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Essentials of Neuroscience > Neurocognitive Disorders > Flashcards

Neurocognitive Disorders Flashcards

1
Q

What are the types of Neurocognitive disorders ?

A

Neurocognitive Disorders
Delirium
-Major and mild Neurocognitive Disorder (NCD)

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2
Q

What kind of disorders are Neurocognitive Disorders?

A

Neurocognitive Disorders:
primarily COGNITIVE disorders
-Acquired and represent Decline ( not development)
-Underlying brain pathology
(need parameters to consider major vs minor neurocognitive disorder)

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3
Q

Ho can you distinguish Dementia vs Neurocognitive Disorder? How does DSM change this?

A

Dementia typically refers to degenerative condition in elderly
-DSM expands category to condition of Younger
Ex: HIV, traumatic brain injury

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4
Q

What are the characteristics of Major NCD (neurocognitive Disorder) ?

A

Major Cognitive Disorder:
-Significant Cognitive Decline
-Interfere with independence
-NOT due to delirium
-NOt due to other mental disorder

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5
Q

How do you differentiate Major NCD from Dementia?

A

Major NCD vs Dementia
-Can be single domain
ex: Amnestic
exception: major NCD due to Alzheimer’s disease

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6
Q

What are the characteristics for Mild NCD (neurocognitive disorder) ?

A

Mild NCD
-Moderate Cognitive Decline
-NOT interfere with independence
-Not due to delirium
-Not due to other mental disorder

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7
Q

How was Mild NCD previously described?

A

Mild NCD is like mild cognitive impairment
-previously:
-Cognitive disorder
-Not otherwise specified

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8
Q

What occurs during Mild vs Major NCD Cognitive Testing ? What are the test scores that are observed? What occurs as a result?

A

Mild vs Major NCD Cognitive Testing
-Mild: 1-2 standard deviation (SD) range (between the 3rd and 16th percentiles)
-Major: Below 2 SD or 3rd percentile
These should NOT be rigidity used. Consider premorbid level. sensitivity of tests
-Major and mild exist on a Continuum

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9
Q

Describe the cognitive domains that have been specified under DSM. Include the specific functions that are under the category

A

Cognitive Domains specified
DSM-5:
-complex attention
-Executive function
-Learning and memory
-Language
-Perceptual-motor
-Social cognition
DSM-IV:
Memory Impairment
-Aphasia (inability to understand or express speech)
Apraxia (inability to make purposeful body movements )
-Agnosia (inability to recognize people’s faces)
Executive dysfunction (inability to do daily functions)

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10
Q

What are other Descriptors used to describe cognitive disorders?

A

Other Descriptors
-Possible vs probable
-behavioral disturbance
With: psychosis, mood, agitation
-Without: (NOT clinically significant)
Severity (level of disability)
-MIld: instrumental ADL’s are preserved ( daily living activities)
-ModerateL BASIC ADL’s affected
Severe: fully dependent

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11
Q

What conditions can lead to Neuorcognitive disorders?

A

Neurocogntiive Disorders (NCD) due to:
Alzheimer’s disease
Vascular disease
Traumatic Brain Injury
Lewy body disease
(Several others)

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12
Q

What are the different diagnoses of Delirium?

A

Differential Diagnosis of Delirium
-Major Neurocognitive disorder
-Delerium due to General medical condition
- substance intoxication Delirium
-Substance Withdrawal Delerium
-Delerium due to Multiple Etiologies
-Delirium NOS (Not otherwise specified)

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13
Q

How does Delirium differ from there NCD (neurocogintive Disorders)

A

Delirium differs from other NCD:
-Rapid onset in hours to days
-Linked to medical condition, substance intoxication/withdrawal, medications and other causes
-May resolve completely
-Symptom length:
Acute- hours to days
Persistent: weeks to months

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14
Q

What is the diagnostic criteria for Delirium? What are the key features and associated features?

A

Delirium Diagnostic Criteria:
Key Features: Rapid and Abrupt onset of:
-Impaired Attention
-Lack of Awareness of environment
Change in at least ONE Cognitive Domain:
-Recent memory
-Orientation
-Language (ex: rambled speech, mumbling, difficult to understand)
-Perceptual disturbance
Associated Features;
-change in sleep-wake cycle
-change in emotional states
-Worsening of behavioral problems in the evening.

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15
Q

Describe the onset and symptoms associated with Mild NCD (neurocognitive disorder) that occurs due to Traumatic Brain injury (TBI)

A

Mild NCD due to TBI
Mild NCD:
-Cognitive: 3-16 percentile
-Functional independence: Mild decline but not impaired
-Onset: Medically documented history of TBI (traumatic brain injury)
(at least 1 of the criteria) :
-Loss of consciousness
-Post-traumatic amnesia
-Confused and disoriented immediately after the event
-Neurological/neuroimaging evidence, NOT required
Symptom Course:
-immediate onset following TBI or after recovering consciousness
-Persist past acute post-injury period
-Any cognitive domain involvement
-Recovery Trajectory: partial or complete
-Weeks to months
(may need assistance but not fully dependent on others)

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16
Q

What are the characteristics of Major NCD (Neurocognitive disorder) that occur due to TBI (traumatic Brain injury). What is the Onset and symptom course?

A

Major NCD due to TBI:
Major NCD
**Cognition: < 3 percentile
**Functional independence: IMPAIRED
Onset: Medically documented history of TBI
(at least 1 of the criteria)
-Loss of consciousness
-Post traumatic-amnesia
-Confused and disoriented immediately after the event
*Neurological/Neuroimaging evidence, IS REQUIRED
Symptom Course
-immediate onset following TBI or after recovering consciousness
-Persist past acute-post injury period
-Any cognitive domain involvement
-Recovery Trajectory: partial or complete
-Weeks to months

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17
Q

What are the characteristics for NCD due to LBD (Lewy body Disease)

A

NCD due to LBD
NCD
Onset: Insidious
Core symptoms
-Fluctuating cognition/attention/alertness
-Visual hallucinations-well formed and detailed
-Parkinsonian movement develops 1 year AFTER cognitive impairment
Suggestive features
-Rapid eye movement (REM) sleep disorder
-Neuroleptic sensitivity

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18
Q

What are the Key issues in NCD (neurocognitive disorder) due to LBD?

A

Key issues in NCD due to LBD (lewy body disease)
- Neuroleptic Sensitivity: Worsening of movement disorder and impaired consciousness
-Onset:
Major NCD BEFORE motor (vs Parkinson’s)
probable/possible
-differ in number of core and suggestive features
Fluctuations: existing measures
REVIEW

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19
Q

what are the characteristics of Major or Mild NCD that occur due to Alzheimer’s disease (AD)

A

Major or Mild NCD due to Alzheimer’s Disease (AD)
-insidious onset and gradual progression
-Major NCD: *2 or more cognitive domains (unliked other Major NCDs) + impaired IADLs (instrumental daily living activitites0
–Mild NCD: 1 or more cognitive domains impaired, IADLA intact

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20
Q

How can the probable vs possible causes of AD be differentiated ?

A

By GENETIC MUTATION
Propable vs Possible cause are differentiated in part by presence of Alzheimer’s disease gene
-This can be from family history or formal genetic testing

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21
Q

Discuss the propable vs possible in Major NCD due to AD (Alzheimer’s disease)

A

Major NCD due to AD
-Propable AD: either one must be present
-Evidence of AD genetic mutation, Or All 3 of the following:
-impairment in memory + 1 other domain
-progressive, gradual decline
-No other possible etiology
-Otherwise, (if don’t meet those above), POSSIBLE AD is diagnosed

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22
Q

What are the Propable and Possible of Mild NCD due to AD

A

Mild NCD due to AD
Propable AD: requires evidence of *Alzheimer’s gene *
Possible AD: NO evidence of AD, but all 3 factors exist:
-Decline in memory and learning
-Progressive, gradual decline
-NO evidence of there etiologies

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23
Q

What is Myelin and what is its function? What kind of cells have myelin and where can they be seen?

A

Myelin:
-Lipid rich modified plasma membrane wrapped around the axon
-Serves as an electrical insulator that facilitates the energy-efficient transfer of action potential
-Myelin is a function of specialized glial cells, Oligodendrocytes in the CNS, Schwann cells and Oligodendrocytes in the PNS.

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24
Q

Differentiate between the speed of conduction in myelinated axon vs unmyelinated axon

A

Unmyelinated Axon: SLOW conduction
Myelinated Axon: FAST conduction

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25
Q

Describe the structure of myelin. What are the roles of internodes?

A

Myelin structure:
-covers the axon at intervals (internodes) with gaps in between (nodes of Ranvier)
-Myelin structure is the Evolutionary product a need to facilitate the rapid and efficient conduction of action potential in vertebrate neurons
-Internodes insulate the axon preventing current flow across the membrane and allowing fast saltatory (node-node) movement of nerve impulses

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26
Q

Where are axonal domains located? What are the two main axonal domains?

A

Axonal domains along the myelinated axons
The axonal membrane is divided into distinct domains : The internodes (INDs) that comprise majority of the axon and the Juxtaparanodes (JXP) located at end of axon

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27
Q

What occurs in salatroy Conduction? Explain why Conduction along myelinated axon occurs so fast

A

Saltatory Conduction: the way electrical impulses jump from node to node down the length of axon
- Conduction along a myelinated axon is fast due to insulation properties of compact myelin along internodes
-Foci of voltage sensitive ion channels at the nodes of Ranvier allow an action potential to jump rapidly from node to node.
(conduction velocity is faster with myelinated axons (compared to unmyelinated that is slower conduction)

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28
Q

How does an action potential begin? What is the reuslt of Damage to Myelin ?

A

Damage to Myelin IMPAIRS Action Potential Conduction
-Action potential beings with the influx of sodium ions followed by efflux of potassium ions, depolarizing the axon at the node and propagating the impulse
-Damage to the myelin results in REDUCTION in the Insulating properties of the internode and a reduction in Conduction Velocity.

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29
Q

What are the different conduction abnormalities that can occur and how does this affect the action potential?

A

White matter diseases manifest range of Conduction Abnormalities
Effects of action poetical can range from partial (decreased conduction velocity) to Complete (total conduction block)
-Can result in positive conduction abnormalities leading to dysregulated action potential and lowered threshold (increased mechanosensitivity), abnormal fiber-fiber excitation (cross-talk)

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30
Q

Compare and contrast Dysmyelination and Demyelination

A

Dysmyelination: Inability to complete the myelination program or the formation of abnormal dysfunctional white matter. Generally manifest early in the developmental window and caused by congenital defects (NO myelin built)
Demyelination: Destruction of myelin sheet after it has Formed. Caused by complex etiological agent that are toxic to the microenvironment.

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31
Q

Describe the development of Myelin. How does it eventually form?

A

Developmental Myelination
-Myelination is a function of specialized glial cells: Oligodendrocytes (CNS)
-In the mammalian brain oligodendrocytes arise from germinal zone formed during mid embryogenesis
-Oligodendrocytes progress through multiple tightly regulated developmental stages that culminate in the formation of myelin at target axons
Development process:
-Olidodendrocyte progenitor cell–> pre-oligodendrocyte—> Mature oligodendrocyte –> Myelinating oligodendrocyte

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32
Q

What kind of process is Myelination? Describe how long it occurs

A

Myelination is a largely postnatal process
-Extends well into adulthood in humans
-Requires an intensive period of myelin synthesis within a relatively finite period: 5000-50000 um^2 per day (Pfieffer et al. 1993)

(majority of neurons seen at synaptic production and Myelination. Fewer neurons (primarily in cortex) during cell birth, migration, axonal/dendritic outgrowth and synaptic elimination/ pruning.

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33
Q

What is the most intensive period of Myelination in Humans?

A

The most intensive period of Myelination in Humans is 0-2 years

(MRi image showed water appearing bright (CSF, cerebral spinal fluid), while hydrophobic lipids (concentrated in white matter) appeared dark)

dys- or demyelination results in increased water content in absence of lipid and abnormally light signal

34
Q

What substance does myelin contain a lot of compared to the brain?

A

Myelin is extremey lipid rich (70%) as compared to the whole brain (30%)
-There are NO myelin-specific lipids, but myelin in enriched in certain lipids
(CEREBROSIDE is higher in Myelin, compared to The Whole brain)

35
Q

What can occur as result in Lipid metabolism? Why does this occur. What are Leukodystrophies?

A

Defects in lipid metabolic can cause white matter disease
-The lipid-rich composition of myelin makes myelination susceptible to defects in lipid metabolism resulting in the formation of of abnormal myelination (dysmyelinaton) and decreased myelin production (hypomyelination)
-Many of these metabolic abnormalities arise from inherited mutations involved in lipid metabolism and are known as Leukodystrophies. Enzymic abnormalities can affect peroxisomes, lysosomes, and gernaly affect developmental myelination.
(leukodystropihes: abnormalities of white matter)

36
Q

What causes Leukodystrophies? What are examples of different medical conditions that arise?

A

Leukodystrophies are caused by Congenital Enzymatic Defects that impact Metabolic Processes
Leukodystrophy:
*Diffuse White matter:
-Canavan
-ALexander
-Van Der Knapp
-Orgaic acidurias
* Subcortical white matter:
-Hydroxyglutaric aciduria
*Deep white matter
-Krabbe’s
-Gangliosidosis
-MLD
-Phenylketonuria
-Peroxisomal
*Frontal predominance
-Alexander
*Occipital predominance
-ALD

37
Q

Describe the different patterns of white matter seen in different Leukodystrophies

A

Different Leukodystrophies have characteristics patterns of white matter abnormalities as revealed by MRI
-Symmetrical periventricular White matter in MLD (Metachromatic leukodystrophy)
- Spreading confluent lesions of cerebral white matter in ALD (Adrenoleukodystrophy)
-Diffuse widespread cerebral white matter in CD (Canavan disease)
-Frontal lobe white matter in AD (Alexander disease)

38
Q

How do enzyme defects affect the Myelin Biochemistry
Discuss the disease that due to inheriting a mutation

A

Enzyme defects affect the fundamental components of Myelin Synthetic Biochemistry
(get a build up toxic things in the pathways)

39
Q

Discuss the disease that is associated with inherited mutations : ABCD1, SMPD1, GBA, HexA, GalC, GLA, ARSA?

A

Disease Inherited Mutation
Adrenoleukodystrophy ABCD1
Nieman-Pick SMPD1
Gaucher GBA
Tay Sachs HexA
Krabbe GalC
Fabry GLA
Metachromatic leukodystrophy ARSA

40
Q

What occurs in Metachromatic Leukodystrophy (MLD)? Describe the deficiency associated with condition? What are the clinical subtypes that occur with this deficiency? What are the symptoms of this condition ? What kind of mutations cause this condition?

A

Metachromatic Leukodystrophy (MLD); Toxic Gain of Function caused by LOSS of function of a Lysosomal enzyme
Arasulfatase A (ARSA) deficiency with three clinical subtypes: late infantile (onset before 30 months), juvenile (onset 30-months-16 years), Adult (onset after 16 years)
Symptoms include progressive motor and cognitive decline with evidence of diffuse symmetric myelin abnormalities as seen by MRI
-Is caused by autosomal recessive mutations to ARSA that result in low/absent enzyme function

41
Q

What is the role of ARSA? What happens when there is a loss of function in ARSA?

A

ARSA is a lysosomal enzyme that catalyzes the hydrolysis of sulfatides as part of the cerebroside biosynthetic pathway
-Loss of ARSA function leads to the toxic build up of sulfatides in myelinating oligodendrocytes
(this ARSA deficient in seen in MLD)

42
Q

What can be seen in MRI image of patient with ARSA deficiency in MLD?

A

Accumulated sulfatides form intracellular granules that pick up color stains differently than surrounding tissue (“Metachromatic”)
-T2-weighted MRI shows diffuse white matter hyperintensity indicating abnormal myelin

43
Q

What are the different kinds of myelin protein and what are their functions?

A

Although lipid rich, white matter contains a relatively finite number of proteins specific to myelin
-The two major myelin proteins: myelin basic protein (MBP) and myelin proteolipid proteins (PLPs), account for 80% of all proteins found in Myelin
-The function of myelin proteins is poorly characterized but they are clearly integral to not only Myelin structure, but function in signaling and metabolic capacities also as evidenced by some diseases

44
Q

Discuss what protein proteolipid proteins (PLP) are? How much of myelin do they make up? How is it expressed? What happens when there are mutations to PLP?

A

Protein Proteolipid Proteins
-Two isoforms (PLP and DM20 variant) of this protein are encoded for by a single locus on the X chromosome via alternative splicing
-PLPs constitute about half of all myelin protein content
-Expressions tightly regulated by development via a complex interplay of signal mechanisms involving all three major neural lineages (neurons, astrocytes, and oligodendrocytes)
-Fundamental components of myelin across phyla
-Mutations to PLP cause Pelizaeus-Merzbacher Disease (PMD)

45
Q

What are the effects of mutations at PLP (protein proteolipid protein ) in humans? What occurs in the Pelizaeus-Merzbacher Disease? What are the clinical features?

A

Pelizaeus-Merzbacher Disease
-All types of mutations at the PLP locus have discernible effects in humans reflecting the highly phylogenetically conserved nature of the locus
-Primary defects are white matter abnormalities, thereby classifying PMD as a leukodystrophy
-Most frequent cases of PMD involve duplications of the PLP gene, making the phenotype a gain of function, but some loss of function mutations exist
The general classification of cases as either classic (onset at 12 months of age) or conical (present at birth) Connatal is the more severe case
Symptoms include : muscle weakness, nystagmus, ataxia, and seizures

46
Q

Describe the clinical spectrum of PMD and Mutation. What do all of the mutations have in common?

A

The clinical Spectrum of PMD and Mutation
-A broad spectrum of mutations, but all result in hypomyelination (a failure of myelin to form normally)
-Although the disease causing locus is known, path-mechanisms of PMD are poorly understood

47
Q

What causes Connatal PMD, vs Classic PMD, and SPG2?

A

Connatal PMD: caused my point mutations in PLP
and mechanism: mutant protein misfolding, leading to gain of function

Classic PMD; caused by duplications in PLP; mechanism: Wt protein overexpression leads to gene dosage effect

SPG2 (milder form of disease for PMD)
caused by null mutations in PLP, lead to no protein and loss of function

48
Q

What occurs in Demyelinating disease? How is it different from dysmyelinating or Hypomyelinating diseases. What happens as a result of Demyelinating disease ?

A

Demyelinating Disease
-Destruction or damage to the myelin sheath with the relative preservation of axons; ex: damage is primarily to myelin directly
-Distinct from dysmyelinating or hypomyelinating diseases which arise from FAILURE of Developmental processes
Demyelinating disease will result clinically in conductance abnormalities resulting from destruction of myelin sheath; manifest clinically as sensory loss, weakness, loss of co-ordination of ataxia

49
Q

What are the Etiologic agents (causes) of Demyelinating diseases for each category
REVIEW

A

Etiologic Agents in Demyelinating Disease
Inflammatory:
Multiple Sclerosis
Neuromyelitis Optica
Acute disseminated encephalomyelitis

Viral inflammation:
-Acute-disseminated enceplomyelitis
-progressive multifocal leukoencephalopathy
-HTLV-1-Associated Myelopathy

Metabolic
-Niemann-Pick Disease
-Adrenoleukodystrophy
-Phenlyketonuria
-type II Gaucher Disease

Toxins
-Alcohol
-Ethambutol

50
Q

What is the most common demyelinating disease ?

A

MULTIPLE SCLEROSIS (100/100,000 US)

51
Q

Describe the medical condition Multiple Sclerosis. What causes it and what are clinical symptoms ?

A

Multiple Sclerosis:
- Most common demyelinating disease (100/100,000 US)
-primary mechanism of injury is inflammatory demyelination
-Average age of onset is 32 years old (post-developmental myelination)
Demyelination in MS results in the slowing or complete failure of conduction
-common symptoms include optic neuritis, muscle weakness, sensory loss ataxia

52
Q

What does it mean when Multiple Sclerosis is considered to be “disseminated” in space and time? Describe the clinical course

A

MS is “disseminated” in space and time: evidence of multiple episodes of CNS dysfunction (time) and evidence of multiple demyelinated foci by imaging (space)
- Clinical course is variable but generally is characterized of multiple episodes of neurologic dysfunction with varying degrees of recovery spaced over weeks to decades

53
Q

What are the different types of multiple Sclerosis? What occurs in these different cases?

A

Multiple Sclerosis- Types
-Relapse-remitting; most common (> 80% of all cases). Defined by discrete episodes of exacerbation of symptoms followed by remission, during which patients experience full or partial recovery.
-Primary-progressive: 10-20% of cases. Gradual progression over time, with no relapses
-progressive- relapsing: Rare. Presents initially as PP (Primary-progressive) , but individuals suffer from exacerbated episodes followed by Partial relapse.
-Secondary-progressive: a lated onset development of primary progressive after an extended period (2-40 years) of R (relapse-remission)

54
Q

What are the Risk factors for MS? What race is MS commonly seen in?

A

Risk Factors for MS
-Has complex genetic patterns: familial susceptibility but no definitive disease causing locus
- Most common in Caucasians, and more common in northern climates
-Environmental factors are believed to play a part in disease, with viral infections and some toxins suggested to promote and autoimmune response.
NO DEFINITIVE CAUSATIVE agent identified

55
Q

Explain how MS is Diagnosed? What kind of medical imaging is used to diagnose MS. What can be observed in CSF of MS patient?

A

MS Diagnosis:
-Diagnosis is mainly clinical, as there is no single definitive genetic or pathological marker available for application to living patients
-MRI used to detect demyelinated foci in brain, although the identification of disseminated episodes is NOT always practical
-CSF fluid often contains a high proportion of IgG antibodies (oligoclonal band) in MS patients, but this is NOT specific to MS

56
Q

What is part of the Diagnostic Criteria for Suspected MS?

A

Diagnostic criteria for suspected MS:
**Two or more clinical attacks (with two or more objective lesions)
-The combination of two or more clinical attacks (with one objective lesion) plus Brain MR that shows dissemination in space
-Two or more clinical attacks with One objective lesion plus positive CSF (oligoclonal igG bands in CSF), plus Brain MR shows two more more lesions consistent with MS
(also two or more clinical attacks with one objective lesson locus further clinical attack involving a different site.

57
Q

Describe the characteristic things that are seen with Multiple Sclerosis? Are there any effective treatment for MS?

A

Multiple focal demyelinated lesions are characteristic of MS
-Relapses are associated with the development of new demyelinated lesions, which ultimately become permanent
-NO effective treatment exists, reflecting poor understanding of disease mechanisms

58
Q

Describe the Multiple Sclerosis Pathology (including the basic features seen in tissues). What is the the pathological hallmark of MS?

A

Multiple Sclerosis Pathology
Basic features: inflammatory processes associated with a large focal demyelinated lesions. Primary pathological hallmark is demyelination with associated inflammatory infiltrate and glial scarring

59
Q

Discuss the inflammation that is seen with Multiple Sclerosis and why it occurs.

A

Inflammation and Multiple Sclerosis
-Ms is characterized by diffuse inflammatory markers throughout the brain and spinal cord that are particularly concentrated at demyelinated plaques
- T-cell, B-cell and macrophage vascular infiltration is believed to be in response to autoimmunity against common myelin antigens
-The exact cause of inflammatory processes in MS remains unknown, and while the general inflammatory profile in MS bears similarities with other CNS inflammatory diseases (ex viral encephalomyelitis ), only mS manifests primarily white matter damage.

60
Q

What are the therapeutic targets for MS? What are the hypotheses for how MS occurs?

A

Therapeutic Targets for MS;
-The classical view of MS (A) is that activation of autoimmunity results in CNS injury,
-But more recent hypotheses (B), propose initial damage to the CNS (ex: toxins) activate an autoimmune reponse

61
Q

What is the most frequent target of attempted therapy?

A

The IMMUNE RESPONSE

62
Q

Describe what is used a therapeutic for MS and the long term effects of it.

A

the immune response is the most frequent target of attempted therapy
-Interferon Beta (IFN B) is the most commonly prescribed therapeutic for relapse-remitting MS. Long term effects are partial, with not all patients responding, and some experiencing adverse effects related to the immune system complications (opportunistic infections, etc)
this IFN B is Believed to limit the spread of an immune response via surface receptors on cells

63
Q

Describe the mechanism of Interferon action in MS. What occurs in this process?

A

Mechanism of Interferon Action in MS
-In the inflammatory stage of Ms, T, cells, B cells and antigen-presenting cells (APCs), including macrophages, enter the central nervous system (CNS), where they secrete cytokines that damage the oligodendroglial cells
-Lymphocytes move across the BBB (blood brain barrier) into the CNS through the 4-integrin surface receptor. This step is impeded by antibodies specific for 4-integrin or by IFN
-Early on, it was recognized that iFN was deficient in CSF of MS patients, leading to formulation of a putative therapy
-The active immune phase is an early event in MS lesion pathology, hence the relatively limited efficacy in progressive forms of disease

64
Q

Explain the recent study regarding white matter damage and the capacity for repair? What cells are involved?

A

Unlike grey matter, white matter exhibits a reasonable capacity for regeneration. MS lesions appear deficient in the ability to execute repair
-Post mortem (dead body) histological analyses of MS lesions have shown evidence of attempted demyelination by endogenous oligodendrocyte progenitors, offering a potential clinical target.
-

65
Q

What kind of cells can be seen in Adult human brain ?

A

discrete populations of Dividing multipoint progenitor cells

66
Q

Describe the research that has been undergoing for stem cells to be useful for white matter disease? How can they be useful?

A

Numerous sources of pluripotent and multipoint stem cells have been explored for application to white matter disease
-All strategies aim to recapitulate the natural oligodendroglial developmental program to provide cells capable of demyelinating damaged regions of the brain

67
Q

Describe the biochemical mechanism of Canavan disease . What causes it? Which enzyme is affected?

A

Canvan Disease: Biochemical mechanism
-disease occurs due to Aspartoacyclase Deficiency
-NO hydrolysis of N-acetyl Aspartate (NAA) due to enzyme deficiency (ASPA)
-This causes a build up of NAA in the brain as well as NAA acidemia and aciduria
(normaly,NAA is supposed to be broken down by enzyme ASPA into products Aspartate and Acetate)

68
Q

What kind of disease is Canavan disease ?

A

Canavana disease is one of the LEUKODYSTROPHIES (group of genetic disorders)
-Canavan disorder is a gene-linked neurological disorder that affects the brain (causes degeneration)

69
Q

Discuss the genetics behind Canavan disease? What kind of mutation causes the disease. Which population has a higher frequency of Caravan trait. What is the prevalence and incidence of Canavan disease ?

A

Canavan Disease: Genetics
-AUTOSOMAL RECESSIVE, ASPA gene mapped to chromosome 17p13
-Loss of ASPA function results in the accumulation of NAA to 8-14 mM (normal range ; 3-10 mM)
-1/45 to 1/60 Ashkenazi Jewish carry Canvan trait
-Different types of mutations are possible in Jewish and non-Jewish populations
-Prevalence of Canavan Disease= 300
-Incidence of Canavan Disease = 35

70
Q

Describe the role of N-acetyl Aspartate (NAA) . Why is it important?

A

N-Acetyl Aspartate (NAA) and Metabolic Integrity
-The second most abundant amino acid derivative in the brain after glutamate
-Can each concentrations of up 10 mM in some brain regions
-Prominent MRS signal provides an index of Neuronal Integrity in pathological contexts ranging from concussion injury to complex mood disorders
-NO Definitively defined function

71
Q

Describe the neuropathology and clinical features seen in Canvan disease

A

Canavan Disease
Neuropathology: Cortex, subcortical white matter, cerebellar Corte,
-Microscopically- accumulation of fluid within myelin lamellae, disintegrating of myelin sheaths, swollen astrocytes, severe vacuolation
-See spongy change in lower parts of brain (myelin rupture, extracellular fluid build up)
Clinical features:
-Patients present in infancy with hypotonia, lack of head control, macrocephaly, seizures, visual abnormalities, failure to thrive.
-Severe motor impairment, epilepsy, mental retardation
-blindness

72
Q

Describe the natural history of the sisters with genetic and Biochemical Canavan Disease

A

Natural History
-Atypical very Mild Phenotype for stistsers with genetic and Biochemical Canavan Disease
(R71H/E914A)

73
Q

Explain how NAA metabolism is highly compartmentalized

A

NAA is synthesized by an acetyl transferase (NAT8L) in neurons and catabolized by oligodendrocyte-specific aspartoacylase (ASPA) to yield free acetate and aspartate

74
Q

Describe the gene therapy programs that are being created for Canavan disease. What animal models have been created for this disease ?

A

Canavan disease : Gene therapy programs
-Single gene disorder with non-invasive markers of efficacy (NAA, myelin, DTI) makes it an attractive candidate for gene therapy
-Concrete, non-invasive clinical endpoints by which different therapeutic technologies can be directly compared.
Recent availability of animal models has enabled more comprehensive definition of therapeutic targets as they related to clinical end point measures
1997: LPD
-gross motor function
-whole brain NAA
-Myelin
2001: AAV-2
-Gross motor function
-Whole brain NAA
-Myelin
-DTI
Present: Oligodendrocyte-targeted gene therapy
-Gross motor function
-whole brain NAA
-MRI/DTI

75
Q

Discuss the clinical gene therapy study what was performed for patients by Canavan Disease

A

clinical gene therapy study
-Safety and efficacy of a Phase I study using AAV-ASPA for Brain gene transfer in patients affected by Canavan Disease
A Phase 1 was conducted under an investigator (IND #9119) using AAV2 presenting NEURONAL TROPISM
-intraparenchymal injection of AAV2-ASPA via 6 injection sites
FDA Approval: April 2001 represent the first clinical use of AAV in the human brain

76
Q

What were the the study outcomes when m measuring effects of Gene Transfer ?

A

Study Outcomes;
Measuring Effects of Gene Transfer
1) Quantification of NAA levels in brain, urine, CSF, serum
2) Magnetic Resonance (ex:: DTI/Anisoptropy/FA, T1/T2, brain atrophy)
3) Serum Analysis
4) CSF analysis: cells, protein, electrolytes
5)* Anti-AAV2 neutralizing antibody* titers
6) Clinical outcomes (ex; Canavan Neurological Exam, Gross motor function Measure/GMFM, HELP-135)
7) Psychometric tests (Mullen scales of early learning, pediatric inventory of disability index/PEDI
8) Data were analyzed with longitudinal, generalized linear-mild effects models with subject specific coefficients for intercept, pre-treatment slope, post-treatment slope

77
Q

what are the main clinical phases for Gene therapy in Canavan Disease

A

Clinical Phases
1. Pretreatment phase (total of 2-6 assessments)
(MRS, MRI, Neuro examination, Neurodevelopment tesitng, CSF analysis, biochemical analysis of urine, NAA, and serum hematology)
2. Surgery and Gene Delivery
-single-arm clinical study with standard dose of 900 billion AAV-ASPA particles to each of 18 patients by intraparenchymal injections to the brain
3. Post Gene Delivery- Serial assesments
-after two weeks, a complete physical and neurological exam will be conducted. Brain MRI obtained asses and postoperative signal changes
(time points; 1, 3, 6, 9, 12, 18, 24 months)
(6 surgical sites were injections placed, ; 2 along frontal lobe, 2 on parietal lobe and 2 on occipital lobe)

78
Q

What’s the criteria that a patient need to enroll in Gene therapy for Canavan Disease ?

A

Enrollment Criteria
1. A definitive diagnosis of Canavan Disease, based upon biochemical criteria and genetic (mutation) analysis
2. The patient must demonstrate clinical or radiological findings consistent with Canavan disease, such as macrocephaly, hypotonia, developmental delay, seizures or other positive findings
3. The patient must be between the age of 3 and 96 months

79
Q

What was later found in AAV2 based Gene therapy ?

A

AAV-2 Based Gene Therapy

production of titer RECOMBINANT (adeno-associated virus) vectors are found in gene therapy

80
Q

Descirbe the improvements that have been seen in patients with Canavan Disease who use Gene Therapy

A

After Gene therapy:
-REDUCTION in NAA
-REDUCED Brain Atrophy
-Stabilization of hydrocephalus (functional improvement; and also retention of brain mass in frontal and posterior parietal regions)

(ex of a 1 year old who underwent gene therapy; 8 years post gene therapy, recover from disease, see improvements)

81
Q

What are the GMFM normative values that are used as assessment for patients with Canavan Disease?

A

GMGM Normative Values (CD patients asses 10-108 months post -gene therapy)
4-6 months: Gross Fine Motor
2 months: Visual
9 months: Receptive Language
15-17 months- Expressive Language

82
Q

Who was the Oldest patient who survived Canavan Disease ?

A

Oldest person with Survived Canavan disease lived up to 27 years old.
She underwent gene therapy

Essentials of Neuroscience (12 decks)

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