Neurocognitive Disorders Flashcards

Question

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

Answer 1

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

Answer 2

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

Answer 3

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)

Answer 4

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.

Answer 5

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)

Answer 6

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.

Answer 7

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

Answer 8

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.

Answer 9

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

Answer 10

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)

Answer 11

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)

Answer 12

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

Answer 13

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)

Answer 14

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

Answer 15

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

Answer 16

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

Answer 17

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)

Answer 18

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

Answer 19

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

Answer 20

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)

Answer 21

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

Answer 22

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

Answer 23

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

Answer 24

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

Answer 25

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

Answer 26

MULTIPLE SCLEROSIS (100/100,000 US)

Answer 27

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

Answer 28

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

Answer 29

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)

Answer 30

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

Answer 31

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

Answer 32

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.

Answer 33

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

Answer 34

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

Answer 35

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.

Answer 36

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

Answer 37

The IMMUNE RESPONSE

Answer 38

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

Answer 39

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

Answer 40

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. -

Answer 41

discrete populations of Dividing multipoint progenitor cells

Answer 42

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

Answer 43

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)

Answer 44

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)

Answer 45

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

Answer 46

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

Answer 47

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

Answer 48

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

Answer 49

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

Answer 50

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

Answer 51

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

Answer 52

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

Answer 53

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)

Answer 54

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

Answer 55

AAV-2 Based Gene Therapy production of titer RECOMBINANT (adeno-associated virus) vectors are found in gene therapy

Answer 56

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)

Answer 57

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

Answer 58

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