In this article, we will discuss the diagnostic criteria, the types of dementia, Alzheimer’s differential diagnostic criteria, dementia screening tools, and pharmacologic and non-pharmacologic therapies used in the treatment of dementia.
Introduction to Dementia
Dementia is a progressive dysfunction of the cortex, resulting in a cognitive decline over a long period of time. It can impact a mild to significant impact on daily functioning, which can lead to complete dependency.
Dementia is not the same as delirium though some symptoms may overlap. Dementia is a cognitive decline occuring over a long period of time. Delirium is a acute decline in cognition and an acute change in the level of consciousness that can occur over hours to days.
Several pharmacologic agents can increase the risk of dementia and worsen dementia symptoms. Some of these are anticholinergic agents, such as first-generation antihistamines, tricyclic antidepressants, first-generation antipsychotics, anti-emetic, antispasmodics, and skeletal muscle relaxants.
Epidemiology and Types of Dementia
Dementia is prevalent in about 10% of individuals age greater than 60 years, and among individuals older than 85 years, the prevalence increases to 30-50%.
Dementia is an umbrella term used to describe a range of cognitive impairment symptoms. There are many types of dementia. The most common are:
- Alzheimer’s disease
- Vascular dementia (multi-infarct demnetia)
- Dementia with Lewy bodies (Parkinsonian)
- Frontotemporal dementia
It is possible to have multiple types of dementia at the same time.
Diagnosing Dementia
Dementia can be hard to detect in routine medical practice because it is often seen as a “normal” aging decline.
It is important to know that a normal cognitive decline involves mild changes that are not progressive and do not affect daily functioning. In mild cognitive impairment, there is an increased impaired memory function, but the individuals can largely preserve activities of daily living. Individuals with mild cognitive impairment are at risk for the development of dementia.
There are also other diseases and factors that can precipitate dementia-like conditions, such as thyroid disorders, vitamin B12 deficiency, neurosyphilis, advanced HIV infection, Creutzfeldt-Jakob disease, and Huntington’s disease.
Dementia screening scales include Mini-Cog, Short Informant Questionnaire on Cognitive Decline in the Elderly, AD8 Dementia Screening Interview, and Quick Dementia Rating System.
The Mini-Mental Status Exam (MMSE) can be used as well. This is a 5-7-minute test that correlated to activities of daily living with a total point of 30. A score of less than 24 is suggestive of cognitive impairment.
The global deteriorating scale ranks individuals into different levels by the degree of cognitive decline with level 1 having no decline and level 7 having a very severe decline (completely dependent).
A clinical improvement is considered to have at least a 10% improvement in the score.
There has been a lot of interest in dementia-specific biomarkers. One caveat is that even though we may be able to detect early, a lot of times we cannot do anything about it. This is the same with genetic testing.
Alzheimer’s Disease (AD)
Alzheimer’s Disease is the most common type of dementia, seen more commonly in females than males. Though AD doesn’t cause death, it is the 6th leading cause of death in the United States due to the increased risk of aspiration, infected bed sore, and fall.
The average survival is 3-4 years. This is dependent on the quality of care. In some cases, patients can survive for much longer than 3-4 years.
Risk factors for AD include:
- Being older than 65 years
- Genetic predisposition (APOE E4)
- Being female (especially after age 80)
- AD is more prevalent in parents of individuals with ADHD
- Hear loss
- Unhealthy lifestyle
- Having cardiovascular risk factors
- Heavy metal toxicity
- African American and Hispanic are more likely to have
Remember that there are two main hypotheses regarding AD: The beta-amyloid plaques and the tau protein tangles.
AD is a progressive disease, which can occur over 15-25 years, ranging from normal cognition (asymptomatic/preclinical AD) to mild cognitive impairment (mild symptoms) to dementia (symptoms that impact daily functioning). The individual is considered to have dementia when that individual cannot function the way they used to.
Vascular Dementia (VaD)
The etiology is thought to stem from cerebrovascular disorders, leading to ischemic or hemorrhagic brain damage. When enough neurons are affected (neuron destruction), dementia happens.
Wherever the damage occurs in the brain, hemiparesis, hemisensory loss, or visual field defects are observed. These are not symptoms seen in AD.
Unlike AD, VaD can progress stepwise in the fluctuating manner of ups and downs where AD individuals can only progressively get worse and worse.
Lewy Body Dementia (LBD)
Lewy bodies are cytoplasmic inclusions found in the substantial nigra cells in patients with Parkinson’s.
It is differentiated from other types of dementia by a fluctuation in symptoms (same as VaD), visual hallucination and delusions (same as AD), and Parkinsonism (not seen in VaD or AD) that leads to resting tremors.
The DSM-5 now refers to dementia as Major Neurocgnitive Disorder.
Criteria of All-Cause Dementia
There are 5 elements:
- Interfere with normal functioning
- Have a decline from the previous level of functioning
- Not delirium or other psychiatric disorder
- Cognitive impairment is shown in both patient history and cognitive assessment
- Having at least 2 of the cognitive impairment behaviors:
- Impaired ability to acquire and remember new information
- Impaired reasoning of complex tasks
- Impaired visuospatial abilities
- Impaired language
- Changes in personality or behavior
Criteria of Alzheimer’s Disease
There are 3 primary elements:
- Meets the criteria for dementia
- Have insidious onset (months to years), clear-cut history of worsening cognition, clear cognitive deficits on history and examination (amnestic presentation and non-amnestic presentations)
- If symptoms are not due to:
- Concomitant cerebrovascular disease (history of stroke)
- Evidence of Lexy bodies
- Frontotemporal dementia
- Concurrent or active neurologic disease
Evaluation of Non-Cognitive Symptoms
Non-cognitive symptoms are present in 90% of dementia patients. There are four categories of non-cognitive symptoms:
- Depression (80%) – this is especially high during the early stages of dementia
- Psychosis – severe agitation and anxiety that can lead to aggressive behaviors and psychotic delusions
- Behavioral disturbances
- Insomnia/sundowning – sometimes associated with secondary factors, such as pain and anxiety, which should be treated. Sundowning describes the worsening of symptoms seen in some dementia patients at night.
The behavioral changes are often most distressing to caregivers and are the leading reason for placement in assisted living.
Goals of Treatment
There is no cure for AD. Treatment is focused on symptom improvement. The goal is to provide neuroprotective therapy, which delays and prevents progress.
Step One: Initial Management
The first step is to eliminate medications that can increase the risk or worsen dementia, such as anticholinergic medications. Any identified co-morbidities that can worsen dementia, such as dehydration, anemia, and UTI, should be aggressively treated.
Step Two: Treatments
Non-pharmacologic treatment
Non-pharmacologic therapy is a crucial part of the treatment. This includes caregiver education, support group, and engagement in cognitively-stimulating activities.
The Nun Study reported that having more positive thoughts and cognitively stimulating activities may help slow the progress.
A study published in the JAMA also reported that individuals with a healthy lifestyle had a lower risk of dementia, even with a genetic predisposition, compared to those with a less favorable lifestyle.
Pharmacotherapy therapy
The mainstay therapy is AChE-Is. Memantine is an additional therapy and can be combined with AChE-Is. VaD can be treated with AChE-I alongside appropriate comorbidity treatments.
A high dose of vitamin E has shown to be beneficial to cognitive sparing but comes with a high risk.
There are new biologics available now that target beta-amyloid proteins, but there is limited evidence of efficacy.
AChE-Is (Donepezil, rivastigmine, galantamine)
These medications can help sustain cognitive function in the short-term (6 months – 1 year). They are used for mild to moderate AD. All of them have similar ADRs, but some have more than others.
Donepezil and galantamine are the preferred agents due to rivastigmine’s significant GI effects. If rivastigmine is going to be used, a transdermal patch is recommended to avoid GI effects.
Treatment can be switched every 6 months if there is a lack of efficacy.
Pro-cholinergic effects are a common set of side effects, which include nausea, vomiting, diarrhea, dizziness, and arrhythmias. The GI ADRs can be best managed by slow titration 2 weeks to a month).
The response to AChE-I can be highly variable and is only effective in mild to moderate cases. Consider discontinuing the medication if MMSE is less than <10, which indicates a complete dependence because it can no longer provide more benefits while still having many ADRs.
Tacrine (Cognex) – this was the first AChE-I that comes with severe GI and hepatotoxicity. It has been removed from the market and replaced by donepezil.
Donepezil (Aricept) (mild to moderate, moderate to severe) – This is the most common AChE-I agent prescribed. A typical dose is 5 or 10 mg once daily after titration for 4-6 weeks. This is also available as the ODT formulation and transdermal weekly patches. A high dose (23mg/day) is not recommended due to a significant increase in GI effect (3x) and no additional benefit.
Rivastigmine (Exelon) – This is typically used for Parkinson-related dementia. It has a higher incidence of GI. A typical dose is twice daily for oral formulation and is titrated every 2 weeks. The transdermal patch is much better tolerated.
Galantamine (Razadyne) – Galantamine has dual mechanisms: AChE-I and nicotinic receptor modulator. It has similar ADRs to donezepil. The ER formulation can be dosed once daily. It also has solution formulation as well.
There has been some studies that are in favor against using AChE-Is due the increased rates of cardiovascular complications, such as bradycardia and syncope as well as hip fractures.
NMDA Receptor Antagonist
Memantine is the only medication in this class. It was approved by the FDA in 2003. It is available as XR for once-daily dosing. While it can be used as a monotherapy, it is typically combined with donepezil. And while it demonstrates some benefits, it is very mild.
Titration still needs to be done carefully starting with 5mg per day for 1 week and slowly titrating up to 10 mg BID. ADRs include dizziness, headache, somnolence, constipation, and diarrhea. Constipation is more common than diarrhea, which is why it typically balances out the diarrhea side effect of donepezil.
Memantine is not as effective for LBD and can make hallucinations worse.
Antioxidants
Oxidative stress and free radicals play a role in the pathogenesis of AD. A study with vitamin E demonstrated a mixed result, and an increase in all-cause mortality in any dose above 400 IU daily, but these studies recommend 800-1000 IU BID.
The TEAM-AD VA Trial also studied the efficacy of vitamin E, memantine, combination, and placebo. Those individuals in the vitamin E group are the ones with the most delayed clinical progression (6.2 months). The caregiver time also increased the last in the vitamin E group.
Anti-inflammatories
Anti-inflammatories have been shown to lower the incidence of AD, but they cannot be recommended at this time due to the risk of GI bleed and cardiovascular risk.
Lipid-Lowering Drugs
There are some correlations between early cholesterol problems in life and the risk of AD. Many studies are underway to confirm this finding, but it is not recommended yet for dementia prevention.
Estrogen Replacement
Estrogen replacement has possibly lowered the incidences of AD in post-menopausal women previously on hormone replacement therapy. It was later discovered that hormone replacement therapy has actually an increased risk of dementia, although the difference was very small.
Ginkgo Biloba (Egb 761)
The Egb 761 has been extensively studied in Europe. Please note that it needs to be this strain. The studies have been that the Egb 761 is likely safe and possibly effective in improving cognition. Due to the standardizing problem, the NCCIH does not recommend ginkgo biloba.
Apoaequorin
Apoaequorin has been touted as a neuroprotectant and is found in jellyfish. There is currently no credible evidence of efficacy, but there are safety issues including stroke and seizures.
Non-Cognitive Symptom Treatment
In most cases, patients will respond to environmental modifications, but it cannot completely eliminate them.
It is also important to address any underlying conditions that may lead to behavioral disturbances.
Psychosis Treatment – antipsychotic medications have a BBW of increased risk of mortality in dementia patients. Older agents and benzodiazepines should be avoided because they increase fall risk and cognitive impairment. The preferred agents are risperidone and olanzapine because they also have sedating and calming effects. It is also important to note that clozapine and olanzapine should be avoided in patients with diabetes, dyslipidemia, or obesity due to potential weight gain and blood glucose change. The CATIE-AD suggested that the use of antipsychotics in AD has inconsistent and little clinical benefit.
Depression Treatment – Citalopram, fluoxetine, and sertraline are the agents of choice. Trazodone can be good because it also reduces aggression and insomnia. Remember that SSRI initiation should start low and go slow. CitAD Trial is the study behind why citalopram is the most recommended agent. The study demonstrated that there is a significant improvement in 40% of the individuals. Interestingly, it does not improve daily living or decrease the use of emergency lorazepam rescue use. Other agents that may be used for depression are buspirone, selegiline, antiepileptic drugs, and methylphenidate. Methylphenidate data is inconclusive.
Insomnia and Sundowning – This is a tough situation. The main therapy is to treat the underlying problems. Trazodone and quetiapine can be used for sleep. Belsomra has the indication for this, but it is extremely expensive.
Other considerations – due to the number of medications, sometimes polypharmacy can become an issue, which is why it is important to always review the medication list. Typically these patients are on treatment for long-term, but the CMS guidelines require justification for a continuation or discontinuation of the therapy.
Aducanumab (Aduhelm) – This is a monoclonal antibody targeting beta-amyloid proteins, both the soluble and insoluble forms. Two crucial trials, EMERGE and ENGAGE, demonstrated a dose-response lowering of beta-amyloid proteins. Both trials stopped prematurely because no clinical benefit was significant. A post hoc analysis suggested that people with milder disease and at the highest dose of aducanumab might benefit from this therapy. ADRs include brain swelling and hemorrhage (14% of patients in phase III). The medication costs $56,000 a year. CMS will cover the treatment cost under phase IV.
Lecanemab (Leqembi) – This is similar to aducanumab, and was just approved on 01/2023 under the accelerated pathway. The trial behind this medication was the CLARITY AD trial.