NEU 165 Exam 2

Why Study Humans?

We are actually the species that is affected

Many human neurological diseases do not occur spontaneously in animals

Animal models allow invasive manipulations of biology but usually in a limited way – animal models are almost always incomplete models of the disease of interest

BUT: Studies of humans are limited by our ability to perform invasive measurements that alter biology

• With one major type of exception

Non invasive approaches (imaging)

X-ray Computed Tomography (CT)

Magnetic Resonance Imaging (MRI)

Positron Emission Tomography (PET)

Non invasive approaches (electrophysiology)

Electroencephalography (EEG)

Magnetoencephalography (MEG)

Non invasive approaches

Neuropsychology

Epidemiology

Biomarkers

Invasive approaches

Electrocorticography (Ecog)

Post mortem measurements (autopsy)

Imaging: Brain structure (x-ray CT and structural MRI)

Neuroanatomy: an image of the brain as if we could hold it in our hand. Allows exploration of size of brain structures, changes over time, individual differences

Imaging: Brain function (functional MRI)

What the brain is doing as we think. Relies on alterations in cerebral blood flow, which is driven by metabolic demand

Imaging: Brain chemistry (PET)

Measurement of neurotransmitters, transmitter receptors and reutake sites, enzymes, abnormal protein aggregates

MRI began life as NMR

MRI Magnetic Fields Information

MRI Voxels

MRI Segmentation

Typical MR Images

Automated Brain Volume and Cortical Thickness Measurements

MRI vs. fMRI

fMRI Activation Statistics

Brain Activation

Resolution of Imaging Techniques

Positron Emission Tomography

Measuring Dopamine Release with PET

Experiment to examine endogenous brain dopamine

Basic Principles of PET

Radiation

Biological effects are related to

• dose

• half-life

• organ distribution

PET tracers are given in the lowest dose compatible with good signal

Half-life is ~1 min to 2 h

Widely distribiuted in the body

Doses are so low that the risk is not measurable

• Risk is usually described in relation to 1 year of background radiation at sea level

PET vs MRI

What can be measured with PET?

In vivo Amyloid Imaging with Pittsburgh Compound B (PIB)

EEG and MEG

EEG Recordings

Different Activity on EEG

Postmortem Methods

Neuropsychology

The study of brain-behavior relationships

Development of tools to measure cognitive function, largely using patients with brain lesions: Correlation of lesions with loss of function used to develop tests that tap that function

More recently, studies of normal people using fMRI and other cognitive neuroscience methods to define how the brain performs cognitive tasks

Phrenology and the Evolution of Neuropsychology and Cognitive Neuroscience

Aphasia

loss of language ability (production, comprehension, auditory, written)

Ataxia

Imbalance, incoordination, unsteadiness

Paresis

weakness (hemiparesis, paraparesis)

Visuospatial dysfunction

disorientation in space, inability to create an internal map of space

Executive function

planning, multi-tasking, judgement

Episodic memory

memory for events

Semantic memory

memory for facts

Working memory

memory over brief time frames for use and manipulation without long term storage

“Focality” In Neurological Disease

Stroke as a Brain Lesion Model

Language Areas of the Brain

Frontal Lobes and Behavior

Epidemiology

Prevalence and Incidence Rate

Analytic Epidemiology: Defining Risks for Disease

Cohort Study

Case-Control Study

Problems with Observational Studies

What is a Biomarker?

Reflects a normal or abnormal biological process

Reflects an exposure or outcome

Objective

Quantitative

May or may not reflect an underlying mechanism

Can be used for diagnosis, monitoring, intervention efficacy, prediction

NOT

A clinical assessment of symptoms or performance

A Biomarker May Reflect an Exposure or Outcome Without Explaining Mechanism

Electrocardiogram and heart attack

• Diagnostic but doesn’t tell us anything about how it happened

CSF myelin and MS

• MS is a disorder of myelin, but how this happens is unclear simply from detecting it in CSF

Biomarkers as Surrogates

What are common surrogate biomarkers and why are they accepted?

Biomarkers for Brain: Challenges

Can’t get tissue

Blood-brain barrier makes blood measures difficult

CSF requires lumbar puncture

Imaging is technically complicated and expensive

EEG can be technically complicated and expensive and non-specific

Biomarker Discovery

Advantages of Biomarkers

Simpler than a clinical evaluation by an expert (usually)

Permit testing/screening of large samples

Predict outcomes

Develop therapeutics faster

Personalized medicine

Limitations of Biomarkers

Must be validated with a ”gold standard”

• Not always present

Standardization may be difficult

Expensive

Can be non-specific

Need replication in diverse samples

Poor Validation is Common

Selection of extreme or highly typical cases

Samples don’t reflect who actually gets the disease – lack of diversity

Statistical differences may have no clinical meaning

Subject to bias

• Incorporation bias - test is used to make the diagnosis (circularity)

• Progression bias (gold standard at a different timepoint)

• Verification bias (not all subjects get the gold standard)

Initial biomarker reports are always more optimistic than later ones

Wrong “gold standard”

Early Measures of Biomarker Success are Rarely Confirmed

Neurological Diseases

Most neurological diseases are complex

• May have a single phenotype – i.e., a syndrome

• Caused by multiple mechanisms

A “cure” for most neurological diseases is simplistic: there maybe multiple cures because of multiple etiologies

In some cases, a “final common pathway” could exist that may be treatable despite multiple etiologies

Diagnoses of neurological disease has evolved from clinical phenomenology to laboratory and biomarker-based

Seizures

Seizure: a transient event caused by abnormal excessive or synchronous neuronal activity in the brain

• Seizures often (but not invariably) occur in conjunction with a precipitating event leading to temporary or permanent brain injury

• Seizures may not recur

Epilepsy

Epilepsy: Chronic, long term predisposition to repeated seizures

Epilepsy can follow from a single seizure if the problem persists after the resolution of the acute brain injury

Seizure Classification

Seizure onset

• Focal (also called “partial”)

• Generalized

• Focal followed by generalization

Level of awareness (of the patient)

• Aware (also called “simple”)

• Unaware (also called “complex”)

The seizure phenomena may be motor (tonic/clonic), sensory (tingling, flashes of light, sounds), cognitive (altered state or level of consciousness)

Seizure Types

Focal Seizures

Major Causes of Epilespy and Seizures

Epilepsy Prevalence by Age

Electrophysiology

How Does Epilepsy Occur?

Paroxysmal Depolarizing Shift

Excitation and Inhibition in a Seizure Focus

Excitotoxicity

Genetics of Epilepsy

Brain Development and Epilepsy

Tonic-Clonic Seizures

Childhood Absence Epilepsy

• 3 Hz spike/wave synchronous discharges

Complex Partial Seizures

• Seizue focus in the temporal lobe

Anti-Epileptic Drugs

Medications are usually effective and are the first line treatment

Many drugs are more effective in focal onset seizures, others generalized seizures, other in both

Side effects are common and can include fatigue/drowsiness, changes in mood, mental slowing

Some patients require multiple drugs and in some patients drug therapy does not provide acceptable relief

Surgical Treatment

May be useful in medically refractory cases

Requires a seizure focus – the point of the surgery is to remove (resect) the focus

Evaluation performed to clearly identify a focus and be sure that it is safe to remove it

After surgery there is usually a reduction in seizure rates and greater likelihood of control with medication

PET and Epilepsy

Surgery for Temporal Seizure Foci

What is Multiple Sclerosis (MS)?

An “autoimmune” disease in which the individual’s immune system is directed against the CNS particularly against myelin

The neuropathology of MS involves inflammation that particularly affects white matter (myelin) as well as neurons and glia, particularly oligodendroglia

MS produces a variety of symptoms that reflect the location and severity of the damage. The symptoms are often focal reflecting a specific CNS location

There are different types of MS based on genetics, clinical profile, and treatment response

Clinical Features of MS

Subacute onset (days) of neurological symptoms

• Vision loss (optic neuritis)

• Double vision

• Sensory loss following neurological distribution

• Asymmetric limb weakness

• Ataxia/incoordination

• Fatigue

Evidence of multiple lesions

• Disseminated in space (different parts of the CNS) and time

Clinically isolated syndrome (CIS)

• Single episode of a neurological syndrome most commonly optic neuritis

Myelin

MS Pathology

MS Types

Relapsing-remitting

• Most common

• Attacks may be followed by complete recovery

Secondary progressive

• Before the availability of disease modifying therapy, most patients developed this after relapsing-remitting

Primary progressive

• Difficult to diagnose

• Less common

• Fewer brain lesions, more common in spine

Different Types of MS Are Defined by Attacks

MS is Also Associated with Brain Atrophy

Optic Neuritis

MS Diagnosis pre-MRI Relied on Principles of Neuroscience

Diagnosis of MS

Characteristic clinical presentation

• Disseminated lesions in space and time

MRI evidence of white matter lesions

CSF measurement of myelin destruction (myelin basic protein), inflammatory proteins, and cellular evidence of inflammation (lymphocytes)

MS Epidemiology

MS and Latitude

Genetics and MS

Over 200 different genetic polymorphisms have been associated with MS in large GWAS series

These genes generally have very small effects (odds ratios of ~1.2): they probably work in combination

Many of the loci appear to regulate expression of genes associated with immune function

Discordance is often seen in monozygotic twins, suggesting a strong environmental factor

Most important genetic associations with the Major Histocompatibility Complex (MHC) also known as Human Leukocyte Antigen (HLA) complex

HLA Genes

The Inflammatory Process in MS

Immune Response in MS

Drug Development in MS: EAE

Drug Development in MS: MRI Surrogate Marker

Treatment for MS

Therapeutic Targets for MS