Alzheimer’s

=**Overview:**= Alzheimer’s disease (AD) is a chronic, progressive neurodegenerative disorder resulting from attacks on the brain’s nerve cells. Although this disease can be diagnosed at any age, it is most commonly recognized later in life. It is characterized by the presence of abnormal protein aggregates in neurons and extracellular space of the central nervous system (CNS). The causes of Alzheimer’s are unknown, but the “amyloid cascade hypothesis” is the most widely accepted and discussed theory. The strongest research in support of this hypothesis suggests that a genetic mutation leads to excessive production of a small peptide, amyloid β-protein (Aβ). Large Aβ fibers create lesions—neurofibrillary tangles and senile plaques—that obstruct the pathways of neural signals. Such interferences lead to complications in axonal transport from one neuron to the next, most often associated with major memory impairments. These lesions can also contribute to movement and motor control disorders [1,2,7].  = = = =

=Progression of Alzheimer's Disease:=

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//Stage One//: Patient becomes increasingly forgetful and experiences short term memory loss, disorientation of time and space, **aphasia**, and **mild apraxia** [3,7]. =====

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//Stage Two//: Patient is now suffering from both short term and remote memory loss, clumsy movement, decreased muscle control, **ideomotor and ideational apraxia**, and **agnosia** [3,7]. =====

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//Stage Three//: Patient is now suffering more severe dementia symptoms, decreased communication abilities, **apraxia resulting in one** **step skills **, minimal motor control, and behavioral problems [3,7]. =====

=Amyloid Cascade Hypothesis:=

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Deposition of **amyloid-β protein (APβ)**, the main component of senile plaques, is the direct cause of AD pathology; neurofibrillary tangles, cell loss, vascular damage, and dementia are the results of such deposition and are therefore indirect causes. AβP is a peptide product of the larger **amyloid precursor protein (APP)**. APP proteolysis leads to AβP deposition when APP is inserted into the cytoplasmic membrane and cleaved within the AβP sequence, resulting in fragments lacking intact AβP. These fragments cannot result in amyloid deposition. Mutations within the APP have empirically shown to cause familial AD. They inhibit the breakdown of a COOH-terminal fragment of APP that contains AβP, alter the anchoring of APP in the cell membrane, and/or stabilize AβP-containing amyloidogenic fragments within lysosomes. The **amyloid cascade hypothesis** claims that AβP, or APP cleavage products containing AβP, are neurotoxic and can lead to neurofibrillary tangles or cell death. For this to lead to AD, AβP must be generated as an intact formation, either  by accumulation of AβP itself or as an AβP-containing fragment of APP, and this molecule must facilitate or cause neuronal death and tangle formation. The overall result is neuron disconnection, leading to cell death, brain shrinkage, and loss of function in many areas[5,8]. =====

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Formed when proteins in the neuron of a cell membrane are processed differently than in a normal, healthy brain. Normally, the enzyme alpha-secretase cuts APP to release a fragment. Gamma secretase, a second enzyme, also cuts APP in a different place and releases a second fragment. The two fragments together benefit the neuron. In AD brains, the first cut, normally done by alpha-secretase, is made instead by beta-secretase. This cut, along with one made by gamma-secretase, release shorter fragments of APP called beta-amyloid fragments. It is when many of these fragments clump together that they become toxic and interfere with neuronal functioning. As they increase in size they become insoluble and constitute as plaques[8,9]. =====

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** Neurofibrillary Fibers: ** =====

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These fibers are formed when **tau protein** is modified. In normal brains, tau stabilizes structures critical to the cells internal transport system. Nutrients and other necessary components of these cells are carried along microtubules to all parts of the neuron. In AD =====

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brains, tau is abnormal and separates from the microtubules, causing them to fall apart. The strands that detached from the microtubules combine and form tangles in the neuron, disabling the transport system and disabling the cell[8,9]. =====

[|Video - Plaques & Tangles] = =

=Apraxia & Alzheimer's:=

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<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">**Apraxia** is defined as difficulty making voluntary gestures in the absence of motor or sensory inputs. Alzheimer’s patients most often suffer from ideomotor apraxia or ideational apraxia. <span style="font-family: 'Times New Roman',serif; font-size: 16px;">Patients with AD who experience apraxia often have been associated with unilateral or bilateral cortical atrophy and diminished activity in parietal regions. These findings indicate parietal lobe hypoperfusion, the inadequate perfusion of tissue within the parietal lobe that results in less than necessary levels of oxygen and nutrients, leads to cell death. Although it is less frequent, apraxia can also be the result of right hemispheric lesions, which suggests that visuokinaesthetic engrams containing spatial and temporal representations may be represented either bilaterally or in the non-dominant hemisphere [4,8]. ===== **<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Basal Gangila in Apraxia: ** <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">The motor and premotor cortices project to the basal ganglia along with the parietal cortex. These areas are interconnected and make up the **parietofrontal circuits**. These circuits are involved in sensorimotor integration or in translation of sensory input into information for the production of movement. Which circuit is activated depends on the activity wanting to be performed is new or learned, and the complexity of the movement overall. Dysfunction of the basal ganglia can lead to errors of the praxis and result in apraxia. Lesions in areas such as the putamen, globus pallidus internus, caudate, and substantia nigra have all empirically been suggested to play a role in the development of apraxia in AD [8].

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 * <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">IMA **<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">is the inability to imitate a gesture or perform a movement on command due to difficulty in translating the concept of a motor sequence into the correct motor action. This may not be immediately perceived by the AD individual as it predominantly undermines gestures when they are asked for in a theoretical setting. Anatomically diverse lesions in the left hemisphere tend to cause IA; they typically involve parietal association areas and white matter bundles that serve to connect frontal and parietal association areas. Less common, but still significant, are premotor and supplemental motor cortex lesions that involve the basal ganglia and/or thalamus [6,8]. =====

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<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">**IA** is a failure to mentally evoke the gesture associated with an object, such as difficulty carrying out complex goal-directed activities, even when the goal is understood. Both IMA and IA severity are directly related to the rate of progression of the Alzheimer’s disease. Damage causing IA is typically thought to involve left parieto-occipital and parietotemporal regions [6,8]. =====

=Agnosia & Aphasia in Alzheimer's:=

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<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">**Agnosia** is defined as the inability to recognize objects, people, sounds, shapes, or smells. It can take on three different forms--visual, auditory, or tactile--and is associated with deficits in neuronal-axonal transport across visual processing areas and sensorimotor areas of the brain. It typically onsets in the second stage of Alzheimer's disease, categorized as the stage of confusion [10]. =====

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<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">**Aphasia** is the loss of ability to express or understand speech as a result of damage in the frontotemporal areas of the brain. This often begins in the early stages of AD and is one of the more frustrating aspects for the patient [2]. ===== [|Video - Effects of Agnosia]

=Summary:=

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<span style="font-family: 'Times New Roman',serif; font-size: 16px;">While there is no known cause of Alzheimer's disease, the amyloid cascade hypothesis offers the most insight to neurological processes and dysfunctions that can lead to the symptoms of the disease. Reduced axon transport is caused by more of amyloid-β protein being produced and released. This leads to lesions in the brain composed of proteins that block the pathways (plaques and neurofibrillary fibers) in the extracellular space of the brain. Such deficits can lead to memory loss, confusion, apraxia, agnosia, and aphasia. There is no cure for Alzheimer's, but there are possible treatments to reduce the effects of the secondary diseases that impair movement and enhance the quality of life for a patient. =====

=Glossary of Terms:=

<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">**Agnosia:** the inability to recognize objects, people, sounds, shapes, or smells.

 * <span style="font-family: 'Times New Roman',serif; font-size: 16px;">Alzheimer’s disease (AD) **<span style="font-family: 'Times New Roman',serif; font-size: 16px;">: chronic, progressive neurodegenerative disorder resulting from attacks on the brain’s nerve cells, usually leading to memory loss, motor control dysfunction, and language deficits.

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<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">**Ideational Apraxia:** failure to mentally evoke the gesture associated with an object, such as difficulty carrying out complex goal-directed activities, even when the goal is understood. =====

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 * <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Ideomotor Apraxia: **<span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> inability to imitate a gesture or perform a movement on command due to difficulty in translating the concept of a motor sequence into the correct motor action. =====

<span style="font-family: 'Times New Roman',serif; font-size: 16px;">**Neurofibrillary Fibers:** fibers formed when tau protein is modified.

 * <span style="font-family: 'Times New Roman',serif; font-size: 16px;">Parietofrontal circuits: **<span style="font-family: 'Times New Roman',serif; font-size: 16px;"> circuits involved in sensorimotor integration or in translation of sensory input into information for the production of movement.

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 * <span style="font-family: 'Times New Roman',serif; font-size: 16px;">Senile Plaques: **<span style="font-family: 'Times New Roman',serif; font-size: 16px;">formed when proteins in the neuron of a cell membrane are processed differently than in a normal, healthy brain. =====

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<span style="font-family: 'Times New Roman',serif; font-size: 16px;">**Tau protein:** <span style="font-family: 'Times New Roman',serif; font-size: 16px; line-height: 1.5;">stabilizes structures critical to the cells internal transport system. =====

=Suggested Readings:=

[|Slowly Progressive Apraxia]
[|Apraxia in Movement Disorders]

[|More on Aphasia]

=Self Quiz=

<span style="font-family: 'Times New Roman',serif; font-size: 16px;">__Multiple Choice__
<span style="font-family: 'Times New Roman',serif; font-size: 16px;">1. Which of the following is not involved in the Amyloid Cascade Hypothesis? <span style="font-family: 'Times New Roman',serif; font-size: 16px;">a) APP <span style="font-family: 'Times New Roman',serif; font-size: 16px;">b) amyloid-beta protein <span style="font-family: 'Times New Roman',serif; font-size: 16px;">c) apraxia <span style="font-family: 'Times New Roman',serif; font-size: 16px;">d) gamma-secretase

<span style="font-family: 'Times New Roman',serif; font-size: 16px;">2. Apraxia is best defined in which of the following ways? <span style="font-family: 'Times New Roman',serif; font-size: 16px;">a) the inability to express of understand speech <span style="font-family: 'Times New Roman',serif; font-size: 16px;">b) difficulty making voluntary gestures in the absence of motor or sensory inputs <span style="font-family: 'Times New Roman',serif; font-size: 16px;">c) <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">inability to recognize objects, people, sounds, shapes, or smells <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">d) <span style="font-family: 'Times New Roman',serif; font-size: 16px;">translation of sensory input into information for the production of movement

<span style="font-family: 'Times New Roman',serif; font-size: 16px;">3. Which symptom of Alzheimer's Disease most commonly has the earliest onset? <span style="font-family: 'Times New Roman',serif; font-size: 16px;">a) short term memory loss <span style="font-family: 'Times New Roman',serif; font-size: 16px;">b) agnosia <span style="font-family: 'Times New Roman',serif; font-size: 16px;">c) ideomotor apraxia <span style="font-family: 'Times New Roman',serif; font-size: 16px;">d) ideational apraxia

__<span style="font-family: 'Times New Roman',serif; font-size: 16px;">True/False __ <span style="font-family: 'Times New Roman',serif; font-size: 16px;">4. Tau protein clumps together to form insoluble patches called senile plaques, leading to disrupted axon-transport systems.

<span style="font-family: 'Times New Roman',serif; font-size: 16px;">5. Amyloid-β Protein is the larger fragment from which Amyloid Precursor Protein is derived from.

<span style="font-family: 'Times New Roman',serif; font-size: 16px;">6. The basal ganglia contains parietofrontal circuits that are involved in sensorimotor integration or translation of sensory input into information for production of movement.

<span style="font-family: 'Times New Roman',serif; font-size: 16px;">7. The main reason Alzheimer's disease leads to motor control disorders is due to the disrupted axonal transport that occurs.

__<span style="font-family: 'Times New Roman',serif; font-size: 16px;">Short Answer __ <span style="font-family: 'Times New Roman',serif; font-size: 16px;">8. Explain the differences between ideomotor apraxia and ideational apraxia. <span style="font-family: 'Times New Roman',serif; font-size: 16px;">9. Compare and contrast the formation of senile plaques and neurofibrillary fibers. <span style="font-family: 'Times New Roman',serif; font-size: 16px;">10. Describe the progression process of Alzheimer's disease as a whole. Include which symptoms occur at which stages.

<span style="font-family: 'Times New Roman',serif; font-size: 16px;">Answers: <span style="font-family: 'Times New Roman',serif; font-size: 16px;">1. c <span style="font-family: 'Times New Roman',serif; font-size: 16px;">2. b <span style="font-family: 'Times New Roman',serif; font-size: 16px;">3. a <span style="font-family: 'Times New Roman',serif; font-size: 16px;">4. F <span style="font-family: 'Times New Roman',serif; font-size: 16px;">5. F <span style="font-family: 'Times New Roman',serif; font-size: 16px;">6. T <span style="font-family: 'Times New Roman',serif; font-size: 16px;">7. T

=References:=

<span style="font-family: 'Times New Roman',serif; font-size: 16px;">[1] Buchman AS, Bennett DA. Loss of motor function in preclinical Alzheimer's disease. //Expert Review Neurotherapy// 11(5): 665-676, 2011.

<span style="font-family: 'Times New Roman',serif; font-size: 16px;">[2] Chapman SB, Highley AP, Thompson JL. Discourse in fluent aphasia and Alzheimer's disease: Linguistic and pragmatic considerations. //<span style="font-family: 'Times New Roman',serif; font-size: 16px;">Journal of Neurolinguistics //<span style="font-family: 'Times New Roman',serif; font-size: 16px;">11: 55-78, 1998.

<span style="font-family: 'Times New Roman',serif; font-size: 16px;">[3] Crystal H, Marks JW, Stoppler MC. (2015). Alzheimer's Disease [Online]. MedicineNet. http://www.medicinenet.com/alzheimers_disease_causes_stages_and_symptoms/article.htm [3 December 2015].

<span style="font-family: 'Times New Roman',serif; font-size: 16px;">[4] Green RC, Goldstein FC, Mirra SS, Alazraki NP, Baxt JL, Bakay RA. Slowly progressive apraxia in Alzheimer's disease. //Journal of Neurology, Neurosurgery, and Psychiatry// 59(3): 312-315, 1995.

<span style="font-family: 'Times New Roman',serif; font-size: 16px;">[5] Hardy JA, Gerald A. Alzheimer's Disease: The Amyloid Cascade Hypothesis. //Science// 184: 256, 1992.

<span style="font-family: 'Times New Roman',serif; font-size: 16px;">[6] Lucchelli F, Lopez OL, Faglioni P, Boller F. Ideomotor and Ideational Apraxia in Alzheimer's Disease. //International Journal of Geriatric Psychiatry// 8(5): 413-417, 1993.

<span style="font-family: 'Times New Roman',serif; font-size: 16px;">[7] N/A. (2015). About Alzheimer's Disease [Online]. Alzheimer's Foundation of America. http://www.alzfdn.org/AboutAlzheimers/definition.html [3 December 2015].

<span style="font-family: 'Times New Roman',serif; font-size: 16px;">[8] Zadikoff C, Lang AE. Apraxia in movement disorders. //Brain// 128: 1480-1497, 2005.
<span style="font-family: 'Times New Roman',serif; font-size: 16px;">[9] Plaques and Tangles: https://www.youtube.com/watch?v=dj3GGDuu15l [10 December 2015].

<span style="font-family: 'Times New Roman',serif; font-size: 16px;">[10] Agnosia: https://www.youtube.com/watch?v=dG8JGg-d2Pk [10 December 2015].

=Image References:=

<span style="font-family: 'Times New Roman',serif; font-size: 16px;">Image 1: https://goinggentleintothatgoodnight.files.worspress.com/2013/06/brain-healthy-brain-ad-best.jpg

<span style="font-family: 'Times New Roman',serif; font-size: 16px;">Image 2: https://www.thehomecarespot.com/wp-content/uploads/2013/08/alzbrain.jpg

<span style="font-family: 'Times New Roman',serif; font-size: 16px;">Image 3: http://www.nia.nih.gov

<span style="font-family: 'Times New Roman',serif; font-size: 16px;">Image 4: http://www.nature.com/nrd/journal/v10/n9/images/nrd3505-f1.jpg

<span style="font-family: 'Times New Roman',serif; font-size: 16px;">Image 5: http://brightfocus.org/sites/default/files/styles/full_width/public/Normal_vs_Alzheimers_Brain.jpf?itok=mQP5SCYz

<span style="font-family: 'Times New Roman',serif; font-size: 16px;">Image 6: http://www.all-creatires.org/health/alzheimers-02.jpg

<span style="font-family: 'Times New Roman',serif; font-size: 16px;">Image 7: http://image.slidesharecdn.com/anatomyofbasalganglia-120616000359-phpapp01/95/anatomy-of-basal-ganglia-3-728.jpg?cb=1339805116

<span style="font-family: 'Times New Roman',serif; font-size: 16px;">Image 8: https://upload.wikimedia.org/wikipedia/commons/3/33/Human_motor_cortex.jpg

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