aging normally or abnormally

Question 5

Cognitive Impairment

Classification

Answer 5

• Impaired cognition established
• Then classify if:
  
  • Minor neurocognitive disorder (mild cognitive impairment)
  • Major neurocognitive disorder (dementia)

Question 6

Mild Cognitive Impairment (MCI)

vs

Dementia

Answer 6

Main determinant of dementia vs MCI is whether cognitive deficit(s) interfere with persons abilities to perform their usual activities of daily living and work.

No affect on ADLs ⇒ mild cognitive impairment

Impairment affects ADLs ⇒ dementia

Question 7

Mild Cognitive Impairment

Answer 7

• MCI could be a:
  
  • Transitional state between normal and dementia
    
    • If caused by progressive neurodegenerative condition
  • Temporary condition caused by reversible causes
  • Static condition
    
    • e.g. in case of cerebrovascular diseases
• ~ 10% of people with MCI reverse to normal
• ~ 10% - stay stable and do not progress
• ↑ Risk for developing dementia, especially AD
  
  • 10-15% progress to AD annually
  • 80% converted to AD over 6 yr period

Question 8

Major Neurocognitive Impairment (Dementia)

Differential Diagnosis

Answer 8

• MCI
• Depression
• Delirium
• Reversible causes of cognitive impairment
  
  • Ex. nutritional deficiencies or metabolic abnl
• Medications

Question 9

Depression Mimicking Dementia

Answer 9

Depression frequently has associated cognitive complaints.

Suspect that mood disorder may be the cause of cognitive complains when:

• The pt gives a lot of “I don’t know” answers
• Mismatch between test results and perception
• Pt notes more problems than are perceived by family or friends
• Hx of depression
• Other symptoms of depression are present: impaired sleep, changes in appetite etc

Question 10

Distinguishing Delirium

Answer 10

• Usually acute-onset
• Impaired attention and alertness – reduced or hypervigilant
• Abnormal sleep pattern
• Attention, alertness fluctuations
• Profound disorientation
• There are metabolic triggers

Question 11

Cognitive Impairment

Reversible Causes

Answer 11

• Nutrition: vitamin B12, folate deficiency
• Metabolic: TSH, other endocrine abnormalities
• Trauma, tumor, other CNS disease
  
  • SDH, hydrocephalus
• Infection – syphilis, meningitis, HIV, systemic
• Anemia
• Vasculitis
• Medications
  
  • Cardiac medications
  • Antidepressants & other psychiatric meds
  • Anti-epileptic drugs (AEDs)
  • Sleep medications
  • Bladder medications

Question 12

Dementia (Major Neurocognitive Impairment)

Overview

Answer 12

• Acquired condition
• Involving more than one cognitive domain
• Severe enough to cause a decline in functioning
• Alzheimer’s disease is the most common type

Question 13

Dementia Etiologies

Answer 13

• Vascular Cognitive Impairment
• Alzheimer’s Disease
• Dementia with Lewy Bodies
• Frontotemporal dementia (FTD)
• Normal Pressure Hydrocephalus

Question 14

Vascular Cognitive Impairment (VCI)

Characteristics

Answer 14

• Abrupt-onset
• Stepwise decline
  
  • Patchy memory loss is usual
  • VCI may know day, but not year
  • More focal cognitive loses, for example naming
  • May improve slightly between episodes
  • Slow mental response
• Focal neurological symptoms and signs could be present
• Strokes are seen on imaging studies
• Hachinski scale: 20-point scale
  
  • Score > 7 – vascular
  • Score < 4 – degenerative

Question 15

Alzheimer’s Disease (AD)

Overview

Answer 15

• The most common cause of dementia – about 60% of all the cases
• Insidious onset, slowly progressive
• The first sx in typical cases is usually memory loss
• Behavior problems and neuropsychiatric symptoms are common

Question 16

Alzheimer’s Disease (AD)

Pathology

Answer 16

• A toxic peptide, beta-amyloid accumulates extracellularly
• Formed from alternate processing of the amyloid precursor protein
• Cognitive deficits do not correlate with plaque burden
• Oligomer is the most likely culprit
  
  • Attacks on the synapse
  • Disrupts communication between neurons
• Intraneuronal hyper-P-tau accumulation
• Associated with neuronal death and development of atrophy and clinical symptoms

Question 17

Alzheimer’s Disease (AD)

Symptoms

Answer 17

• Cognitive symptoms
  
  • Memory impairment; in almost all cases disease affects memory
  • Orientation
  • Visuospatial function
  • Language
  • Frontal networks
• Neuropsychiatric
  
  • Behavioral symptoms – aggression, agitation, restlessness, wandering, delusions, hallucinations, etc

The above affect ADLs

Question 18

Alzheimer’s Disease (AD)

Atypical Signs/Symptoms

Answer 18

• Something other than memory issues as first symptom
• Presence of movement problems, seizures, or tremor early in disease
• Anyone under 35
• Suspected history of stroke
• History of cancer
• HIV risk factors
• Head injury
• Headache or focal symptoms

Question 19

Alzheimer’s Disease (AD)

Genetics

Answer 19

• Sporadic – not associated with specific mutation, might carry gene variants which increase the risk of developing the disease
  
  • amyloid is not being cleared well in cases of sporadic disease
• Genetic – carries specific AD mutations with 100% penetration
  
  • amyloid is overproduced in these cases

Question 20

Genes associated with AD

Answer 20

• Autosomal dominant / early onset
  
  • Chromosome 1 – Presenilin 2
  • Chromosome 14 – Presenilin 1
  • Chromosome 21 – APP
• Susceptibility genes
  
  • APOE 4 genotype (chromosome 19)
  • Chromosome 12, and other

Question 21

APOE Gene

Answer 21

• APOE E4 allele is a genetic risk factor for developing AD
• There are 3 human alleles – E2, E3 and E4
• APOE E3 allele is the most common form
• E4 allele (10%) increases the risk of developing AD
  
  • Shifts age of onset from ~75 to late 60’s or early 70’s
• E2 allele (10%) is protective

Question 22

Alzheimer’s Disease (AD)

Diagnosis

Answer 22

• Clinical assessment
• Neuropsychological testing
• Biomarker studies
• Structural imaging – looking for neurodegeneration
• Functional imaging – looking for functional changes related to neurodegeneration
• Identifying amyloid

Question 23

Alzheimer’s Disease (AD)

Biomarker Studies

Answer 23

• Studies evaluating amyloid accumulation
  
  • Amyloid PET scan
  • CSF A-beta level measurements
• Studies evaluating neurodegeneration
  
  • Structural evaluation – MRI, CT
  • Functional evaluation (areas of synaptic dysfunction / loss) – FDG-PET

Question 24

Alzheimer’s Disease (AD)

Treatment

Answer 24

• Cholinergic medications: donepezil, rivastigmine, galantamine
• NMDA modulators: memantine
• Disease modifying treatments
  
  • ↓ Beta-amyloid
  • Preventing accumulation or removing amyloid from the brain
  • Immunotherapy is in development for humans

Question 25

Dementia with Lewy Bodies

Answer 25

* Cognitive impairment with **poor attention and relative sparing of memory** * **Fluctuation of cognition** * **Parkinsonism** * Psychotic symptoms, especially **visual hallucinations** * **REM sleep behavior disorder** * **Autonomic instability**

Question 26

Frontotemporal Dementia (FTD) Overview

Answer 26

* Variants: **behavioral and language variants** (Primary progressive aphasia) * _Behavioral variant FTD_ initially presents with: * **Changes in personality** * **Loss of social decorum** * **Impulsivity** * **Inappropriate behaviors** * **Withdrawal** * **Bizarre behaviors** * **Primarily dysexecutive cognitive syndrome** * _Language variants_ (Progressive aphasias) initially presents with: * **Language function disintegration**

Question 27

Frontotemporal Dementia (FTD) Anatomy of Impairment

Answer 27

**Left frontal**: expressive language, depression, frustration **Orbitofrontal**: disinhibition **DLPF**: executive function **Cingulate gyrus**: apathy **Right temporal**: bizarre, schizophrenic, facial recognition **Right frontal**: irritable, disinhibition, euphoric **Left temporal**: semantic impairment

Question 28

Frontotemporal Dementia (FTD) Genetics

Answer 28

* **Tau gene** – chromosome 17 * **Progranulin gene** – chromosome 17, TDP-43 * **C9orf72** – chromosome 9 * Many unlinked mutations

Question 29

Normal Pressure Hydrocephalus

Answer 29

* Classical clinical triad: * **Dementia** * **Urinary incontinence** * **Magnetic (apraxic gait)** * It can be **treatable**, and **sometimes fully reversible** if dx early enough * Treatment: drainage of CSF fluid (V-P shunt) * **Cognitive impairment** is the most resistant sx to improve with tx