Week 7: Alterations in Cognitive Systems and Motor Function

Question 1

Differentiate between Delirium and Dementia

Answer 1

Delirium is an acute state of brain dysfunction and onset is typically abrupt. In the case of delirium, the autonomic nervous system is overactive. Delirium is common in critical care units, post-surgically, or during withdrawal from CNS depressants (e.g., alcohol, narcotics).

Dementia is the progressive failure of many cerebral functions and onset is typically gradual. Progressive dementias produce nerve cell degeneration and brain atrophy, age is the greatest risk factor.

Question 2

Describe risk and protective factors for Alzheimer’s disease

Answer 2

Risk factors:
- age
- family history (early or late onset, which is more frequent)
- diabetes, hyperlipidemia, midlife hypertension
- physical inactivity, midlife obesity
- smoking, depression
- female sex, estrogen deficit during menopause
- elevate serum homocysteine, oxidative stress, neuroinflammation

Protective factors:
- life long activity
- presence of apoE2 and antioxidant substances
- omega-3 fatty acids
- low-calorie diet
- use of NSAIDs

Question 3

Explain the progression of Early-onset familial Alzheimer’s disease

Answer 3

Early onset can be familial (FAD) or sporadic. The cause of sporadic EOAD is unknown. FAD is an autosomal dominant disease and has been linked to three causal genes with mutations on chromosome 21, although the mechanism of how they cause disease is not clear. The mutations result in dysregulation of amyloid precursor protein (APP) processing and leads to alterations of folding and concentration of the derived amyloid beta protein. The consequence is the formation of amyloid plaque in the brain. The three mutations are:

1. APP gene mutation resulting in abnormal APP. Mutations change the structure and result in accumulation of beta-amyloid.
2. PSEN1 gene mutation - this protein normally functions as a protease to cleave APP, generating amyloid-beta protein of varying lengths. Either loss or gain of function may alter amyloid beta production and accumulation.
3. PSEN2 gene mutation leading to alterations in amyloid-beta structure and aggregation.

Question 4

Explain the progression of Late-onset Alzheimer’s disease

Answer 4

Sporadic late-onset AD is the most common type of AD and does not have a specific genetic association; however, the cellular pathology is the same as that for gene-associated early-and-late-onset AD. The main genetic risk factor for late-onset AD is related to age and APO4E. Late-onset AD is related to a gene on chromosome 19 which interferes with amyloid beta clearance from the brain. Amyloid can be processed into neurotoxic fragments found in plaques and tangles.

Question 5

What is Parkinson’s Disease?

Answer 5

PD is a complex motor disorder accompanied by systemic nonmotor and neurologic symptoms. Etiologic classification includes primary parkinsonism and secondary parkinsonism. The onset of primary PD usually begins after 40 years of age, with the incidence increasing after 60 years. Men are much more likely to have PD than women.

Question 6

Discuss the neural systems essential to cognitive function

Answer 6

1. Attentional: systems that provide arousal and maintenance of attention over time
2. Memory and language: systems by which information is communicated
3. Affective or emotive: systems that mediate mood, emotion, and intention

These core systems are fundamental to the processes of abstract thinking and reasoning

Question 7

Define the data processing deficit Aphasia

Answer 7

Aphasia is typically an acquired impairment of comprehension or production of language with impaired written or verbal communication. The terms aphasia and dysphasia are often used interchangeably. Aphasia results from dysfunction in the left cerebral hemisphere (e.g., Broca area [inferior frontal gyrus] and Wernicke area [superior temporal gyrus]) and the subcortical and cortical connecting networks.

Question 8

Define the data processing deficit Agnosia

Answer 8

Agnosia is a defect of pattern recognition—a failure to recognize the form and nature of objects by one or more of the senses. Agnosia can be tactile, visual, or auditory. For example, an individual may be unable to identify a safety pin by touching it with a hand but able to name it when looking at it.

Agnosia is produced by damage to the primary sensory area or in the interpretive areas of the cerebral cortex (parietal, temporo-occipital areas—Broca area and Wernicke area). The symptoms of agnosia vary according to the location of the damage.

Question 9

Define the data processing deficit Acute confusion state of delirium

Answer 9

Delirium (also known as acute confusional states or acute organic brain syndromes) are disorders of awareness, may be transient (acute) or persistent (chronic), and have either a sudden or a gradual onset. Delirium can be considered as a type of ACS, but for this discussion, ACSs, acute organic brain syndrome, and delirium are synonymous. Hospitalized older individuals are at greatest risk for delirium

Question 10

Define the data processing deficit Dementia

Answer 10

Dementia is an acquired deterioration and a progressive failure of many cerebral functions that includes impairment of intellectual processes with decreasing abilities in the areas of orientation, memory, language, judgment, and decision making. Because of declining intellectual ability, the individual may exhibit alterations in behavior, for example, agitation, wandering, and aggression. Dementias can be classified according to etiologic factors (e.g., genetics, trauma, tumors, vascular disorders, infections) and to associated clinical and laboratory signs. AD is the most common cause followed by vascular dementia, then dementia with Lewy bodies

Question 11

Define the data processing deficit Alzheimer disease

Answer 11

Also known as Alzheimer type dementia (ATD) is the leading cause of severe cognitive and behavioral dysfunction in older adults. It is a chronic, progressive disease that profoundly diminishes memory, reasoning ability, and thinking skills. It is the leading cause of dementia in older adults and is considered irreversible, the exact cause is not known. There are three forms:

1. Late-onset Non-hereditary Sporadic AD (70-90%)
2. Early-onset familial AD
3. Early-onset AD (very rare)

Question 12

What are data processing deficits?

Answer 12

Data processing deficits are problems associated with recognizing and processing sensory information and include agnosia, aphasia, and acute confusional states (ACSs).

Question 13

Describe the etiology, pathophysiology, manifestations and complications of Alzheimer’s Disease

Answer 13

Pathologic alterations in the brain in both early- and late-onset AD include accumulation of extracellular neuritic plaques containing a core of abnormally folded beta amyloid proteins, intraneuronal neurofibrillary tangles consisting of hyper-phosphorylated tau proteins, and degeneration of basal forebrain cholinergic neurons with loss of acetylcholine. Failure to process and clear APP results in the accumulation of toxic fragments of amyloid-beta protein that leads to formation of diffuse neuritic plaques, disruption of nerve impulse transmission, and death of neurons.

Misfolded and aggregated proteins trigger immune responses with activation of glial cells and release of cytokines leading to:
- neuroinflammation and oxidative stress
- decreased oxygen and glucose transport
- molecular changes in vascular smooth muscle and in the blood-brain barrier
- mitochondrial defects that alter cell metabolism and processing of proteins, including amyloid (apoe4 - apolopopprotein-4) that leads to cell death .

Amyloids:
- failure to clear the amyloid precursor protein results in accumulation of toxic fragments of amyloid beta protein and the formation of diffuse neuritic plaques, disrupting nerve impulse transmission and neuronal death
- they are also deposited in the cerebral arteries impairing blood flow

Tau proteins:
- a micro-tubule binding protein detaches and forms and insoluble filament called a neurofibrillary tangle, contributing to neuronal death
- the tangles are flame shaped and are often concentrated in the cerebral cortex and hippocampus
- degeneration of basal forebrain cholinergic neurons with loss of acetylcholine

All of this leads to loss of memory, attention, and cognitive function!

AD has a long preclinical and prodromal course, and pathophysiologic changes can occur decades before the appearance of clinical dementia syndrome. The disease progresses from mild, short-term memory deficits to total loss of cognition and executive functions. Initial clinical manifestations are insidious and often attributed to forgetfulness, emotions, or other illness.

• Includes forgetfulness; emotional upset; disorientation; confusion; lack of concentration; and declines in abstraction; problem solving; and judgement
• Dyspraxia may appear
• Mental status changes induce behavioral changes, including irritability, agitation, and restlessness

Question 14

Discuss the progressive stages of Alzheimer disease

Answer 14

1. Mild Cognitive Impairment: mild memory loss. particularly for recent event (episodic memory) and new information (semantic memory); possibly depression and mild anxiety
2. Early Stage: measurable short-term memory loss with difficulty planning; disorientation to location; mild IADL problems
3. Middle Stage: significant forgetfulness; easy to get lost; may dress inappropriately; may hallucinate; IADL-dependent; some ADL problems
4. Late Stage: little cognitive ability; language not clear; personality change; does not recognize family members; wandering, repetitive behavior; ADL dependent, incontinent, difficulty eating
5. End Stage: no significant cognitive function; loss of word speech; non-ambulatory, unable to eat

Question 15

Discuss evaluation and treatment for Alzheimer’s disease

Answer 15

The clinical diagnosis of AD is made by ruling out other causes and utilizing the criteria that have been developed to assist in making a diagnosis.65 A definitive diagnosis can only be made at autopsy. The clinical history, including mental status examinations (mini–mental status examination, clock drawing, and geriatric depression scale), cerebrospinal fluid analysis, brain imaging of structure, blood flow and metabolism, and the course of the illness (which may span 5 years or more) is used to assess progression of the disease. Genetic susceptibility tests for PSEN1, PSEN2, and APP are used to screen for EOAD.

No disease-arresting therapies are available. Treatment is focused on using devices to compensate for the impaired cognitive function, such as memory aids and maintaining or improving the general state of hygiene, nutrition, and health.

Goals of pharmacotherapy include improving the function of ADLs, behavior & cognition, and slowing the progression of disease. Therapy is initiated as soon as a diagnosis is confirmed. The mainstay treatment is the use of acetylcholinesterase inhibitors.

Question 16

Discuss alteration in neuromotor function

Answer 16

Movements are complex patterns of activity controlled by the cerebral cortex, upper motor neurons of the pyramidal system, lower motor neurons (LMNs) (including the cranial and spinal nerves and gamma motor neurons) originating in the spinal cord and terminating at the myoneural junction (see section on Neuromuscular Junction), and the extrapyramidal system (EPS) (basal ganglia, thalamus, reticular formation, and cerebellum). Dysfunction in any of these areas can cause motor dysfunction. Alterations in motor function are associated with changes in muscle tone, muscle movement, and complex motor performance. Some types of diseases and disorders have concurrent alterations in cognitive, sensory, and autonomic nervous system function.

Question 17

What is Dyspraxia?

Answer 17

Dyspraxia is the partial inability and apraxia is the complete inability to perform purposeful or skilled motor acts in the absence of paralysis, sensory loss, abnormal posture and tone, abnormal involuntary movement, incoordination, or inattentiveness. There is a disconnect between movement and the purpose of the movement

Question 18

Discuss the differences between primary and secondary causes of Parkinsonism

Answer 18

Primary:
- Sporadic (idiopathic); most common form
- Genetic: autosomal dominant; autosomal recessive
- Phenotype may be influenced by gene-environment interactions

Secondary:
- Neurodegenerative disorders
- Genetically mediated disorders with occasional Parkinsonian features
- Miscellaneous acquired condition
- Repeated head trauma
- Infectious and post-infectious diseases
- Metabolic conditions
- Multiple sclerosis
- Neoplastic disease
- Drugs
- Toxins

Question 19

What drugs are known to cause secondary Parkinsons?

Answer 19

• Neuroleptics (typical antipsychotics)
• Selected atypical antipsychotics
• Antiemetics (e.g., prochlorperazine, metoclopramide)
• Dopamine-depleting agents (reserpine, tetrabenazine)
• alpha-Methyldopa
• Lithium carbonate
• Valporic acid
• Fluoxetine

Question 20

Discuss the pathology of Parkinson’s

Answer 20

The pathogenesis of primary PD is unknown. Several gene mutations have been identified, including those associated with Lewy body (inclusions with high concentrations and abnormal folding of alpha-synuclein and other proteins) dementia and epigenetic interactions are probable causes of neurodegeneration in PD. Potential environmental risk factors include exposure to pesticides, herbicides, chlorinated solvents, and heavy metals and head injury. The hallmark pathologic features of PD are loss of dopaminergic pigmented neurons in the SN pars compacta with dopaminergic deficiency in the putamen portion of the striatum (the striatum includes the putamen and caudate nucleus). Dopamine loss in other brain areas, including the brainstem, thalamus, and cortex, also occurs. The primary pathology is degeneration of the basal ganglia (corpus striatum, globus pallidus, subthalamic nucleus, and SN) with formation of Lewy bodies in the SN and dorsal striatum. Degeneration of the locus coeruleus (LC), which contains noradrenergic neurons, also occurs in PD. Norepinephrine is thought to be neuroprotective, and loss of LC neurons may be associated with a worsening of disease progression and the behavioral symptoms of PD. Other molecular events thought to be associated with the neurodegeneration of PD include neuroinflammation and mitochondrial oxidative stress.

Question 21

Discuss the dopamine pathway in PD

Answer 21

Dopamine is an inhibitory neurotransmitter for the regulation of unconscious muscle movement. It is synthesized in the substantia nigra, which is impacted in PD. Neurons in the substantia nigra supply dopamine to the corpus striatum, which is the area of the brain responsible for unconscious muscle movement. The resulting depletion of dopamine and relative excess of cholinergic activity in the feedback circuit are manifested by hypertonia (tremor and rigidity) and episodes of akinesia (freezing of movement) producing a syndrome of abnormal movements called parkinsonism.

Question 22

Discuss the clinical manifestations of PD

Answer 22

The classic manifestations of PD are resting tremor (decreases with voluntary movement), muscular rigidity, bradykinesia/akinesia (slowness of movement and freezing, postural instability and difficulty maintaining balance, dysarthria, and dysphagia). Nonmotor symptoms may precede motor symptoms by up to 20 years. The symptoms may develop alone or in combination, but as the disease progresses, all are usually present. There is no true paralysis. Onset of symptoms is insidious, and symptoms appear after a significant loss of pigmented nigral neurons and striatal dopamine. The symptoms are always bilateral but usually involve one side early in the illness.

Nonmotor symptoms are common. Sleep disorders and excessive daytime sleepiness are commonly experienced. Sensory disturbances (pain and impaired smell and vision), urinary urgency, difficulty concentrating, depression, apathy, and hallucinations are some of the nonmotor symptoms of PD. Autonomic nervous system changes (i.e., alterations in blood pressure, heart rhythm, temperature control, digestion, bladder function, and sexual function) often begin early in the disease process and contribute to nonmotor symptoms.

Question 23

Discuss evaluation and treatment for PD

Answer 23

There is no diagnostic marker for sporadic PD, and definitive diagnosis is made by postmortem examination of neural tissue revealing the loss of nigrostriatal dopaminergic neurons and the presence of Lewy bodies within neurons. The clinical diagnosis of PD is based on the history and presenting features of the disease. Causes of secondary parkinsonism are first excluded.

Treatment of PD is symptomatic, with drug therapy to protect or restore striatal dopamine levels and decrease akinesia and manage nonmotor symptoms. Levodopa is first-line treatment and is generally well tolerated. ChE-Is may be helpful for MCI or dementia. Deep brain stimulation (i.e., subthalamic neurostimulation) is replacing surgery to treat persons unresponsive to drug therapy. Rehab, PT, OT, and speech therapy are also used.

Question 24

Describe the loss-of-drug effect and on-off syndrome in the pharmacotherapy of PD

Answer 24

Loss of drug effect: symptoms worse because the concentration of the drug has fallen below the therapeutic level

On-off syndrome: alternation between symptom-free periods (on) and times when the drugs stop working and symptoms abruptly reappear (off)

Question 25

Discuss Dopa decarboxylase inhibitors: carbidopa & levodopa (Sinemet) in the treatment of PD

Answer 25

Indication: parkinson’s disease - it takes up to 6 months to reach max therapeutic effect

Mechanisms of action: levodopa can enter the blood brain barrier. As an intermediate precursor to dopamine, levodopa crosses the blood brain barrier and is converted to dopamine. Dopamine cannot enter the blood brain barrier, hence why dopamine therapy is not used. Cabidopa cannot enter the blood brain barrier, as such it functions to decrease the metabolism of levodopa to dopamine outside the CNS, which allows levodopa to be more available to enter the brain. So, Carbidopa “boosts” levodopa’s effectiveness.

Desired effects: reduction of involuntary movements

Adverse effects: uncontrolled and purposeless movements such as extending the fingers and shrugging shoulders, involuntary movements, loss of appetite, N/V, orthostatic hypotension

Question 26

What are demyelinating disorders?

Answer 26

Demyelinating disorders are the result of damage to the myelin nerve sheath and affect neural transmission. They can occur in either the central (i.e., MS) or the peripheral (i.e., GBS) nervous system. Contributing factors include genetics, infections, autoimmune reactions, environmental toxins, and unknown factors.

Question 27

What is Multiple Sclerosis?

Answer 27

MS is a chronic immune-mediated inflammatory disease involving degeneration of CNS myelin, scarring (sclerosis or plaque formation), and loss of axons. MS is caused by an autoimmune response to self or microbial antigens in genetically susceptible individuals. The etiology of MS is unknown. The onset of MS is usually between 20 and 40 years of age and is more common in women. Men may have a more severe progressive course. Inconclusive risk factors that may be involved include a gene-environment interaction including factors such as smoking, vitamin D deficiency, obesity, and Epstein-Barr virus infection. Life expectancy is not greatly altered by MS, and the disease course often extends over 30 years.

Question 28

Discuss the pathophysiology of MS

Answer 28

MS is a diffuse and progressive CNS autoimmune inflammatory disease that affects white and gray matter throughout the brain and spinal cord. There are multiple focal areas of myelin loss within the CNS called plaques. The plaques form when autoreactive T cells and B cells cross the blood–brain barrier into the brain and spinal cord. T cells recognize myelin as autoantigens and attack it. B cells produce myelin-specific antibodies, which are recognized by glial cells (macrophages). Activated glial cells engulf the antibodies, damaging the myelin. These attacks on myelin leave patches disrupting neurotransmission. With resolution of inflammation (a period of remission), the injury leaves a glial scar or sclerosis, the classic lesion of MS. During early stages oligodendrocytes (myelin-producing cells) repair myelin. With progressive attacks, oligodendrocytes are also injured and lost. The loss of oligodendrocytes prevents remyelination, and over time the injury is irreversible with loss of axons. Loss of myelin disrupts nerve conduction, leading to symptom presentation. There is at least partial myelin repair during relapse of symptoms. Ultimately there is death of neurons and brain atrophy in the most progressive forms of the disease. The multifocal, multistage features of MS lesions produce symptoms that are multiple and variable. Thus, inflammation, demyelination, myelin repair, loss of oligodendrocytes, and scar formation distinguish MS from other demyelinating disorders of the CNS.

Question 29

Discuss the clinical manifestations of MS

Answer 29

The onset, duration, and severity of symptoms are different for each person and depend on the location and extent of disease. A clinically isolated syndrome of neurologic symptoms (e.g., paresthesia, impaired gait, weakness, visual/hearing/speech abnormalities, urinary incontinence) that lasts 24hours or less may initially occur. It can be related to inflammation and demyelination but may never progress to develop into MS. There is no evidence of previous episodes of demyelination. Work is in progress to identify the prodromal symptoms of MS more specifically. MS develops when symptoms last more than 24hours; occur in the absence of fever, infection, or encephalopathy; and are caused by inflammation and demyelination in the CNS.

Question 30

What is optic neuritis?

Answer 30

One eye experiences progressive blurring of vision and pain with eye movement

Question 31

What is spinal cord syndrome?

Answer 31

Both sensory and motor tracts starting on one side and progressing to the other

Question 32

What are brainstem syndromes?

Answer 32

Facial sensory loss or weakness, vertigo, or double vision

Question 33

What are cerebellar syndromes?

Answer 33

Lack of coordination, tremor, gait instability, and ataxia

Question 34

What are cognitive deficits?

Answer 34

Memory and attention as well as later dementia and psychiatric disorders

Question 35

Discuss the symptom subtypes of MS

Answer 35

The subtypes of MS are based on the clinical course. The most common initial symptoms of MS are paresthesia of the face, trunk, or limbs; weakness; impaired gait; or urinary incontinence, indicating diffuse CNS involvement.

Relapsing/remitting: most common and is characterized by relapses or exacerbations (flares) of previous symptoms or worsening of neurologic symptoms - common in women

Primary progressive: least common and is characterized by gradual progression of the disease without periods of remission - equally in men and women.

Secondary progressive: characterized by an initial period of relapsing/remitting MS followed by a gradual worsening of the symptoms between relapses.

Progressive relapsing MS: characterized by steady worsening symptoms from the onset with clear acute relapses but often with more severe symptoms.

Question 36

Discuss evaluation and treatment of MS

Answer 36

There is no single test available to diagnose or rule out MS. Diagnostic criteria include history, clinical examination, CSF findings, and evoked potentials in combination with MRI (most sensitive test for detecting demyelinated plaque, disease progression [new lesions], and treatment response).Clinical symptoms include neurologic findings not attributable to another diagnosis with two or more episodes lasting at least 24hours and occurring at least 1 month apart. Persistently elevated levels of CSF immunoglobulin G (IgG) are found in about two-thirds of individuals with MS, and oligoclonal IgG bands on electrophoresis are found in more than 90% of individuals with MS.

Treatment goal in MS is prevention of exacerbations, prevention of permanent neurologic damage, and control of symptoms.
- corticosteroids
- immunotherapy
- immune system modulators (main strategy)
- continuous monitoring for signs of infections while on these drugs
- vitamin D
- stem cell Tx under investigation
- regular exercise program
- smoking cessation
- avoidance of overwork, extreme fatigue, and heat exposure

Question 37

Discuss the use of interferon Beta-1b: Betaseron in MS therapy

Answer 37

Indication: ambulatory patients with relapsing or remitting MS

Mechanisms of action: drug that’s not clearly understood. Believed to act by suppressing the activity of T-cells and reducing the inflammatory actions of cytokines.

Desired effect: decreased symptoms of ms

Adverse effect: transient flu-like symptoms (symptomatic therapy can be given to prevent this, leukopenia, H/A, insomnia, asthenia, increased liver enzymes, rash, peripheral edema, depression, suicidal ideation and malaise