IQ Case 9*

7. List the differential diagnosis of frontal lobe lesions.

Alzheimer Disease Alzheimer Disease in Individuals With Down Syndrome Amyloid Angiopathy Anterior Circulation Stroke Aphasia Apraxia and Related Syndromes Arteriovenous Malformations Cardioembolic Stroke Cerebral Aneurysms Glioblastoma Multiforme Low-Grade Astrocytoma Meningioma Pick Disease Primary CNS Lymphoma

Dementia signs and symptoms

Dementia affects the brain's ability to think, reason and remember clearly. The most common affected areas include memory, visual-spatial, language, attention, and executive function (problem solving). Most types of dementia are slow and progressive. By the time the person shows signs of the disease, the process in the brain has been happening for a long time.

Frontotemporal dementia (First Aid)

-Dementia, aphasia, parkinsonian aspects; change in personality. -Spares parietal lobe and posterior 2/3 of superior temporal gyrus -Also called Pick disease. Note the Pick bodies: silver-staining spherical Tau protein aggregates. -Frontotemporal atrophy

Alzheimer's brain changes (wiki)

The part of the brain most affected by Alzheimer's is the hippocampus. Other parts of the brain that will show shrinking (atrophy) include the temporal and parietal lobes. Although this pattern suggests Alzheimer's, the brain shrinkage in Alzheimer's disease is very variable, and a scan of the brain cannot actually make the diagnosis.

Lewy body dementia (First Aid)

-Initially dementia and visual hallucinations followed by parkinsonian features -Alpha-synuclein defect (Lewy bodies, primarily cortical)

Alzheimer's (First Aid)

-Most common cause of dementia in the elderly. (inc. in Down syndrome) -Familial form (10%) associated with the following proteins: -ApoE2 = decreased risk -ApoE4 = increased risk -APP, presenilin-1, presenilin-2 = increased risk of early onset -Widespread cortical atrophy. Narrowing of gyri and widening of sulci -Decreased Ach -Senile plaques in gray matter: extracellular beta-amyloid core; may cause amyloid angiopathy leading to intracranial hemorrhage, amyloid-beta synthesized by cleaving amyloid precursor protein (APP) -Neurofibrillary tangles: intracellular, hyperphosphorylated tau protein = insoluble cytoskeletal element; number of tangles correlates with degree of dementia

Creutzfeldt-Jakob disease (First Aid)

-Rapidly progressive (weeks to months) dementia with myoclonus (startle myoclonus) -Spongiform cortex -Prions form beta-pleated sheet resistant to proteases

6. Explain the role of neuroimaging in the evaluation of dementia.

Although detailed clinical assessment forms the basis of evaluating a patient with cognitive impairment, structural and functional imaging techniques are increasingly being used. Neuroimaging can identify changes to supplement the clinical diagnosis and help to distinguish dementia subtypes. This may be important for treatment, prognosis and care planning. Furthermore, early changes on structural and functional imaging may have a role in preclinical detection, perhaps allowing people to start any treatments early. The role of imaging in dementia has traditionally been directed at ruling out treatable and reversible etiologies and not to use imaging to better understand the pathophysiology of the different dementias. Different brain imaging techniques allow the examination of the structure, biochemistry, metabolic state, and functional capacity of the brain. All of the major neurodegenerative disorders have relatively specific imaging findings that can be identified. New imaging techniques carry the hope of revolutionizing the diagnosis of neurodegenerative disease so as to obtain a complete molecular, structural, and metabolic characterization, which could be used to improve diagnosis and to stage each patient and follow disease progression and response to treatment. Structural and functional imaging modalities contribute to the diagnosis and understanding of the different dementias.

3. Compare and contrast the clinical presentation of the three most common primary degenerative dementias (Alzheimer's disease, Frontotemporal dementia (FTD) and Dementia with Lewy Bodies).

Alzheimer's = The most common early symptom is difficulty in remembering recent events (short term memory loss). As the disease advances, symptoms can include: problems with language, disorientation (including easily getting lost), mood swings, loss of motivation, not managing self-care, and behavioral issues. As a person's condition declines they often withdraw from family and society. Gradually, bodily functions are lost, ultimately leading to death. FTD = Dementia, aphasia, parkinsonian aspects, change in personality Lewy body dementia = Initially dementia and visual hallucinations followed by parkinsonian features

Dementia causes

Alzheimer's disease Frontotemporal dementia Lewy body dementia Creutzfeldt-Jakob disease Other causes: multi-infarct (2nd most common cause of dementia in the elderly), syphilis, HIV, vitamins B1, B3, or B12 deficiency, Wilson disease, normal pressure hydrocephalus The most common type of dementia is Alzheimer's disease which makes up 50% to 70% of cases. Other common types include vascular dementia (25%), Lewy body dementia (15%), and frontotemporal dementia. Less common causes include normal pressure hydrocephalus, Parkinson disease, syphilis, and Creutzfeldt-Jakob disease among others.

1. Define the term dementia.

Dementia = decrease in intellectual functioning without affecting the level of consciousness Characterized by memory deficits, apraxia*, aphasia, agnosia**, loss of abstract thought, behavior/personality changes, impaired judgment. * a motor disorder caused by damage to the brain, in which someone has difficulty with the motor planning to perform tasks or movements when asked, provided that the request or command is understood and he/she is willing to perform the task. ** the inability to process sensory information. Often there is a loss of ability to recognize objects, persons, sounds, shapes, or smells while the specific sense is not defective nor is there any significant memory loss

Lewy body dementia (wiki)

Dementia with Lewy bodies (DLB) is a dementia that has the primary symptoms of visual hallucinations and "Parkinsonism." Parkinsonism is a term that describes a person with features of Parkinson's disease. This includes tremor, rigid muscles, and a face without emotion. The visual hallucinations in DLB are generally very vivid hallucinations of people and/or animals and they often occur when someone is about to fall asleep or just waking up. Other prominent symptoms include problems with attention, organization, problem solving and planning (executive function) and difficulty with visual-spatial function. Again, imaging studies cannot necessarily make the diagnosis of DLB, but some signs are particularly common. A person with DLB will often show occipital hypoperfusion on SPECT scan or occipital hypometabolism on a PET scan. Generally, a diagnosis of DLB is straightforward and unless it is complicated; a brain scan is not always necessary.

4. Describe the three major syndromes associated with the clinical presentation of FTD: behavioral variant, progressive aphasia and motor neuron disease.

FTD is traditionally difficult to diagnose due to the heterogeneity of the associated symptoms. Signs and symptoms are classified into three groups based on the functions of the frontal and temporal lobes: § Behavioral variant frontotemporal dementia (BvFTD) is characterized by changes in social behavior and conduct, with loss of social awareness and poor impulse control. § Semantic dementia (SD) is characterized by the loss of semantic understanding, resulting in impaired word comprehension, although speech remains fluent and grammatically faultless. § Progressive nonfluent aphasia (PNFA) is characterized by progressive difficulties in speech production. However, the following abilities in the person with FTD are preserved: Perception Spatial Skills Memory Praxis In rare cases, FTD can occur in patients with motor neuron disease (MND) (typically amyotrophic lateral sclerosis). The prognosis for people with MND is worse when combined with FTD, shortening survival by about a year.

Frontotemporal dementia (wiki)

Frontotemporal dementia (FTD) is a dementia that is characterized by drastic personality changes and language difficulties. In all FTD the person will have a relatively early social withdrawal and early lack of insight into the disease. Memory problems are not a main feature of this disease.

Vascular dementia (wiki)

It is caused by disease or injury to blood vessels that damage the brain, including strokes. The symptoms of this dementia depend on where in the brain the strokes have occurred and whether the vessels are large or small. Multiple injuries can cause progressive dementia over time, while a single injury located in an area critical for cognition (i.e., hippocampus, thalamus) can lead to sudden cognitive decline. On scans of the brain, a person with vascular dementia may show evidence of multiple different strokes of different sizes. They tend to have risk factors for artery disease such as tobacco smoking, high blood pressure, atrial fibrillation, high cholesterol or diabetes, or other signs of blood vessel disease such as a previous heart attack or angina.

Alzheimer's presentation (wiki)

Its most common symptoms are short-term memory loss and word-finding difficulties. People with Alzheimer's also have trouble with visual-spatial areas (for example they may begin to get lost often), reasoning, judgement, and insight. Insight refers to whether or not the person realizes he/she has memory problems.

Alzheimer's drugs

Memantine MOA: NMDA receptor antagonist; helps prevent excitotoxicity (mediated by calcium) Toxicity: dizziness, confusion, hallucinations Donepezil, galantamine, rivastigmine, tacrine MOA: AChE inhibitors. Since a loss of cholinergic neuronal activity has been noted in Alzheimer disease, it has been speculated that an increase in the stimulation of cholinergic neurons may be beneficial in treating the disease. Slows progression by about 6 months. Doesn't improve memory loss. Toxicity: nausea, dizziness, insomnia

8. Describe the so called 'primitive reflexes": suck, snout and palmo-mental reflexes.

Primitive reflexes = CNS reflexes that are present in a healthy infant, but are absent in a neurologically intact adult. Normally disappear within first year of life. These primitive reflexes are inhibited by a mature/developing frontal lobe. They may remerge in adults following frontal lobe lesion leading to loss of inhibition of those reflexes. § Suck = sucking response when roof of mouth is touched § Snout = a pouting or pursing of the lips that is elicited by light tapping of the closed lips near the midline § Palmo-mental = a primitive reflex consisting of a twitch of the chin muscle elicited by stroking a specific part of the palm (thenar eminence)

Progressive supranuclear palsy (wiki)

Progressive supranuclear palsy (PSP) is a form of dementia that is characterized by problems with eye movements. Generally the problems begin with difficulty moving the eyes up and/or down (vertical gaze palsy). Since difficulty moving the eyes upward can sometimes happen in normal aging, problems with downward eye movements are the key in PSP. Other key symptoms of PSP include falls backwards, balance problems, slow movements, rigid muscles, irritability, apathy, social withdrawal and depression. The person may also have certain "frontal lobe signs" such as perseveration, a grasp reflex and utilization behavior (the need to use an object once you see it). People with PSP often have progressive difficulty eating and swallowing, and eventually with talking as well. Because of the rigidity and slow movements, PSP is sometimes misdiagnosed as Parkinson's disease. On scans of the brain, the midbrain of people with PSP is generally shrunken (atrophied), but there are no other common brain abnormalities visible on images of the person's brain.

5. Compare and contrast the mechanism of action of selective serotonin reuptake inhibitors with acetylcholinesterase inhibitors.

SSRIs § Fluoxetine, paroxetine, sertraline, citalopram § Mechanism: 5HT-specific reuptake inhibitors. They have varying degrees of selectivity for the other monoamine transporters, with pure SSRIs having only weak affinity for the noradrenaline and dopamine transporter. § Clinical use: depression, generalized anxiety disorder, panic disorder, OCD, bulimia, social phobias, PTSD § Toxicity: Fewer than TCAs. GI distress, SIADH, sexual dysfunction (anorgasmia, decreased libido) § Serotonin syndrome: with any drug that increases 5HT (e.g. MAOIs, SNRIs, TCAs) - hyperthermia, confusion, myoclonus, cardiovascular instability, flushing, diarrhea, seizures. Treat w/ cyproheptadine (5HT2 receptor antagonist) AChE inhibitors § Donepezil, galantamine, rivastigmine, tacrine § Mechanism: a chemical that inhibits the acetylcholinesterase enzyme from breaking down acetylcholine, thereby increasing both the level and duration of action of the neurotransmitter acetylcholine. § Clinical use: To treat Alzheimer's disease, Lewy Body Dementia and Parkinson's disease. In these neurodegenerative conditions AChEIs are primarily used to treat the cognitive (memory and learning deficits mostly) symptoms of dementia. Myasthenia gravis § Toxicity: nausea, dizziness, insomnia

2. Distinguish the cognitive changes in dementia from normal aging.

Some changes in the ability to think are considered a normal part of the aging process. Most healthy older adults experience mild decline in some areas of cognition. These changes may occur in the areas of visual and verbal memory, visuospatial abilities, immediate memory or the ability to name objects. Research indicates that age-related changes in the brain such as decreased hippocampal, frontal and temporal lobe volumes can occur. However, the extent to which these age-related changes contribute to cognitive decline has yet to be determined. Non-verbal memory impairments are also considered to be a common cognitive deficit associated with aging. Control and maintenance of attention and immediate memory can be affected in normally aging individuals. With regards to the language abilities associated with normal aging, vocabulary and verbal reasoning remain unchanged or even improve during the aging process. However, the ability to generate words declines more quickly than the ability to name objects. This is particularly true with advancing age beginning in the 70s.

Dementia differential

Some mental illnesses, including depression and psychosis, may produce symptoms that must be differentiated from both delirium and dementia. Therefore, any dementia evaluation should include a depression screening such as the Neuropsychiatric Inventory or the Geriatric Depression Scale. It used to be thought that anyone who came in with memory complaints had depression and not dementia (because it was thought that those with dementia are generally unaware of their memory problems). This is called pseudodementia. However, in recent years we have realized that many older people with memory complaints in fact have MCI, the earliest stage of dementia. Depression should always remain high on the list of possibilities, however, for an elderly person with memory trouble.

9. Describe the alternate splicing of the tau protein, its function and its expression in Alzheimer's disease and FTD.

Tau proteins are proteins that stabilize microtubules. They are abundant in neurons of the central nervous system and are less common elsewhere, but are also expressed at very low levels in CNS astrocytes and oligodendrocytes. Pathologies and dementias of the nervous system such as Alzheimer's disease can result when tau proteins become defective and no longer stabilize microtubules properly. The tau proteins are the product of alternative splicing from a single gene that in humans is designated MAPT (microtubule-associated protein tau) and is located on chromosome 17. Six tau isoforms exist in human brain tissue, and they are distinguished by their number of binding domains. The isoforms with four binding domains are better at stabilizing microtubules than those with three binding domains. The isoforms are a result of alternative splicing in exons 2, 3, and 10 of the tau gene. Phosphorylation of tau is regulated by a host of kinases, including PKN, a serine/threonine kinase. When PKN is activated, it phosphorylates tau, resulting in disruption of microtubule organization. Hyperphosphorylation of the tau protein (tau inclusions, pTau) can result in the self-assembly of tangles of paired helical filaments and straight filaments, which are involved in the pathogenesis of Alzheimer's disease, frontotemporal dementia, and other tauopathies. All of the six tau isoforms are present in an often hyperphosphorylated state in paired helical filaments from Alzheimer's disease brain. In other neurodegenerative diseases, the deposition of aggregates enriched in certain tau isoforms has been reported. When misfolded, this otherwise very soluble protein can form extremely insoluble aggregates that contribute to a number of neurodegenerative diseases.

Frontotemporal dementia (wiki) Semantic dementia or temporal variant

The main feature of this is the loss of the meaning of words. It may begin with difficulty naming things. The person eventually may also lose the meaning of objects as well. For example, a drawing of a bird, dog, and an airplane in someone with FTD may all appear just about the same. In a classic test for this, a patient is shown a picture of a pyramid and below there is a picture of both a palm tree and a pine tree. The person is asked to say which one goes best with the pyramid. In TV-FTD the person would not be able to answer that question.

Frontotemporal dementia (wiki) Behavioral variant

This is called behavioral variant FTD (bv-FTD) and is the most common. In bv-FTD, the person will have a change in personal hygiene, they will become rigid in their thinking, they rarely recognize that there is a problem, they will be socially withdrawn, and they will often have a drastic increase in appetite. The person may also be socially inappropriate. For example, the person may make inappropriate sexual comments, or may begin using pornography openly when they had not before. One of the most common signs is apathy, or not caring about anything. Apathy, however, is a common symptom in many different dementias.

Frontotemporal dementia (wiki) Progressive non-fluent aphasia

This is mainly a problem with producing speech. They have trouble finding the right words, but mostly they have a difficulty coordinating the muscles they need to speak. Eventually, someone with PNFA will only use one-syllable words or may become totally mute.