Alzheimer’s disease (AD) is a gradually progressive, neurodegenerative dementia affecting cognition, behavior, and functional status. It is the leading cause of dementia in late adult life and accounts for seventy five percent of the cases of dementia in the United States.
Alzheimer’s disease is the sixth leading cause of death in the United States and the only cause of death in the top ten that cannot be prevented, cured, or slowed.
In 2015, Alzheimer’s and other dementias cost the United States $225 billion in total medical costs; these costs are estimated to continue to increase each year.
Today more than 5 million Americans are living with Alzheimer’s disease and require more than 15 million caregivers.1 A report from the Alzheimer’s Association, projects that Medicare spending on Alzheimer’s disease will more than quadruple to $589 billion annually by 2050. This analysis showed that a treatment delaying the onset of Alzheimer’s by just 5 years would save Medicare $345 billion in the first 10 years alone. A historic $350 million increase in research funding in the FY2016 budget was announced into law in December 2015.
An estimated 5.3 million Americans had Alzheimer’s disease in 2015.1 Of these, two-thirds are women, and 5.1 million are above 65 years old. Additionally, the disease takes a devastating toll on its caregivers.
Approximately two-thirds of the caregivers are women and 34% are age 65 or older.
The incidence of Alzheimer’s dementia dramatically increases after the age of 65 (53 new cases per 1,000 people aged 65 to 74; 170 per 1,000 people aged 75 to 84; and 231 per 1,000 people older than 85).2
Although the exact etiology of AD is unknown, several genetic and environmental factors have been explored as potential causes. The disorder is characterized by intracellular neurofibrillary tangles and extracellular amyloidal protein deposits contributing to plaque formation3 (Figs. 13–1 and 13–2).
Figure 13–1
Pathophysiology of Alzheimer’s disease: Some processes involved in Alzheimer’s disease. From the left: mitochondrial dysfunction, possibly involving glucose utilization; synthesis of protein tau and aggregation in filamentous tangles; synthesis of amyloid beta (Aβ) and secretion into the extracellular space, where it may interfere with synaptic signaling and accumulates in plaques. (From Roberson ED, Mucke L: 100 years and counting: prospects for defeating Alzheimer’s disease. Science 2006;314:781. Reprinted with permission from AAAS.)
Figure 13–2
Small section of the neocortex from a patient with Alzheimer’s disease showing two classical neuropathological lesions of the disease. (A) The modified silver staining shows one dense senile (amyloid) plaque indicated by three arrowheads. The plaque consists of aggregated extracellular deposits of Aβ fragments surrounded by silver-positive dystrophic neuritis. The arrow indicates a neuron containing neurofibrillary tangles, which appear as dark masses of abnormal filaments occupying most of the cytoplasm. (B) The image shows higher magnification of two neurons containing neurofibrillary tangles (indicated by arrows). (Used with permission from Shahriar Salamat, MD, PhD, University of Wisconsin School of Medicine and Public Health, Department of Pathology and Laboratory Medicine.)
In addition to the amyloid plaque deposition, cholinergic pathway disturbances and increased and unregulated inflammatory free radical accumulation promote neuronal apoptosis at specific regions that are associated with new learning and memory, such as the hippocampus and amygdala.3
In mild and moderate AD, diminution of choline acetyl transferase activity is also observed.4 Choline acetyl transferase is responsible for the synthesis of the neurotransmitter acetylcholine. This results in losses of acetylcholine, specifically in areas of the brain associated with memory and learning. The cholinergic dysfunction is not considered the cause of the illness but rather a consequence. This mechanism of decreased cholinergic activity is the target of the currently approved treatments for AD. Enhancement of cognitive function occurs when the activity of acetylcholine is increased by the inhibition of this metabolizing enzyme.
In addition to the dysfunction of the cholinergic system, increased loss of glutamatergic neurons has been found in AD. It is accompanied by disturbances in N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor expression in the cerebral cortex and hippocampus. Increased depolarization of the postsynaptic membrane resulting from increased glutamate concentration and reduction in physiological NMDA receptor–mediated signals is noted in AD.5
Several genes have been identified that increase the risk, while others are protective.
Molecular imaging technologies have been the most active area of research aimed at early diagnosis of the disease. Pittsburgh compound B (PIB) was the first radiotracer capable of highlighting deposits of beta amyloid in living individuals during a positron emission tomography (PET) scan. Florbetaben is another radiotracer designed to detect the amyloid deposits in PET scans.
In Alzheimer’s disease, what is commonly lost first is short-term memory, followed by problems with long-term memory, language (e.g., paraphasias due to inability to recall appropriate vocabulary), and executive functioning. This is in contrast to normal aging, where short-term memory and speed of recall may be impaired, but these issues do not affect activities of daily living and awareness of such problems.6 Language deficits and visual spatial deficits are also noted.
Mild cognitive impairment (MCI) refers to the predementia stage of AD. It is a degree of impairment that does not relate to the age and educational background, followed by further decline in one or more domains of cognition over time. Several neuropsychological tests are available to examine these domains. Other causes of cognitive decline include trauma; medications; degenerative, vascular, and depressive conditions.7
Currently, Alzheimer’s disease is diagnosed clinically by cognitive decline when the disease progression is irreversible and has resulted in severe neural damage. As a result, several biological markers are being studied with a goal of an early diagnosis. These include certain proteins in blood and cerebrospinal fluid (CSF) which include total tau, phospho-tau, and the 42 amino acid form of β-amyloid.8 Other promising areas of research are genetic profiling and neuroimaging. A tracer known as florbetapir F-18 is a molecule that binds to beta-amyloid in the brain. It is labeled with a radioactive tracer that allows it to be visualized during a PET brain scan, thereby revealing the presence of amyloid plaques in the brains of living patients. Amyloid plaques are thought to be nonspecific to the disease and cannot be used to make a diagnosis.9
However, atrophy of the specific regions in the brain such as the hippocampus may be an early sign of Alzheimer’s. Functional imaging with fluorodeoxyglucose-PET indicates that the disease is associated with reduced utilization of sugar in those areas of the brain involved with memory, new learning, and problem solving. However, translation of these patterns of reduced activity into diagnostic information has not been validated (Fig. 13–3).
Figure 13–3
MRI findings in Alzheimer’s disease: Axial T1-weighted magnetic resonance images of a healthy 71-year-old (A) and a 64-year-old with AD (C). Note the reduction in medial temporal lobe volume in the patient with AD. Fluorodeoxyglucose positron emission tomography scans of the same individuals (B and D) demonstrate reduced glucose metabolism in the posterior temporoparietal regions bilaterally in AD, a typical finding in this condition. HC, healthy control. (Photo contributor: Gil Rabinovici, University of California, San Francisco and William Jagust, University of California, Berkeley.)
Management of AD patients is focused on providing care with a goal to maintain the highest level of function and therefore quality of life as long as possible. A multidisciplinary team consisting of family physicians, physical medicine and rehabilitation specialists, psychiatrists, geriatricians, physical therapists, occupational therapists, speech language pathologists, social workers, nurses, pharmacists, and a dietitian makes the treatment most effective. Caregiver training is of paramount importance in this interdisciplinary approach.
Cholinesterase inhibitors have been approved in Alzheimer dementia, which can help delay or prevent symptoms from becoming worse for a limited time. These include Razadyne® (galantamine), Exelon® (rivastigmine), and Aricept® (donepezil). Namenda® (memantine) is an NMDA antagonist approved in moderate-to-severe Alzheimer’s disease. As NMDA antagonists work very differently from cholinesterase inhibitors, the two types of drugs can be prescribed in combination. The U.S. Food and Drug Administration (FDA) has approved five medications (Table 13–1) to treat the symptoms of Alzheimer’s disease.
| Drug Name | Brand Name | Approved For | FDA Approved |
| 1. Donepezil | Aricept® | All stages | 1996 |
| 2. Galantamine | Razadyne® | Mild to moderate | 2001 |
| 3. Memantine | Namenda® | Moderate to severe | 2003 |
| 4. Rivastigmine | Exelon® | All stages | 2000 |
| 5. Donepezil and memantine | Namzaric® | Moderate to severe | 2014 |
Effect of exercise has been studied extensively. While favorable effects of exercise on memory have been reported in patients not diagnosed with AD in some studies,9 long-term clinical trials are needed to show the alteration in the hallmarks of AD.
In a study conducted by Voss Heo et al,10 70 sedentary, cognitively normal older individuals ages 55 to 80 were assigned to either an aerobic walking program or a flexibility, toning, and balance program. Both groups were followed for 1 year. Intervention consisted of 40-minute exercise sessions led by a trainer three times a week. In the aerobic walking group, greater increases in aerobic fitness were associated with greater increases in white matter integrity and improved short-term memory. These benefits were not seen in the other training program. These findings add to growing evidence indicating that aerobic exercise may benefit cognition as people age.
In another study, increased cardiorespiratory fitness was found to be associated with reduced whole-brain atrophy and increased white matter volume in adults with AD.11 Baker and colleagues completed a 6-month study with 28 participants comparing aerobic exercise (participants used treadmills, stationary bicycles, or elliptical trainers to reach 75% to 85% of their heart rate reserve) to stretching (participants carried out stretching and balancing exercises while maintaining their heart rates at or below 50% of their reserve). This study found benefits in executive function (p = 0.04) but not in memory in the aerobic exercise group.12
Cognitive training focuses on improving skills in specific realms of memory, processing, and executive functioning. Anguera et al utilized a game called “Neurotracer” for a sample population of 46 cognitively intact participants, ages 60 to 85 years. The group was randomized to three groups: one that practiced with the game in multitasking mode for a total of 12 hours, one that practiced with it in single-task mode (first driving and then responding to screen signals but not both simultaneously), and one that did neither.
The group that had practiced in multitasking mode showed significantly better performance on the driving task while being challenged with the signal response task than did the other two groups. This performance boost lasted for up to 6 months.
Electroencephalography of participants who had trained in multitasking showed increased levels of brain waves (indicative of improved cognition), compared with their peers, and performed better on tests of attention and memory.13
Studies have shown that intellectual stimulation, social engagement, and memory training are positively stimulated to adjuvant treatment.14
Other approaches include regular physical exercise and diets low in fat and rich in fruits and vegetables, omega-3 fatty acids (FA), vitamin E, and ginkgo. However, studies are lacking that show a clear benefit. While Witt et al showed beneficial effects of omega-3 FA intake on both brain structure and function, studies by Dangour et al and Van de Rest et al did not observe any significant effect.15–17
Rehabilitation plays an important role in the nonpharmacological management of AD. It focuses more on patients’ abilities rather than their disabilities. Functional impairment is a core symptom of a patient with AD. As the disease progresses, one of the most accurate indicators of functional impairment is the decline in performance of the activities of daily living (ADLs) and instrumental activities of daily living (IADLs).18 A regular exercise program is recommended for patients with Alzheimer’s disease to improve and support physical health as well as behavioral and psychological symptoms, including depression.
Depending on the specific needs of the patients with AD, rehabilitation services may include physical therapy, occupational therapy, and/or speech language pathology remediation.
One of the tools used by the occupational therapists to determine the abilities and needs of an AD patient is the Allen Cognitive Levels (ACL). The ACL is obtained by systematic observation of ADL’s and IADLs and is scored on a scale of 1 to 6, with 1 denoting severe cognitive impairment and 6 referring to normal functional status.
Cognitive remediation therapy is a behavioral treatment that uses drill and practice, compensatory, and adaptive strategies to facilitate improvement in targeted cognitive areas like attention, memory, planning, organization, abstract thinking, and problem solving. Cognitive behavior therapy teaches patients to think through emotionally challenging problems.
A study published by Teri and associates demonstrated that a regular exercise program combined with caregiver education and training on supervising exercise improved the physical and emotional health of individuals with moderate-to-severe Alzheimer’s disease.19
Subsequent research published in the American Journal of Alzheimer’s Disease showed that a 6-month specific walking program resulted in a slower decline in cognitive function and stabilization of the progressive cognitive dysfunction in nursing home-assisted residents with Alzheimer’s disease.20
The American Alzheimer’s Association, reported that there is sufficient evidence to link several modifiable risk factors with a reduced risk for cognitive decline, and sufficient evidence to suggest that some modifiable risk factors may be associated with a reduced risk of dementia. Specifically, the association believes there is sufficiently strong evidence, from a population-based perspective, to conclude that regular physical activity and management of cardiovascular risk factors (diabetes, obesity, smoking, and hypertension) reduce the risk of cognitive decline and may reduce the risk of dementia. The association also believes there is sufficiently strong evidence to conclude that a healthy diet and lifelong learning/cognitive training may also reduce the risk of cognitive decline.21
Further research needs to be conducted to determine the adequacy of the biomarkers in the prevention, diagnosis, and severity of AD.
Additional research with larger sample sizes and a longer follow-up will be required to determine the long term effects of exercise and other comorbidities on the development of AD and its progression.
Parkinson’s disease (PD) was first described in detail by James Parkinson in 1817. The symptoms of the disease usually begin between the ages of 45 and 70.
Idiopathic parkinsonism is a proteinopathy and is due to the misfolding and aggregation of the protein alpha-synuclein.22 The clinical manifestations of PD appear to be due to the altered patterns of inhibition and excitation within the basal ganglia. The normal balance between the two antagonistic neurotransmitters in this region, dopamine and acetylcholine, is disturbed due to dopamine depletion in the dopaminergic nigrostriatal system23 (Fig. 13–4).
Figure 13–4
Neurons Involved in Parkinson’s disease: Schematic representation of the sequence of neurons involved in parkinsonism. Top: Dopaminergic neurons (dark blue) originating in the substantia nigra normally inhibit the GABAergic output from the striatum, whereas cholinergic neurons (grey blue) exert an excitatory effect. Bottom: In parkinsonism, there is a selective loss of dopaminergic neurons (dashed, blue). (Reproduced with permission from Aminoff MJ. Pharmacologic Management of Parkinsonism & Other Movement Disorders. In: Katzung BG, eds. Basic & Clinical Pharmacology, 14e New York, NY: McGraw-Hill; 2018.)
Currently, there is no laboratory or diagnostic test that can confirm Parkinson’s disease. When patients fail to respond to dopaminergic therapy, however, it is critical to rule out secondary causes of parkinsonism (Table 13–2).
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More recently, genetic testing that seeks to identify the presence of the PARK gene mutation has been employed; however, this is generally indicated in patients less than 40 years old with a strong family history.
The use of DaTSCAN (123I-ioflupane) single-photon emission computed tomography [SPECT] imaging to detect presynaptic dopamine transporters has been approved by the FDA. These scans are helpful in distinguishing PD patients from those with essential tremor. PD patients typically will have decreased signal in the basal ganglia (putamen) (Fig. 13–5).
Figure 13–5
Positron emission tomography findings in a Parkinson’s Patient [11C]Dihydrotetrabenazine positron emission tomography (a marker of VMAT2) in healthy control (A) and Parkinson’s disease (B) patient. Note the reduced striatal uptake of tracer, which is most pronounced in the posterior putamen and tends to be asymmetric. (Photo contributor: Dr. Jon Stoessl.)
The features of PD include motor and nonmotor abnormalities.22,23 The motor abnormalities include abnormal flexed posture and resting tremor, gait disturbance, bradykinesia, and rigidity (Fig. 13–6). The nonmotor abnormalities associated with the disease (or the adverse side effects of antiparkinsonian medications) include cognitive impairment; neuropsychiatric conditions; and sleep, autonomic, and sensory disturbances.
Early in the disease, pharmacologic treatment may not be needed for the motor impairment. Initial discussions with the patient regarding different types of treatment options and the nature and prognosis of the disorder is critical. Specifically, discussions regarding future potential medications and their side effects in addition to an appropriate rehabilitation program (beneficial effects of activity modification and exercise) are key.
Although PD remains an incurable disease, the mainstay of pharmacologic treatment is symptom management and mitigation of disease progression. From a rehabilitative standpoint, maintenance and improvement of function are critical.
The mainstay of therapy is levodopa, which is the best studied of these agents. Levodopa is converted by DOPA-decarboxylase into dopamine and can significantly decrease bradykinesia, rigidity, and tremor.
Levodopa is typically administered with carbidopa, a peripheral decarboxylase inhibitor, which can decrease gastrointestinal symptoms.
Unfortunately, levodopa is not as responsive in the late stages of PD in which impairments of speech, gait, and cognition are prevalent. Nevertheless, the agent has significantly improved life expectancy. Common side effects of levodopa include nausea, vomiting, lightheadedness, dizziness, and somnolence.
Dopaminergic agonists stimulate dopamine receptors in the striatum. Examples of these medications include pramipexole, ropinirole, and transdermal rotigotine. Often, patients will require the addition of carbidopa after several years of monotherapy with levodopa. Unfortunately, these agents are poorly tolerated in older adults who develop magnified symptoms (hallucinations, nausea, vomiting, cognitive impairment).
Other, less frequent medications utilized in PD include COMT inhibitors (e.g., entacapone, tolcapone) and MAO-B inhibitors (selegiline and rasagiline). These medications inhibit the breakdown of levodopa and are often used to decrease motor symptoms. Amantadine is used for dyskinesia, but again is limited by profound cognitive side effects in older individuals.
Surgical options are left for those patients who cannot be managed adequately with medications and therapies. Deep brain stimulation (DBS) of the subthalamic nucleus consists of implantation of electrical leads into each brain hemisphere, which are connected to a pulse generator typically placed in the chest wall. DBS can substantially decrease dyskinesia, tremor, rigidity, and bradykinesia but may worsen cognition and speech. DBS has a risk of infection and hardware malfunction and need to be closely monitored and adjusted by clinicians.
For severe or refractory cases in which deep brain stimulation is contraindicated, patients may be referred for consideration of pallidotomy or thalamotomy and may decrease dyskinesia.
A comprehensive rehabilitation program has been shown to be beneficial for patients with PD.25 Additionally, there is accumulating evidence that vigorous exercise may have a neuroprotective effect in patients with PD.26 Two studies have suggested that moderate-to-vigorous physical activity during midlife may significantly reduce the risk of later developing Parkinson’s disease.27,28 Additionally, such exercise may mitigate progression of the devastating effects of the disease.
The goal of exercise in patients with PD is to improve both physical and cognitive function. A recent observational study of 4,866 patients with PD has supported the importance of regular physical exercise.29 This study demonstrated that those patients who participated in regular physical exercise had higher quality of life, better physical function, and lower caregiver burden.
Several recent aerobic exercise studies, utilizing treadmill or stationary bicycle exercise, have shown improvements in various measured parameters, including cardiorespiratory fitness, strength, balance, walking speed, cognition, and PD disease symptoms and signs.30,31 The addition of transcranial magnetic stimulation has been shown to enhance corticomotor excitability and gait performance. Additionally, forced exercise (bicycling at a tempo higher than the subject would self-select) resulted in greater improvements in motor function, rigidity, tremor, and bradykinesia.
Several strength-training exercises have been shown to improve a number of parameters in PD patients, including overall strength, balance, and gait.32,33 Recent studies have demonstrated that a variety of balance and gait training techniques (traditional gait training, computerized dance training, robot-assisted training, partial weight-supported treadmill gait training, aquatic balance training) significantly improve locomotor function.34,35 Additionally, 6 weeks of balance training has favorably affected structural brain plasticity as measured by functional magnetic resonance imaging.
Several recent studies have shown the beneficial effects of combined exercise programs (stretching, strengthening, balance training, individualized coaching, etc.).36,37
Additional studies have demonstrated the beneficial effect of various types of dance therapy (tango, Irish set dance, American ballroom, and virtual reality dancing) in patients with PD.24,38,39
Movement strategy training teaches patients with Parkinson’s disease to use the frontal cortex to move more quickly, easily, and safely by using cognitive control. This type of therapy has been shown to be effective in short-term functional improvement.40,41 Patients are taught how to improve their mobility by using focused attention (part-practice, mental rehearsal visualization cues, or auditory cues.42–45
Although Parkinson disease has been primarily identified as a movement disorder, it also results in significant nonmotor deficits which significantly reduce the quality of life and increase the burden to family and care providers. The role of occupational therapy–related interventions for people with PD therefore has been identified to be of great importance. Occupational therapists help patients (and their families) with PD function better in their home and community. An occupational therapist may intervene in three separate categories to aid patients with PD: (1) physical activities/exercise; (2) environmental cues, stimuli, and objects; and (3) self-management and cognitive-behavioral therapy. Occupational therapists also help restore performance and participation in daily activities and address physical and psychological adaptation to disability strategies.
Several studies have shown that individualized cognitive therapy focused on promoting patient wellness initiatives and personal control can help the patient modify their lifestyle and improve their quality of life. These studies often used cognitive-behavioral intervention, which involved education, goal setting, performance skill training, repetitions (practice), and feedback related to incorporating these skills into daily habits.46,47 Positive outcomes have been found to be more likely to occur with prolonged therapy sessions which consist of 20 or more sessions over a 6- to 8-week period of time. Positive benefits have been shown up to 6 months after intervention (the longest follow-up period reported). Further study is needed, however, to determine the length of time that these positive benefits can persist.
A recent innovative study has shown that PD patients who underwent occupational therapy had improvements in their activities of daily living and social participation.48,49 This study was unique as the investigators enrolled and randomized couples rather than patients (because occupational therapy also focuses on the care provider).
Additionally, the results of this trial demonstrated that occupational therapy interventions improved the patient’s abilities to perform activities of daily living, as perceived by the patient. Also, caregivers allocated to the occupational therapy group reported lower health care costs and a reduction in institutional care.
The majority of PD patients have difficulties with speech (70% to 89%) and/or swallowing (up to 95%).50,51
Speech frequently becomes softer and more monotonous with progression of the disease. In addition to impairment of limb musculature as the disease progresses, Parkinson’s disease affects the respiratory motor system. It has been shown that both inspiratory and expiratory muscle impairments are found in patients with PD. Respiratory impairments are attributed to a decrease in strength and poor coordination of the respiratory muscles, which will contribute to reduced expiratory flow and resultant hypophonia.52,53
Speech exercises to emphasize loudness and vocal quality have been demonstrated to be beneficial. Over the past two decades the Lee Silverman Voice Treatment (LSVT- LOUD) has been established as the most effective treatment for voice loudness in Parkinson’s disease.54,55
Speech and language pathologists can help PD patients with dysphagia to improve their ability to swallow. The disease may affect any or all stages of swallowing, including the oral, pharyngeal, and esophageal stages. To ascertain the specific causes for dysphagia in the PD patient, a detailed evaluation by a speech and language pathologist is indicated, which often will include a video swallow study. The treatment program can then be designed for that individual. The traditional therapies can include environmental modifications, postural changes, compensatory maneuvers, and dietary modifications.56 One example of an environmental modification is eating smaller portions more frequently. An example of a postural change is the chin tuck technique, whereby the patient tucks the chin into the chest, which facilitates laryngeal elevation and protection of the airway. An example of a compensatory technique is the double swallow if there is residue in the oropharyngeal tract after a single swallow.
Dietary modifications include altering the consistency of solids and liquids. Solids can be made softer with a more uniform consistency to prevent aspiration. Liquids can be made thicker using commercially available thickeners so that the liquid can be adjusted from thin liquid to nectar, honey, or pudding thickness as appropriate for the patient.
One recent study has shown that video-assisted swallowing therapy (VAST) was better than conventional therapy.57 Subjects received therapy once weekly for 30 minutes for 6 weeks. The video-assisted therapy helped educate the patients about the swallowing mechanisms. At the completion of 6 weeks of therapy the VAST group had significantly improved swallowing as compared to conventional therapy (less food residue in the pharynx).
Patients with PD may experience a progressive decrease in cognitive function in the domains of language, visuospatial function, long-term memory, and executive function.58
Two recent studies have shown that physical exercise may improve cognition in various cognitive domains in patients with PD. One study showed that both LSVT-Big training and Nordic walk training had similar and significant improvements in cued reaction time. It was concluded that both of these exercise programs resulted in improvement in cognitive aspects of movement preparation. Another study showed that a 2-year progressive resistive exercise program resulted in improved attention and working memory as compared to baseline function.59,60 The exercise program was a program recommended by the National Parkinson Foundation and focused on stretches, balance, breathing, and nonprogressive strengthening exercises.61
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