Functional Implications of Alzheimer’s Disease
Search Terms
  • Pubmed and google scholar were the only comprehensive review sources used by all
  • Boolean term used: AND
  • Search Terms: Alzheimer’s, prognosis, functional tests, tests, exercises.
  • Any combination of these terms was searched for more than once by different researchers. Varying levels of evidence were found and included in the project ranging from systematic reviews to quasi experimental (control vs. Alzheimer's) studies.

Clinical Question
What does the progression of Alzheimer’s look like, and do exercise and pharmaceutical interventions help reduce the symptoms?



What is Alzheimer’s?
According to the Alzheimer’s Association: “Alzheimer's is a type of dementia that causes problems with memory, thinking and behavior.Symptoms usually develop slowly and get worse over time, becoming severe enough to interfere with daily tasks.” In addition to this catch-all quote, it mentions that Alzheimer’s is a progressive disorder that gets worse over time as we age and currently has no cure, but symptoms can be treated [1]

Why is Alzheimer's Important to discuss?
  • About 46 million people are living with dementia worldwide
  • Every 3 seconds 1 person is diagnosed with Dementia throughout the world
    • ~ 9.9 million new cases diagnosed annually
    • Every 66 seconds 1 person will develop dementia in the United States
  • In 2015 an estimated 18.1 billion hours of unpaid care was provided
  • Family caregivers can easily spend more than $5,000 a year on care
  • In 2016, Alzheimer’s and other dementias are estimated to cost the United States $236 billion [2]

Tests, Pathology, and Cellular Level Effects
There is no one single exam that can determine the diagnosis of Alzheimer’s. This is done through a thorough medical history, the patient's age, and any number of the following tests
  • Mini-mental state exam (MMSE)
  • Eye examination
  • Speech Tests
  • “Mini-Cog”
  • Clinical dementia rating scale
  • Reflex and sensation may also be tested, though there are no specific indications found with these types of tests [3]

Various Tests of Cognitive Function
  • Rapid Evaluation of Cognitive Functions Test, Symbol Digit Test,Verbal Fluency Test, Trail Making Test, Wechsler Memory Scale revised, Verbal Learning Memory Test, and Rivermead Verbal Learning Test
  • As you can see, there are a number of tests, but we’ve decided to go into more detail about the specific ones that are typically used as part of the diagnosis listed on the previous slide

Mini-Mental State Examination (MMSE)
  • During the MMSE, a health professional asks a patient a series of questions designed to test a range of everyday mental skills
  • The maximum MMSE score is 30 points. A score of 20 to 24 suggests mild dementia, 13 to 20 suggests moderate dementia, and less than 12 indicates severe dementia. On average, the MMSE score of a person with Alzheimer's declines about two to four points each year [3]
  • Here’s a Link to the Exam itself: https://www.mountsinai.on.ca/care/psych/on-call-resources/on-call-resources/mmse.pdf

Eye Examination
Optical Coherence Tomography
  • Has been used clinically for Diagnosis of Glaucoma and Macular Degeneration
  • Has biomarkers specifically for Mild Cognitive Impairment and AD
  • AD damages the Lateral Geniculate Nucleus and areas of the primary visual cortex and associated structures
  • AD also damages retinal ganglion cells which is also likely correlated with damage to the optic nerve caused by changes due to AD (neurofibrillary tangles). These tangles also seem to affect processes of the visual cortex even if they’re not located in that area of the brain [4]

Speech Test
The “Set-Test”
  • “The set-test evaluates the verbal fluency in 4 categories: colors, animals, fruits and cities. It has been proposed as a diagnostic aid in dementia in elderly patients...It had a positive correlation of 73 with mini-mental test. The cut-off value was 29 in adults and 27 in elderly people. A lower score is indicative of dementia. Sensitivity was 79% and specificity 82%, with 20% of incorrectly classified patients” [5]

“Mini-Cog”
During the mini-cog, a person is asked to complete two tasks:
  1. Remember and a few minutes later repeat the names of three common objects
  2. Draw a face of a clock showing all 12 numbers in the right places and a time specified by the examiner [3]

Clinical Dementia Rating Scale
  • Developed primarily for Alzheimer patients and it is also used to stage dementia in other illnesses
  • Five-point scale
    • 0 = no cognitive impairment
    • 0.5 = very mild dementia
    • 1 = mild dementia
    • 2 = moderate dementia
    • 3 = severe dementia
  • Six domains are:
    • Memory
    • Orientation
    • Judgment and Problem solving
    • Comunity affairs
    • Home and Hobbies
    • Personal Care
  • Assesses the patient’s cognitive ability to function in these areas [6]

Cellular Level Effect
  • Level of Amyloid Beta Plaque (present in older people most of the time)
  • Tau Protein in CSF increase (not present normally in CSF)
  • Number of Neurofibrillary Tangles-Necrotic Tau protein(not present normally)
  • Decline in CSF AB42 gene [8]
  • Various Gene Levels increasing or decreasing

Specific Genes for Alzheimer's? Not so much..
“Risk genes: While there is a blood test for APOE-e4, the strongest risk gene for Alzheimer's, this test is mainly used in clinical trials to identify people at higher risk of developing Alzheimer's. Carrying this gene mutation only indicates a greater risk; it does not indicate whether a person will develop Alzheimer's or whether a person has Alzheimer's” [9]

Pathology
  • Hippocampus (memory) Size Decrease
  • Brain Ventricle Size Increase
  • Cortex Size decreases [7]


alzheimer_brain.jpg
alzheimer_brain.jpg

















Types of AD
  • sAD (sporatic)
  • fAD (familial) or Autosomal dominant Alzheimer’s Disease (ADAD)
  • LOAD (late-onset)
  • AR-AD (asymptomatic at-risk)
  • Can belong to one or more of these groups at a time! [8]

AR-AD
Preclinical Alzheimer's:
Using some of those things mentioned in the previous slides to categorize someone who is asymptomatic with Alzheimer's, but essentially it’s based on one criteria; whether or not the amyloid plaques and tau proteins are present in the brain. Many researchers believe that this alone is enough to diagnose someone with AD [8]

Progression [10,11]
  • Stage 1: Early Stage
  • Stage 2: Middle Stage
  • Stage 3: Late Stage

Stage 1: Mild Alzheimer’s (Early-Stage) [10,11]
Carla 1.jpg
Duration: 2-4 years
  • May still maintain functional independence (drive/social)
  • Occasional memory lapses
  • Friends/family begin to notice difficulties
  • During a detailed medical exam, doctors would likely detect
  • Memory losses or concentration difficulties

Examples Include:
  • Problems coming up with right word or name
  • Social life and work is beginning to become hindered
  • Losing/misplacing objects
  • Forgetting material just presented to them

Stage 2: Moderate Alzheimer’s (Middle-Stage) [10,11]
Duration: 2-10 years carla 6.jpg
  • Greater level of care required
  • Unexplained behavior occurs
  • More emotions expressed
  • Damage to nerve cells increases difficulty to perform tasks and communicate thoughts
Examples:
  • Forget past details about own life
  • Feeling moody/withdrawn
  • Increased wandering/feeling lost
  • Trouble controlling bladder/bowels
  • Compulsive behavior. Getting angry or frustrated when confusing words

Stage 3: Severe Alzheimer’s (Late-Stage) [10,11]
Duration: 1-3 years
  • Loss of ability to respond environment
  • Can no longer carry out full conversations
  • Movement impairment
  • Memory and Cognitive skills decline significantly
  • Full time care required (24/365)
  • Required high levels of assistance with ADLs/personal care
  • Loss of awareness in surroundings
  • Vulnerable to infections; specifically pneumonia

Predicting the progression of Alzheimer’s disease dementia: A multi domain health policy model [12]
  • Purpose: Demonstrate the utility of a multidomain approach to modeling progression of AD and provide a foundation from which to develop a model to support the health policy context
  • 3009 Participants. Requirements were:
    • MMSE score of 26 or less
    • Age 50 or above
    • Continuous data collected over time on at least two consecutive assessments
  • Outcome measures
    • Multi-Mental State Examination (MMSE)
    • Functional Assessment Questionnaire (FAQ)
    • Neuropsychiatric Inventory (NPI)
  • Conclusion:
    • Over a 5 year period, it was found Mild AD mortality risk = 5%. Progressing to Moderate inc. to 48%. Additional inc. to 83% severe AD

10 Signs and Symptoms of Alzheimer’s [11]

Signs & Symptoms 1.jpg
Signs & Symptoms 1.jpg
Signs and Symp 2.jpg
Signs and Symp 2.jpg


Signs and Symptoms 3:4.jpg
Signs and Symptoms 3:4.jpg
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5 and 6 .jpg

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Treatment for Symptoms

Pharmaceuticals
  • Acetylcholinesterase Inhibitors- for memory loss
    • Galantamine
    • Donepezil
    • Rivastigmine
    • Memantine
    • Ginkgo biloba
      • Not approved by the FDA, but currently used in Europe
  • Antipsychotic drugs-for aggressive behavior
  • Memantine-NMDA receptor blockers, typically this receptor binds glutamate which in excess can cause cell death

Systematic Review on Drug Treatment [13]
  • Included 31 studies and 9,611 subjects
  • Standardized Mean Change score using Raw score standardization (SMCR) of cognitive performance were calculated
    • This allowed the authors to compare studies that used different cognitive/functional tests as the outcome measure
  • Analyzing the five available drugs in AD, there is a small but statistically significant difference, favoring drug over placebo (SMCR: 0.23, 95% confidence interval [CI]: 0.20–0.25)
  • Tests for Heterogeneity: Q (df= 58) = 195.04, p<0.01; I2= 72.12%
  • Test for Overall Effect: Z= 33.86, p<0.01

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Cognitive and Functional Decline and Their Relationship in Patients with Mild Alzheimer's Dementia [14]
  • Purpose: Assess the relationship between cognitive and functional decline and the relationship between cognitive and functional treatment effects in patients with mild AD
  • 2 groups
    • 1 group received 400-mg of solanezaumad (664)
    • 1 group received a placebo (660)
    • Every 4 week for 18 months
  • Outcome measures
    • AD Assessment Cognitive Scale
    • AD Cooperative Study -Activities of Daily Living
  • Conclusion:
    • Congnition declines precede functional declines, and that in slowing cognitive decline you can slow functional declines as well

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Exercise Program for Nursing Home Residents with Alzheimer's Disease: A 1-Year Randomized, Controlled Trial [15]
  • Purpose: determine if a 12 month exercise program could reduce ADL declines in individuals who were diagnosed with with Alzheimer’s Disease (AD)
  • Randomized controlled Trial
    • 5 nursing homes
    • 134 patients with mild to moderate AD
    • 1 group received standard medical care (67)
    • 1 group participated in exercise program (67)

  • Intervention
    • Exercise: 1 hour twice a week with at least 2 days in between sessions
    • 88 sessions
    • Supervised by an OT
    • Groups of 2-7 people
  • Exercise Program external image dUJqs_CXA7bfFdljWYAWkcyLRFc6cfck6l8ksmLvVqIsC26pl9b-fA-_QMv_i2JoOZiL9bdnmHdumF-629rVVHC-JxMxwxfoGXtIYLpV41yKGB0UWmHiMKb_6VMSntUqGs6D81p429A
    • Aerobic
    • Strength
    • Flexibility
    • Balance
  • Program Requirements
    • Walk for at least 30min
    • Then 30min of strength, balance, and flexibility
  • Strength:
    • Focused mainly on Lower Extremity
      • Squats or sit to stands
      • Standing lateral leg elevations and heel raises
  • Flexibilityexternal image 9xQjsJrLMx_VNm7SP3dWa13wa1K7AIc9IVcawjcQiJJbFTjDhHa6_DZDdiAz-_lLyIyeTbNWP2C9Nv-rBHqNBWXA2glak7pg2V_K_Qka3b959o0ncsqLjpuv5uaw7QxfYIkduP00eYQ
  • Patients mirrored exercises demonstrated by OT
  • Balance
    • Step drills with cones and hoops
    • 1 and 2 legged balance exercises on ground or foam-rubber
  • Primary outcome measure
    • Katz ADL score
  • Secondary outcome measures
    • Physical performance: 6m walking test, TUG, one leg balance test
    • Nutrition
    • Behavior
    • Depression
  • 110 people completed the study
  • Adherence
    • 13 completed: > 60 sessions
    • 19 completed: 30-60 sessions
    • 28 completed: <30 sessions
    • 7 completed: 0 session
  • After 12 months, mean ADL score was significantly lower in exercise group (P =.02) than in standard medical care group
  • Significant increase in walking speed at 6 and 12 months for the exercise group compared to the standard medical care group


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Effects of Exercise on Cognition: The Finnish Alzheimer Disease Exercise Trial: A Randomized, Controlled Trial [16]
  • Purpose: To see the cognitive effect of a long term exercise program on individuals diagnosed with AD
  • 3 groups
    • home-dwelling individuals (70)
    • Group-based exercise at an adult daycare center (70)
    • Control group (70)
    • 12 month program
  • Cognition was evaluated via:
    • Clock-drawing test (Part of Mini-Cog)
    • Verbal fluency
    • Mini-mental state examination
    • Clinical dementia rating scale
    • Physical fitness
    • 10 meter walking test

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  • All groups deteriorated in verbal fluency
  • Decreased scores on MMSE
  • external image aaS2EmSoFBC7l7EYPIPQeQWlMmVFtyqFiaCakarkggj2hu40zJW3uR3bbYGG69qfn1wmivtE1BADqY_ZJfWkDlECqfkYy0tx6GqpZZD4fI7nz14NmmGX1Wimz-fWlAq_EMIHre-KeAcNo significant findings with:
  • Number of sessions attended and change in clock drawing test
    • Attending less than half or more than half of the sessions
  • Home exercise group
    • Mild increase in executive function
    • Had to exercise for 12 months until results were seen
  • Conclusion:
    • Long term exercise program may have some mild cognitive effects, nevertheless, the exercise program enhanced individual's physical functioning and independence

Systematic Review on Exercise Treatment [13]
  • Included 4 studies and 119 subjects
  • Standardized Mean Change score using Raw score standardization (SMCR) of cognitive performance were calculated
    • This allowed the authors to compare studies that used different cognitive/functional tests as the outcome measure
  • Exercise had a moderate to strong effect in AD (SCMR: 0.83, 95% CI: 0.59–1.07)
  • Test for Heterogeneity: Q (df= 3) = 7.82, p= 0.05
  • Test for Overall Effect: Z= 6.88, p<0.01

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Discussion
  • Exercise treatment resulted in moderate to strong effects on cognition in AD [13]
  • Exercise treatment showed the ability for less deterioration in neuropsychiatric disorders and performance of instrumental activities, better physical functioning, and improved balance and mobility and a reduced risk of falls

Home Modifications [17]
“A vast array of strategies that include structural renovation, assistive devices, placement of visual cues and memory aids, and rearrangement or removal of furniture and dangerous household items as well as the simplification of tasks”
Carla 3.jpg <----- Mental Aid
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<---- Visual Cue


Importance of Caregiver Training/Role [17]
  • Caregiver takes more responsibility as the care recipient’s cognitive status declined
  • Insufficient knowledge/lack of resources resulted in decrease caregiver efficacy
  • After caregiver training and education, caregivers reported 73% of home modifications still in place
  • Caregiver Responsibilities: Education of potential hazards, implementation of modifications, aid in social environment of patient

Importance of Caregiver Training/Role [17]

Example: Open Floor Plan
Carla 5.jpg

Client Centered Collaborative Approach to Assessment and Intervention [17]
  • Establish rapport with patient
  • Identify the individual needs of patient with AD along with caregiver
  • Quite often patient with AD will resist home modifications
  • Promote participation and safety

Importance of Environmental Modifications [17]
  • Physical
  • Cognitive
  • Social
Goal: Aiming to improve safety and Function

Importance of Environmental Modifications [17]
Physical
  • Examples: Wandering off, falls, inattention, poor judgement, medication management, adaptations for temperature, cooking, sharp objects, appliance use
    • 71% of caregivers identified unsafe behaviors
    • Only 24% took precautions

Importance of Environmental Modifications [17]
Cognitive
  • Creative routines and engagement of person with AD
  • Setup of task supplies (e.g. simple cooking activities)
  • Simplify tasks
  • Example: Caregiver engaged her mother (AD) in a gardening activity that was incorporated into their routine

Importance of Environmental Modifications [17]
Social
  • Additional support networks
  • Verbal Cueing
  • Use of Communication strategies




Carla 2.jpg


Assistive Devices [18]
    • At any point during life, assistance may be necessary to facilitate safe ambulation. When an individual begins to cognitively fail and consequently lose motor control, surely the use of an assistive device will be implemented
    • The decision to begin using an assistive device may be difficult for someone suffering from a degenerative disease such as Alzheimer’s. As physical therapists, we need to be able to gain patients’ trust and educate them on the benefits of an assistive device as well as explain the changes they are experiencing in a way they will understand

Some things to take into consideration…

    • Prior level of functioning
      • Due to the progression of AD, the goal of any treatment almost always will not be to regain prior functioning levels. An assistive device should be used to facilitate safe ambulation and to hopefully increase the confidence of the patient and to reduce the decline of the patient as much as possible

    • Current level of functioning
      • From a study done by Muir-Hunter and Montero-Odasso, the use of an assistive device with an individual suffering from AD needs to be considered only if it truly benefits them. Their study found that at a certain point during the progression of AD, the use of an assistive device causes more cognitive stress and in turn dysfunction than actual benefit in ambulation. As physical therapists, we need to be aware of these changes and use our expertise to prescribe the proper device for these patients

    • Goals
      • It is always important to discuss the individual goals of each patient. People suffering from any form of dementia may not be cognitively aware enough to interpret their goals, so a discussion with the caregiver may be necessary
      • The main goal of any assistive device is to facilitate safe ambulation and to increase the functioning of the patient. At a certain point in the progression of AD, the use of a wheelchair will most likely be necessary

Education [19]
    • Discuss the symptoms listed above and educate the caregiver about the type of AD the patient has
    • Discuss the various home modification with the patient and caregiver that will be important and the 3 stages of progression
    • Discuss the importance of exercise, if not for the cognitive functioning, at least for the physical and functional aspects that they can improve upon
    • Discuss the assistive device usage and attempt to answer any question they have about medications that were not discussed with the diagnosing physician

Summary
    • Alzheimer's is difficult to diagnose and done through a combination of medical history and a battery of different cognitive examinations.
    • Exercise ≥ 12 months for at least 1 hour twice a week, may have a mild to significant effect on preventing both cognitive and functional decline.
      • Include: Aerobic, Strength, Flexibility and Balance exercises
    • The use of an assistive device, although typically helpful, needs to be considered in combination with the cognitive functional level of the patient
    • Exercise needs to be further studied with larger sample sizes, and it also need to analyze effectiveness of different exercise types, exercise intensities, and motivational interventions to increase adherence, as well as patient characteristics


References
[1] "What Is Alzheimer's." Alzheimer's Disease & Dementia:. Alzheimer's Association, n.d. Web. 12 Apr. 2016.”
[2] Latest Alzheimer's Facts and Figures. (2013). Retrieved March 30, 2016, from http://www.alz.org/facts/
[3] "Tests for Alzheimer's & Dementia | Alzheimer's Association." Tests for Alzheimer's & Dementia | Alzheimer's Association. Alzheimer's Association, n.d. Web. 12 Apr. 2016.
[4] Valenti, Denise A. "Alzheimer's Disease and Glaucoma: Imaging the Biomarkers of Neurodegenerative Disease." International Journal of Alzheimer's Disease 2010 (2010): 1-9. Web. 4 Apr. 2016.
[5] Pascual, Millán LF, Quiñones JV Martínez, Pardo P Modrego, Miguel E Mostacero, J. López Del Val, and Asín F Morales. "The Set-test for Diagnosis of Dementia." Neurologia. 5.3 (1990): 82-85. Pubmed. Web
[6] T. M. (2001, January). Clinical Dementia Rating Scale. Retrieved April 06, 2016, from http://alzheimer.wustl.edu
[7] "Healthy Brain Versus Alzheimer's Brain | Alzheimer's Association." Healthy Brain Versus Alzheimer's Brain | Alzheimer's Association. Alzheimer's Association, n.d. Web. 12 Apr. 2016.
[8] Dubois, B., Hampel, H., Feldman, H., et al. (2016). Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria. Alzheimer's and Dementia, 12(3), 292-323. Retrieved April 4, 2016.
[9] "Alzheimer's & Dementia Risk Factors." Alzheimer's & Dementia. Alzheimer's Association, n.d. Web. 12 Apr. 2016.
[10] Gauthier, Serge. Clinical Diagnosis and Management of Alzheimer's Disease. London: Martin Dunitz, 1999.
[11] Stages of Alzheimer's & Symptoms | Alzheimer's Association." Stages of Alzheimer's & Symptoms. Alzheimer's Association, n.d. Web. 12 Apr. 2016.[
[12] Green C, Zhang S. Predicting the progression of Alzheimer's disease dementia: A multidomain health policy model. Alzheimer's & Dementia 2016.
[13] Ströhle, Andreas, Dietlinde K. Schmidt, Florian Schultz, Nina Fricke, Theresa Staden, Rainer Hellweg, Josef Priller, Michael A. Rapp, and Nina Rieckmann. "Drug and Exercise Treatment of Alzheimer Disease and Mild Cognitive Impairment: A Systematic Review and Meta-Analysis Of Effects on Cognition in Randomized Controlled Trials." The American Journal of Geriatric Psychiatry 23.12 (2015): 1234-249. Web
[14] Liu-Seifert, H., Siemers, E., Sundell, K., Price, K., Han, B., Selzler, K., . . . Mohs, R. (2015). Cognitive and Functional Decline and Their Relationship in Patients with Mild Alzheimer's Dementia. Journal of Alzheimer's Disease, (43), 949-955. Retrieved April 1, 2016.
[15] Rolland, Y., Pillard, F., Klapouszczak, A., Reynish, E., Thomas, D., Andrieu, S., . . . Vellas, B. (2007). Exercise Program for Nursing Home Residents with Alzheimer's Disease: A 1-Year Randomized, Controlled Trial. Journal of the American Geriatrics Society, 55(2), 158-165. doi:10.1111/j.1532-5415.2007.01035.x
[16] Ohman, H., MD, Savikko, N., PhD, Stranberg, T., PhD, Kautiainen, H., PhD, Rivio, M. M., PhD, Laakkonen, M., PhD, . . . Pitkala, K. H., PhD. (2013). Effects of Exercise on Cognition: The Finnish Alzheimer Disease Exercise Trial: A Randomized, Controlled Trial. Journal of the American Geriatrics Society, 173(10), 1-8. doi:10.1111/(issn)1532-5415
[17] Struckmeyer, L. R., & Pickens, N. D. (2016). Home modifications for people with Alzheimer’s disease: A scoping review. American Journal of Occupational Therapy, 70
[18] Muir-Hunter SW, Montero-Odasso M. Gait cost of using a mobility aid in older adults with Alzeheimer’s Disease. Journal of American Geriatric Society 2016;64(2):437-438.
[19] Hernandez, L., Ozen, A., Dossantos, R., & Getsios, D. (2016). Systematic Review of Model-Based Economic Evaluations of Treatments for Alzheimer’s Disease. PharmacoEconomics. doi:10.1007/s40273-016-0392-1