Alzheimer’s and Dementia Guidelines and Tables

Abstract

Introduction

The purpose of this guide is to provide convenient and useful information on about Alzheimer’s disease and dementias of late life. The information includes selected facts, diagnostic criteria tables, descriptions of selected tests and screens, guidelines, clinical pharmacological data and references.

This guide is divided into several sections:

1. Background facts

2. Diagnostic aids and criteria for dementia diagnoses

3. Medications used for Alzheimer’s disease and dementia

Basic information on marketed treatments is provided although the treatment may not be FDA approved for this use. Approved cholinesterase inhibitors, memantine, and monoclonal antibodies are listed. No treatment is recommended or endorsed, however. This guide does not address the evidence base for the efficacy of the treatments listed.

Caveats: Except for treatments above, discussions of medications for people with dementia nearly always involve off label use. For example, antidepressants and antipsychotics are indicated in the FDA-approved prescribing information for major depression and schizophrenia, and not for depressive symptoms or the delusions or hallucinations occurring within the context of dementia with two exceptions. In these instances, the doses listed are for reference only and should not be considered as recommendations or appropriate use.

Physicians should consult the product package labeling for any drug mentioned.

A. Epidemiology, Etiology, Neuropathology of AD

1. Prevalence and Incidence of AD by Age

Age		Prevalence (%)		Incidence (%)
60–64		<0.5		0.1
65–69		<1.0		0.2
70–74		<2.0		0.4
75–79		4.3		0.7
80–84		8.5		1.4
85–89		16.0		2.9
90–95		28.5		6.0

Comment: Incidence and prevalence roughly doubles every 5 years. The median age of patients with AD is approximately 82 years, 38% of patients are between 75 and 84, and 35% 85 or older. Overall rates of dementia are higher.

REF: Brookmeyer R, Gray S, Kawas C. Projections of Alzheimer’s disease in the United States and the public health impact of delaying disease onset. Am J Public Health. 1998;88(9):1337–1342.

Number and Ages of People 65 or Older with Alzheimer's Dementia, 2023*.

*Percentages do not total 100 due to rounding. Created from data from Rajan et al.

REF: Rajan KB, Weuve J, Barnes LL, McAninch EA, Wilson RS, Evans DA. Population estimate of people with clinical AD and mild cognitive impairment in the United States (2020–2060). Alzheimers Dement 2021;17(12):1966–75.

Alzheimer’s Association. 2023 Alzheimer’s Disease Facts and Figures. Alzheimers Dement 2023;19(4). DOI 10.1002/alz.13016.

2. Neuropathology and Pathogenesis of AD

Key neuropathological features include neuronal and synaptic loss, the appearance of neuritic plaques, and NFTs.

Aβ42 and neuritic plaques

Plaques are composed of small poorly soluble, insoluble proteins derived from much larger β-APP encoded on chromosome 21.

β-APP is found in neuronal membrane. Aβ42 is a product of β-APP cleavage by a β-secretase and a gamma-secretase. PS-1 is the gamma-secretase.

NFT and neuronal loss

Abnormally-phosphorylated tau proteins. Tau is necessary for the assembly and function of microtubules (the molecular-transport system within neurons).

Progression of pathology

The first neurons susceptible to neurofibrillary degeneration are the phylogenetically oldest:

Limbic areas (ie, amygdala and hippocampus) which are critical for memory and learning.

Later, heteromodal association areas (ie, temporal-parietal regions important for language and visual spatial function, and prefrontal lobe, necessary for abstract reasoning) are affected.

Primary motor and sensory areas involved in movement, vision, hearing, and somatosensory perception are relatively spared.

The deposition of Aβ42, accumulation of Aβ-protein in fibrils and plaques, and as soluble toxic oligomers is hypothesized to accelerate neurofibrillary degeneration. Neuroinflammation and accumulation of abnormal forms of tau in tangles and neurites are important downstream events.

β-secretase and γ-secretase inhibitors have not shown efficacy in pharmacological trials. Muscarinic agonists and cholinesterase inhibitors may also decrease the production of Aβ42. Anti-amyloid antibodies effectively reduce amyloid plaques and are associated with small clinical effects seen in large trials.

Aβ42=amyloid; β-APP=beta-amyloid precursor protein; PS-1=Presenilin 1; NFT=neurofibrillary tangles.

3. Genetics of AD

Autosomal Dominant Mutations

Represents 1% of all cases

Age of onset is 40 to 60 years (or earlier)

PS-1 Chromosome 14

PS-2 Chromosome 1

β-APP Chromosome 21

The PS-1 mutations account for more than 50% of autosomal dominant AD

Susceptibility Polymorphism

Apolipoprotein E Chromosome 19

Risk factor

3 Allele types: ∈2, ∈3, ∈4

∈4—>greater risk of late onset AD

∈2—protective

Percentage of African Americans, European Americans and American Indians with Specified APOE Pairs.

APOE		African Americans		European Americans		American Indians†
e3/e3		45.2		63.4		71.6–73.2
e3/e4		28.6		21.4		22.7–23.9
e3/e2		15.1		10.2		2.6–3.0
e2/e4		5.7		2.4		0.5
e4/e4		4.5		2.4		1.0–1.2
e2/e2		0.7		0.2		0.0–0.1

REF: Alzheimer’s Association. 2023 Alzheimer’s Disease Facts and Figures. Alzheimers Dement 2023;19(4). DOI 10.1002/alz.13016. Created from data from Rajan et al. and Katakota et al.

4. Potentially Modifiable Risk Factors of AD

Not Modifiable: Age, Family History, Down syndrome, genetic mutation (see above)

Potentially Modifiable Risk Factors

Early life: less education

Midlife (45–65): hearing loss, traumatic brain injury, hypertension, alcohol use, obesity (BMI > 30)

Late life (>65): smoking, depression, social isolation, physical activity, diabetes, air pollution

Population Attributable Risks for Dementia: PAF for 12 Dementia Risk Factors.

		Relative risk for dementia (95% CI)		Risk factor prevalence		Communality		Unweighted PAF		Weighted PAF*
Early life (<45 years)
Less education		1.6 (1.3–2.0)		40.0%		61.2%		19.4%		7.1%
Midlife (age 45–65 years)
Hearing loss		1.9 (1.4–2.7)		31.7%		45.6%		22.2%		8.2%
TBI		1.8 (1.5–2.2)		12.1%		55.2%		9.2%		3.4%
Hypertension		1.6 (1.2–2.2)		8.9%		68.3%		5.1%		1.9%
Alcohol (>21 units/week)		1.2 (1.1–1.3)		11.8%		73.3%		2.1%		0.8%
Obesity (body-mass index ⩾ 30)		1.6 (1.3–1.9)		3.4%		58.5%		2.0%		0.7%
Later life (age > 65 years)
Smoking		1.6 (1.2–2.2)		27.4%		62.3%		14.1%		5.2%
Depression		1.9 (1.6–2.3)		13.2%		69.8%		10.6%		3.9%
Social isolation		1.6 (1.3–1.9)		11.0%		28.1%		4.2%		3.5%
Physical inactivity		1.4 (1.2–1.7)		17.7%		55.2%		9.6%		1.6%
Diabetes		1.5 (1.3–1.8)		6.4%		71.4%		3.1%		1.1%
Air pollution		1.1 (1.1–1.1)		75.0%		13.3%		6.3%		2.3%

Data are relative risk (95% CI) or %. Overall weighted PAF = 39.7%. PAF = population attributable fraction. TBI = traumatic brain injury. *Weighted PAF is the relative contribution of each risk factor to the overall PAF when adjusted for communality.

REF: Livingston G, Huntley J, Sommerlad A, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. The Lancet 2020;396(10248):413–46.

Population Attributabe Fraction of Potentially Modifiable Risk Factors for Dementia.

REF: Livingston G, Huntley J, Sommerlad A, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. The Lancet 2020;396(10248):413–46.

5. 10 Warning Signs of Alzheimer’s Disease

The Alzheimer’s Association uses a list of common symptoms of AD. Individuals who show several symptoms might consult a physician.

1. Memory loss that affects job skills. It is normal to occasionally forget an assignment, deadline, or colleague’s name, but frequent forgetfulness or unexplainable confusion at home or in the workplace may signal that something is wrong.

2. Difficulty performing familiar tasks. Busy people get distracted from time to time. For example, you might leave something on the stove too long or not remember to serve part of a meal. People with Alzheimer’s might prepare a meal and not only forget to serve it but also forget they made it.

3. Problems with language. Everyone has trouble finding the right word sometimes, but a person with AD may forget simple words or substitute inappropriate words, making his or her sentences difficult to understand.

4. Disorientation to time and place It is normal to momentarily forget the day of the week or what you need from the store. But people with AD can become lost on their own street, not knowing where they are, how they got there, or how to get back home.

5. Poor or decreased judgment. Choosing not to bring a sweater or coat along on a chilly night is a common mistake. A person with Alzheimer’s, however, may dress inappropriately in more noticeable ways, wearing a bathrobe to the store or several blouses on a hot day.

6. Problems with abstract thinking. Balancing a checkbook can be challenging for many people, but for someone with AD, recognizing numbers or performing basic calculation may be impossible.

7. Misplacing things. Everyone temporarily misplaces a wallet or keys from time to time. A person with AD may put these and other items in inappropriate places—such as an iron in the freezer or a wrist-watch in the sugar bowl—and then not recall how they got there.

8. Changes in mood or behavior. Everyone experiences a broad range of emotions—it is part of being human. People with AD tend to exhibit more rapid mood swings for no apparent reason.

9. Changes in personality. People’s personalities may change somewhat as they age. But a person with AD can change dramatically, either suddenly or over a period of time. Someone who is generally easygoing may become angry, suspicious, or fearful.

10. Loss of initiative. It is normal to tire of housework, business activities, or social obligations, but most people retain or eventually regain their interest. The person with AD may remain uninterested and uninvolved in many or all of his usual pursuits.

REF: www.alz.org/alzheimers-dementa/10_signs

B. Diagnostic Criteria for Dementia-related Syndromes

6. Alzheimer’s Disease Continuum

REF: Alzheimer’s Association. 2023 Alzheimer’s Disease Facts and Figures. Alzheimers Dement 2023;19(4). DOI 10.1002/alz.13016.

Alzheimer’s Disease Stages.

Severity		Symptoms		Brain Region Involved
Early
Mild cognitive impairment, mild dementia (1–3 years)		Clear impairments of memory and learning Depressed or anxious mood may be manifested Impairment in financial judgment and ability		Limbic-diencephalic memory system
Middle
Moderate and severe dementia (3–6 years)		Aphasia (loss of language ability): word-finding problems		Multi-modal association areas
		Visual spatial impairment
		“Dysexecutive” syndrome: poor judgment, insight, and planning
		Impaired ADLs: dressing, hygiene, toileting		Paralimbic areas
		Behavioral changes: agitation, wandering, delusions and hallucinations
Late
Profound and terminal dementia (7–10 years)		Global cognitive decline Unable to recognize family Unable to make needs known		Widespread and severe involvement of neocortical brain regions

7. DSM-5 Diagnostic Criteria for Major and Mild Neurocognitive Disorders

Major Neurocognitive Disorder

1. Evidence of significant cognitive decline from a previous level of performance in one or more cognitive domains (complex attention, executive function, learning and memory, language, perceptual-motor, or social cognition) based on:

   1. Concern of the individual, a knowledgeable informant, or the clinician that there has been a significant decline in cognitive function; and

   2. A substantial impairment in cognitive performance, preferably documented by standardized neuropsychological testing or, in its absence, another quantified clinical assessment.

2. The cognitive deficits interfere with independence in everyday activities (i.e., at a minimum, requiring assistance with complex instrumental activities of daily living such as paying bills or managing medications).

3. The cognitive deficits do not occur exclusively in the context of a delirium.

4. The cognitive deficits are not better explained by another mental disorder (e.g., major depressive disorder, schizophrenia).

Mild Neurocognitive Disorder

1. Evidence of modest cognitive decline from a previous level of performance in one or more cognitive domains (complex attention, executive function, learning and memory, language, perceptual motor, or social cognition) based on:

   1. Concern of the individual, a knowledgeable informant, or the clinician that there has been a mild decline in cognitive function; and

   2. A modest impairment in cognitive performance, preferably documented by standardized neuropsychological testing or, in its absence, another quantified clinical assessment.

2. The cognitive deficits do not interfere with capacity for independence in everyday activities (i.e., complex instrumental activities of daily living such as paying bills or managing medications are preserved, but greater effort, compensatory strategies, or accommodation may be required).

3. The cognitive deficits do not occur exclusively in the context of a delirium.

4. The cognitive deficits are not better explained by another mental disorder (e.g., major depressive disorder, schizophrenia).

For either Major or Mild Neurocognitive Disorder specify whether due to:

Alzheimer’s disease, frontotemporal lobar degeneration, Lewy body disease, vascular disease, traumatic brain injury, substance/medication use, HIV infection, prion disease, Parkinson’s disease, Huntington’s disease, Another medical condition, multiple etiologies, unspecified.

Coding note: Code based on medical or substance etiology. In some cases, there is need for an additional code for the etiological medical condition.

Specify also:

Without behavioral disturbance: If the cognitive disturbance is not accompanied by any clinically significant behavioral disturbance.

With behavioral disturbance: (specify disturbance): If the cognitive disturbance is accompanied by a clinically significant behavioral disturbance (e.g., psychotic symptoms, mood disturbance, agitation, apathy, or other behavioral symptoms).

REF: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, DSM-5, American Psychiatric Publishing, Washington DC 2013.

8. National Institute of Neurological and Communicative Disorders and Stroke and the AD and Related Disorders Association Criteria for Alzheimer’s Disease – (“NINCDS-ADRDA”) 1984 criteria

1. The criteria for the clinical diagnosis of PROBABLE AD include:

   Dementia established by clinical examination and documented by the Mini Mental State Examination, Blessed Dementia Scale, or some similar examination, and confirmed by neuropsychological tests.

   Deficits in two or more areas of cognition.

   Progressive worsening of memory and other cognitive functions.

   No disturbance of consciousness.

   Onset between ages 40 and 90, most often after 65 years of age.

   Absence of systemic disorders or other brain disease that in and of themselves could account for the progressive deficits in memory and cognition.

2. Other clinical features consistent with the diagnosis of PROBABLE AD, after exclusion of causes of dementia other than AD, include:

   Plateaus in the course of progression of the illness;

   Associated symptoms depression, insomnia, incontinence, delusions, illusions, hallucinations, catastrophic verbal, emotional, or physical outbursts, sexual disorders, and weight loss; other neurologic abnormalities in some patients, especially with more advanced disease and including motor signs such as increased muscle tone, myoclonus, or gait disorder; Seizures in advanced disease; and CT normal for age

3. Clinical diagnosis of POSSIBLE AD:

   May be made on the basis of the dementia syndrome, in the absence of other neurologic, psychiatric, or systemic disorders sufficient to cause dementia, and in the presences of variations in the onset, in the presentation, or in the clinical course;

   May be made in the presence of a second systemic or brain disorder sufficient to produce dementia, which is not considered to be the cause of the dementia; and

   Should be used in research studies when a single, gradually progressive severe cognitive deficit is identified in the absence of other identifiable cause.

NINCDS-ADRDA=National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association; CT=computed tomography.

REF: McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s disease. Neurology. 1984;34(7):939–944.

9. National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease – 2011 criteria

Criteria for all-cause dementia: Core clinical criteria

Dementia is diagnosed when there are cognitive or behavioral (neuropsychiatric) symptoms that:

1. Interfere with the ability to function at work or at usual activities; and

2. Represent a decline from previous levels of functioning and performing; and

3. Are not explained by delirium or major psychiatric disorder;

4. Cognitive impairment is detected and diagnosed through a combination of

   • (1) history-taking from the patient and a knowledgeable informant and

   • (2) an objective cognitive assessment, either a “bedside” mental status examination or neuropsychological testing.

     Neuropsychological testing should be performed when the routine history and bedside mental status examination cannot provide a confident diagnosis.

5. The cognitive or behavioral impairment involves a minimum of two of the following domains:

   1. Impaired ability to acquire and remember new information––symptoms include:

      repetitive questions or conversations, misplacing personal belongings, forgetting events or appointments, getting lost on a familiar route.

   2. Impaired reasoning and handling of complex tasks, poor judgment––symptoms include:

      poor understanding of safety risks, inability to manage finances, poor decision-making ability, inability to plan complex or sequential activities.

   3. Impaired visuospatial abilities––symptoms include:

      inability to recognize faces or common objects or to find objects in direct view despite good acuity, inability to operate simple implements, or orient clothing to the body.

   4. Impaired language functions (speaking, reading, writing)— symptoms include:

      difficulty thinking of common words while speaking, hesitations; speech, spelling, and writing errors.

   5. Changes in personality, behavior, or comportment––symptoms include:

      uncharacteristic mood fluctuations such as agitation, impaired motivation, initiative, apathy, loss of drive, social withdrawal, decreased interest in previous activities, loss of empathy, compulsive or obsessive behaviors, socially unacceptable behaviors

Probable AD dementia: Core clinical criteria

Probable AD dementia is diagnosed when the patient

1. Meets criteria for dementia (above) and has the following characteristics:

   1. Gradual or insidious onset over months to years, not sudden over hours or days;

   2. Clear-cut history of worsening of cognition by report or observation; and

   3. Initial and most prominent cognitive deficits are evident on history and examination in one of the following categories:

      1. Amnestic presentation: It is the most common syndromic presentation of AD dementia. The deficits should include impairment in learning and recall of recently learned information. There should also be evidence of cognitive dysfunction in at least one other cognitive domain.

      2. Nonamnestic presentations:

         • – Language presentation: The most prominent deficits are in word-finding, but deficits in other cognitive domains should be present.

         • – Visuospatial presentation: The most prominent deficits are in spatial cognition, including object agnosia, impaired face recognition, simultanagnosia, and alexia. Deficits in other cognitive domains should be present.

         • – Executive dysfunction: The most prominent deficits are impaired reasoning, judgment, and problem solving. Deficits in other cognitive domains should be present.

   4. The diagnosis of probable AD dementia should not be applied when there is evidence of

      • (a) substantial concomitant cerebrovascular disease, defined by a history of a stroke temporally related to the onset or worsening of cognitive impairment; or the presence of multiple or extensive infarcts or severe white matter hyperintensity burden; or

      • (b) core features of Dementia with Lewy bodies other than dementia itself; or

      • (c) prominent features of behavioral variant frontotemporal dementia; or

      • (d) prominent features of semantic variant primary progressive aphasia or nonfluent/agrammatic variant primary progressive aphasia; or

      • (e) evidence for another concurrent, active neurological disease, or a non-neurological medical comorbidity or use of medication that could have a substantial effect on cognition.

Note: All patients who met criteria for “probable AD” by the 1984 NINCDS–ADRDA criteria [1] would meet the current criteria for probable AD dementia.

REF: McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s & Dementia: the Journal of the Alzheimer’s Association 2011;7(3):263–9.

AD Dementia Criteria Incorporating Biomarkers.

Diagnostic category		Biomarker probability of AD etiology		Aβ (PET or CSF)		Neuronal injury (CSF tau, FDG-PET, Structural MRI)
Probable AD dementia
Based on clinical criteria		Uninformative		Unavailable, conflicting, or indeterminate		Unavailable, conflicting, or indeterminate
With three levels of evidence of AD pathophysiological process		Intermediate		Unavailable or indeterminate		Positive
		Intermediate		Positive		Unavailable or indeterminate
		High		Positive		Positive
Possible AD dementia (atypical presentation)
Based on clinical criteria		Uninformative		Unavailable, conflicting, or indeterminate		Unavailable, conflicting, or indeterminate
With evidence of AD pathophysiological process		High but does not rule out second etiology		Positive		Positive
Dementia-unlikely due to AD		Lowest		Negative		Negative

REF: McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s & Dementia 2011;7(3):263–9.

10. National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for mild cognitive impairment – 2011

MCI—Core clinical criteria

Individuals in this category meet the criteria based on the characteristics of the clinical syndrome and an examination of potential causes for the cognitive decline. These individuals typically have a prominent impairment in episodic memory, but other patterns can also progress to AD dementia over time (e.g., visuospatial impairments).

MCI due to AD—Intermediate likelihood

Meets the core clinical criteria for MCI and has either a positive amyloid biomarker or a positive biomarker reflecting neuronal injury then there is increased likelihood for Alzheimer’s disease.

MCI due to AD—High likelihood

Meets the core clinical criteria for MCI and has positive biomarkers for both amyloid and neuronal injury. Provides the highest level of certainty of progression to AD dementia.

REF: Albert MS, DeKosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s & dementia: 2011;7(3):270–9.

11. 2018 National Institute on Aging—Alzheimer’s Association (NIA-AA) Research Framework: Toward a biological definition of Alzheimer’s disease. The “ATN” criteria

Alzheimer’s disease is defined by its underlying pathologic processes that can be documented postmortem or by biomarkers. ATN diagnosis is not based on the clinical symptoms/signs in this framework, which shifts the definition of AD in to a biological construct. The framework focuses on the diagnosis of AD with biomarkers in living persons.

AT(N) Biomaker Grouping.

A:	Aggregated Aβ or associated pathologic state CSF Aβ42, or Aβ42/Aβ40 ratio Amyloid PET
T:	Aggregated tau (neurofibrillary tangles) or associated pathologic state CSF phosphorylated tau Tau PET
(N):	Neurodegeneration or neuronal injury Anatomic MRI FDG PET CSF total tau

Nomenclature for Syndromal Cognitive Stage with ATN Biomarker Profile.

Biomarker Profile
					Cognitively unimpaired		MCI		Dementia
			A– T– (N)–		normal AD biomarkers, cognitively unimpaired		normal AD biomarkers with MCI		normal AD biomarkers with dementia
			A+ T– (N)–		Preclinical Alzheimer’s pathologic change		Alzheimer’s pathologic change with MCI		Alzheimer’s pathologic change with dementia
			A+ T– (N)+		Alzheimer’s and concomitant suspected non Alzheimer’s pathologic change, cognitively unimpaired		Alzheimer’s and concomitant suspected non Alzheimer’s pathologic change with MCI		Alzheimer’s and concomitant suspected non Alzheimer’s pathologic change with dementia
			A+ T+ (N)– A+ T+ (N)+		Preclinical Alzheimer’s disease		Alzheimer’s disease with MCI (Prodromal AD)		Alzheimer’s disease with dementia

REF: Jack CR, Jr., Bennett DA, Blennow K, et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease. Alzheimer’s & Dementia 2018;14(4):535–62.

12. DSM-5 Major or Mild Vascular Neurocognitive Disorder

Diagnostic Criteria

1. The criteria are met for major or mild neurocognitive disorder.

2. The clinical features are consistent with a vascular etiology, as suggested by either of the following:

   1. Onset of the cognitive deficits is temporally related to one or more cerebrovascular events.

   2. Evidence for decline is prominent in complex attention (including processing speed) and frontal-executive function.

3. There is evidence of the presence of cerebrovascular disease from history, physical examination, and/or neuroimaging considered sufficient to account for the neurocognitive deficits.

4. The symptoms are not better explained by another brain disease or systemic disorder. Probable vascular neurocognitive disorder is diagnosed if one of the following is present; otherwise, possible vascular neurocognitive disorder should be diagnosed:

   1. Clinical criteria are supported by neuroimaging evidence of significant parenchymal injury attributed to cerebrovascular disease (neuroimaging-supported).

   2. The neurocognitive syndrome is temporally related to one or more documented cerebrovascular events.

   3. Both clinical and genetic (e.g., cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) evidence of cerebrovascular disease is present.

      Possible vascular neurocognitive disorder is diagnosed if the clinical criteria are met but neuroimaging is not available and the temporal relationship of the neurocognitive syndrome with one or more cerebrovascular events is not established.

Coding note: For probable major vascular neurocognitive disorder, with behavioral disturbance, code 290.40 (F01.51). For probable major vascular neurocognitive disorder, without behavioral disturbance, code 290.40 (F01.50). For possible major vascular neurocognitive disorder, with or without behavioral disturbance, code 331.9 (G31.9). For mild vascular neurocognitive disorder, code 331.83 (G31.84).

REF: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, DSM-5, American Psychiatric Publishing, Washington DC 2013.

13. ADDTC California Criteria for Ischemic Vascular Dementia

Probable IVD

1. The criteria for the clinical diagnosis of PROBABLE IVD include all of the following:

   1. Dementia

   2. Evidence of two or more ischemic strokes by history, neurological signs, and/or neuroimaging(T1-weighted MRI) or a single stroke with a clearly documented temporal relationship to the onset of dementia

   3. Evidence of at least one infarct outside the cerebellum by CT or T1-weighted MRI.

2. The diagnosis of PROBABLE IVD is supported by:

   1. Evidence of multiple infarcts in brain regions known to affect cognition

   2. A history of multiple transient ischemic attacks

   3. History of vascular risk factors (eg, hypertension, heart disease, diabetes mellitus)

   4. Elevated Hachinski Ischemia Scale

3. Clinical features that are thought to be associated with IVD, but await further research, include:

   1. Relatively early appearance of gait disturbance and urinary incontinence

   2. Periventricular and deep white matter changes on T2-weighted MRI that are excessive for age

   3. Focal changes in electrophysiologic studies (eg, EEG, EPs) or physiologic neuroimaging (eg, SPECT, PET, NMR spectroscopy).

4. Other clinical features that do not constitute strong evidence either for or against a diagnosis of PROBABLE IVD include:

   1. Periods of slowly progressive symptoms

   2. Illusions, psychosis, hallucinations, delusions

   3. Seizures

5. Clinical features that cast doubt on a diagnosis of PROBABLE IVD include:

   1. Transcortical sensory aphasia in the absence of corresponding focal lesions on neuroimaging studies

   2. Absence of central neurologic symptoms/signs, other than cognitive disturbance.

Possible IVD

1. clinical diagnosis of POSSIBLE IVD may be made when there is:

   • 1. Dementia, and one or more of the following:

   • 2a. History or evidence of a single stroke (but not multiple) without a clearly documented temporal relationship to the onset of dementia; OR

   • 2b. Binswanger’s syndrome (without multiple strokes) that includes all of the following;

     1. Early-onset urinary incontinence not explained by urologic disease, or gait disturbance, eg, parkinsonian, magnetic, apraxic, or “senile” gait, not explained by peripheral cause

     2. Vascular risk factors

     3. Extensive white matter changes on MRI

ADDTC=Alzheimer’s Disease Diagnostic and Treatment Centers; IVD=ischemic vascular dementia; CT=computed tomography; MRI=magnetic resonance imaging; EEG=electroen-cephalogram; SPECT=single photon emission computed tomography; PET=positron emission tomography; NMR=nuclear magnetic resonance.

REF: Chui HC, Victoroff JI, Margolin D, Jagust W, Shankle R, Katzman R. Criteria for the diagnosis of ischemic vascular dementia proposed by the State of California Alzheimer’s disease Diagnostic and Treatment Centers [see comments]. Neurology. 1992;42(3 Pt l):473–480.

14. Revised Criteria for the Clinical Diagnosis of Dementia with Lewy Bodies (DLB)

1. Dementia, defined as a progressive cognitive decline sufficient to interfere with normal social or occupational functions, or with usual daily activities. Prominent or persistent memory impairment may not necessarily occur in the early stages but is usually evident with progression. Deficits on tests of attention, executive function, and visuoperceptual ability may be especially prominent and occur early.

2. Core clinical features (The first 3 typically occur early and may persist throughout the course.)

   • Fluctuating cognition with pronounced variations in attention and alertness.

   • Recurrent visual hallucinations that are typically well formed and detailed.

   • REM sleep behavior disorder, which may precede cognitive decline.

   • One or more spontaneous cardinal features of parkinsonism: (1) bradykinesia (slowness of movement and decrement in amplitude or speed), (2) rest tremor, or (3) rigidity.

3. Supportive clinical features

   Severe sensitivity to antipsychotic agents; postural instability; repeated falls; syncope or other transient episodes of unresponsiveness; severe autonomic dysfunction, e.g., constipation, orthostatic hypotension, urinary incontinence; hypersomnia; hyposmia; hallucinations in other modalities; systematized delusions; apathy, anxiety, and depression.

4. Indicative biomarkers

   Reduced dopamine transporter uptake in basal ganglia demonstrated by SPECT or PET.

   Abnormal (low uptake) ¹²³iodine-MIBG myocardial scintigraphy.

   Polysomnographic confirmation of REM sleep without atonia.

5. Supportive biomarkers

   Relative preservation of medial temporal lobe structures on CT/MRI scan.

   Generalized low uptake on SPECT/PET perfusion/metabolism scan with reduced occipital activity +/− cingulate island sign on FDG-PET.

   Prominent posterior slow-wave activity on EEG with periodic fluctuations in the pre-alpha/theta range.

Probable DLB can be diagnosed if:

1. Two or more core clinical features of DLB are present, with or without the presence of indicative biomarkers, or

2. Only one core clinical feature is present, but with one or more indicative biomarkers. Probable DLB should not be diagnosed based on biomarkers alone.

Possible DLB can be diagnosed if:

1. Only one core clinical feature of DLB is present, with no indicative biomarker evidence, or

2. One or more indicative biomarkers is present but there are no core clinical features.

REF: McKeith IG, Boeve BF, Dickson DW, et al. Diagnosis and management of dementia with Lewy bodies. Fourth consensus report of the DLB Consortium Neurology 2017;89(1):88–100.

15. International Consensus Criteria for Diagnosis and Classification of Behavioral Variant Frontotemporal Dementia (bvFTD)

Neurodegenerative disease

• Must be present for any FTD clinical syndrome

• Shows progressive deterioration of behavior and/or cognition by observation or history

Possible bvFTD

• Three of the features (A–F) must be present; symptoms should occur repeatedly:

  1. Early (within first 3 years) behavioral disinhibition

  2. Early (within first 3 years) apathy or inertia

  3. Early (within first 3 years) loss of sympathy or empathy

  4. Early (within first 3 years) perseverative, stereotyped or compulsive/ritualistic behavior

  5. Hyperorality and dietary changes

  6. Neuropsychological profile: executive dysfunction with relative sparing of memory and visuospatial functions

Probable bvFTD

• All the following criteria must be present to meet diagnosis

  1. Meets criteria for possible bvFTD

  2. Significant functional decline

  3. Imaging results consistent with bvFTD (frontal and/or anterior temporal atrophy on CT or MRI or frontal hypoperfusion or hypometabolism on SPECT or PET)

Definite bvFTD

• Criteria A and either B or C must be present to meet diagnosis:

  1. Meets criteria for possible or probable bvFTD

  2. Histopathological evidence of FTLD on biopsy at post mortem

  3. Presence of a known pathogenic mutation

Exclusion criteria for bvFTD

• Criteria A and B for possible bvFTD must be answered negatively; criterion C can be positive for possible bvFTD but negative for probable bvFTD:

  1. Pattern of deficits is better accounted for by other nondegenerative nervous system or medical disorders

  2. Behavioral disturbance is better accounted for by a psychiatric diagnosis

  3. Biomarkers strongly indicative of Alzheimer’s disease or other neurodegenerative process

bvFTD: Behavioral-variant frontotemporal dementia; CT: Computerized tomography; FTD: Frontotemporal dementia; FTLD: Frontotemporal lobar degeneration; SPECT: Single-photon emission computed tomography.

REF: Rascovsky K, Hodges JR, Knopman D, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain. 2011;134(Pt 9):2456–2477.

16. Proposed Criteria for Psychosis of AD

• A. Characteristic symptoms

  Presence of one (or more) of the following symptoms:

  1. Visual or auditory hallucinations

  2. Delusions

• B. Primary diagnosis

  All the criteria for dementia of the Alzheimer’s type are met.

• C. Chronology of the onset of symptoms of psychosis versus onset of symptoms of dementia

  There is evidence from the history that the symptoms in Criterion A have not been present continuously since prior to the onset of the symptoms of dementia.

• D. Duration and Severity

  The symptom(s) in Criterion A have been present, at least intermittently for 1 month or longer. Symptoms are severe enough to cause some disruption in patients’ and/or others’ functioning.

• E. Exclusion of schizophrenia and related psychotic disorders

  Criteria for schizophrenia, schizoaffective disorder, delusional disorder, or mood disorder with psychotic features have never been met.

• F. Relationship to delirium

  The disturbance does not occur exclusively during the course of a delirium.

• G. Exclusion of other causes of psychotic symptoms

  The disturbance is not better accounted for by another general medical condition or direct physiological effects of a substance (eg, a drug of abuse, a medication)

Associated Features (specify if associated):

With agitation: When there is evidence, from history or examination, of prominent agitation with or without physical or verbal aggression

With negative symptoms: When prominent negative symptoms, such as apathy, affective flattening, avolition, or motor retardation, are present

With depression: When prominent depressive symptoms, such as depressive mood, insomnia or hypersomnia, feelings of worthlessness or excessive or inappropriate guilt, or recurrent thoughts of death, are present.

REF: Jeste DV, Finkel SI. Psychosis of Alzheimer’s disease and related dementias. Diagnostic criteria for a distinct syndrome. Am J Geriat Psychiatry. 2000;8(l):29–34.

17. NIMH Provisional Diagnostic Criteria for Depression of AD

1. Three (or more) of the following symptoms have been present during the same 2 week period and represent a change from previous functioning; at least one of the symptoms is either depressed mood or decreased positive affect or pleasure:

   • (1) Clinically significant depressed mood (eg, depressed, sad, hopeless, discouraged, and tearful)

   • (2) Decreased positive affect or pleasure in response to social contacts and usual activities

   • (3) Social isolation or withdrawal

   • (4) Disruption in appetite

   • (5) Disruption in sleep

   • (6) Psychomotor changes (eg, agitation or retardation)

   • (7) Irritability

   • (8) Fatigue or loss of energy

   • (9) Feelings of worthlessness, hopelessness, or excessive or inappropriate guilt

   • (10) Recurrent thoughts of death, suicidal ideation, plan or attempt

   Note: Do not include symptoms that, in your judgment, are clearly due to a medical condition other than AD, or a direct result of non-mood related dementia symptoms (eg, loss of weight due to difficulties with food intake).

2. All DSM-IV-TR criteria are met for dementia of the Alzheimer’s type.

3. The symptoms cause clinically significant distress or disruption in functioning.

4. The symptoms do not occur exclusively during the course of a delirium.

5. The symptoms are not due to the direct physiological effects of a substance (eg, a drug of abuse, medication).

6. The symptoms are not better accounted for by other conditions such as major depressive disorder, bipolar disorder, bereavement, schizophrenia, schizoaffective disorder, psychosis of AD, anxiety disorders, or substance-related disorder.

Specify if:

Co-occurring Onset: if onset antedates or co-occurs with the AD diagnosis

Post AD Onset: if onset occurs after AD diagnosis

Specify if:

With delusions, hallucinations, other behavioral signs or symptoms, or history of mood disorder

REF: Olin JT, Schneider L, Katz IR, et al. National Institue of Mental Health – Provisional diagnostic criteria for depression of Alzheimer’s disease. American Journal of Geriatric Psychiatry. 2001;10(2):129–141.

C. Clinical Instruments, Scales, and Assessments

18. Rating Instruments for Evaluation of Efficacy in AD Clinical Trials

Rating Scale		Symptoms/Domains Assessed		Information Source		Scale/Interpretation/Comment
Primary Outcomes Alzheimer’s Disease Assessment Scale—Cognitive Subscale (ADAS-Cog)		Battery of brief individual performance-based tests; assesses word recall, naming, response to commands, constructional and ideational praxis, orientation, word recognition, spoken language ability and comprehension, word-finding, recall of test instructions		Patient		0–70 points 0=no errors, 70 severe impairment Most commonly used to assess efficacy of drugs
Clinician’s Interview-Based Impression of Change+ (CIBIC+), or ADCS-CGIC		7-point rating scale used to assess change in three areas (cognition, daily function, and behavior). (Note: The “Plus” represents information from the caregiver.)		Patient and caregiver		1–7 points 1, 2, 3 minimal, moderate, marked improvement, 4=no change, 5, 6, 7, minimal, moderate, marked deterioration
Clinical Dementia Rating Scale (CDR)		Domains assessed: memory, orientation, judgment and problem solving, community affairs, home and hobbies, personal care		Patient and caregiver		0 to 3 (0=normal, 0.5 questionable, 1 mild, 2 moderate, 3severe) CDR-SB, box scores 0–18
Secondary Measures Mini-Mental State Examination (MMSE)		Screening and staging of cognitive severity		Patient		1–30 points (higher score better)
Montreal Cognitive Assessment (MoCA)		Screening for mild cognitive dysfunction. Domains: attention and concentration, executive function, memory, language, visuospatial, abstraction, calculations, orientation		Patient		1–30 points (higher score better)
Global Deterioration Scale (GDS)		Staging of disease severity; cognition, memory self-care, activities of daily living (ADL)		Patient and caregiver		1 to 7 (1=no decline, 7=severe decline)
AD Cooperative Study – Activities of Daily Living Disability Assessment Dementia Interview for Deterioration in Daily Living Activities in Dementia				Caregiver interview		Various scaling is used. to assess ADLs of patients.
Cohen-Mansfield Agitation Inventory (CMAI)		Consists of 29 agitated behaviors, each rated on a 7-point frequency scale, 1 to 6, never to several times an hour		Caregiver rating		Score range 29 to 203
Neuropsychiatric Inventory (NPI)		Behavior rating scales addressing the following NPI rates severity and frequency of 10–12 behaviors.		Caregiver interviews.		NPI: 0 to 120 or 144 for NPI-NH. Individual behaviors are assessed.
Behavioral Pathology in AD Rating Scale (BEHAVE-AD)		BEHAVE-AD is 25-items in several domains, 7 involving delusions and hallucinations				BEHAVE-AD: 0–75, overall severity. Each item rated 0 to 3 on severity.

19. Mini-Mental State Examination

A widely used brief mental status test; scoring system enhances communication. Used to help screen for cognitive impairment, as a clinical index of severity and change.

Interpretations: Normal or mild cognitive impairment >26, MCI or mild dementia 20–26, moderate dementia 10–20, severe dementia <10.

Education adjustments: <8 years of education >17 might be normal, >16 years of education, >27 might be normal.

Orientation

1. What is today’s date?

2. What is the year?

3. What is the month?

4. What day is today?

5. Can you also tell me what season it is?

6. Can you also tell me the name of the hospital?

7. What floor are we on?

8. What town or city are we in?

9. What country are we in?

10. What state are we in?

Immediate Recall

Ask patient if you may test their memory. Say: “ball,” “flag,” “tree.” Ask them to repeat items. First repetition determines the score. If the subject could not repeat all 3 words in the first trial then keep saying “ball,” “flag,” “tree” until subject can repeat all 3, up to 6 trials. If he/she does not eventually learn all 3, recall cannot be meaningfully tested.

Attention and Calculation

Ask the subject to begin with 100 and count backwards by 7. Stop after 5 subtractions. Score the total correct answers.

Or spell W-O-R-L-D backwards.

Delayed Recall

Ask the patient to recall the 3 words you previously asked him/her to remember.

Language

Object naming: Watch, pencil

Repetition: “No ifs, ands, or buts”

Three-stage command: “Take the paper in your right hand, fold it in half and put it on the floor”

Reading: Close eyes

Writing: Writes a sentence with a subject and a verb and is sensible

Copying: Intersecting pentagons

REF: Folstein MF, Folstein SE, McHugh PR. “Mini-Mental State.” A practical method for grading the cognitive state of patients for the clinical. Journal of Psychiatric Research. 1975;12(3):189–198.

20. Montreal Cognitive Assessment (MOCA)

Domains: attention and concentration, visuospatial, executive function, language, memory, attention, abstraction, orientation.

REF: Successful completion of 1-hour training is required to administer the MoCA. Become certified at https://mocacognition.com/

21. Hachinski Ischemic Scale

Features		Point Value
Abrupt onset		2
Stepwise deterioration		1
Fluctuating course		2
Nocturnal confusion		1
Relative preservation of personality		1
Depression		1
Somatic complaints		1
Emotional incontinence		1
History of presence of hypertension		1
History of strokes		2
Evidence of associated atherosclerosis		1
Focal neurological symptoms		2
Focal neurological signs		2

REF: Rosen WG, Terry RD, Fuld PA, Katzman R, Peck A. Pathological verification of ischemic score in differentiation of dementias. Ann Neurology. 1980;7(5):486–488.

22. Clinical Dementia Rating Scale Interview

Impairment		None (0)		Questionable (0.5)		Mild (1)		Moderate (2)		Severe (3)
Memory		No memory loss or slight inconsistent forgetfulness		Consistent slight forgetfulness; partial recollection of events; “benign” forgetfulness		Moderate memory loss; more marked for recent events; defect interferes with everyday activities		Severe memory loss; only highly learned material retained; new material rapidly lost		Severe memory loss; only fragments remain
Orientation		Fully orientated		Fully oriented except for slight difficulty with time relationships		Moderate difficulty with time relationships; oriented for place at examination; may have geographic disorientation elsewhere		Severe difficulty with time relationships; usually disoriented to time, often to place		Oriented to person only
Judgment and Problem Solving		Solves everyday problems and handles business and financial affairs well; judgment good in relation to past performance		Slight impairment in solving problems, similarities, and differences		Moderate difficulty in handling problems, similarities, and differences; social judgment usually maintained		Severely impaired in handling problems, similarities, and differences; social judgment usually impaired		Unable to make judgments or solve problems
Community Affairs		Independent function at usual level in job, shopping, volunteer and social groups		Slight impairment in these activities		Unable to function independently at these activities although may still be engaged in some; appears normal to casual inspection		No pretense of independent function outside home Appears well enough to be taken to functions outside a family home		Appears too ill to be taken to functions outside family home
Home and Hobbies		Life at home, hobbies, and intellectual interests well maintained		Life at home, hobbies, and intellectual interests slightly impaired		Mild but definite impairment of function at home; more difficult chores abandoned; more complicated hobbies and interests abandoned		Only simple chores preserved; very restricted interests, poorly maintained		No significant function in home
Personal Care		Fully capable of self-care				Needs prompting		Requires assistance in dressing, hygiene, keeping of personal effects		Requires much help with personal care; frequent incontinence

https://knightadrc.wustl.edu/professionals-clinicians/cdr-dementia-staging-instrument/

https://knightadrc.wustl.edu/professionals-clinicians/cdr-dementia-staging-instrument/cdr-scoring-algorithm/

REF: Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology. 1993;43(11):2412–2414.

23. Global Deterioration Scale

Stage		Example of Deficits
1. No cognitive decline either by subjective complaint or a clinical interview		None
2. Very mild cognitive decline		Subjective complaints of memory loss only – e.g., forgetting where one has placed familiar objects. No objective evidence of loss in clinical interview
3. Mild cognitive decline		Decreased performance in demanding employment and social settings. Objective evidence of impairment only obtained in intensive interview
4. Moderate cognitive decline		Decreased knowledge of current events. Decreased ability to perform complex tasks. Decreased ability to market, handle finances
5. Moderately severe cognitive decline		Unable to recall a major aspect of current life. May have difficulty with choice of clothing; can no longer survive without some assistance
6. Severe cognitive decline		Largely unaware of recent life events. Increasing difficulties with dressing and bathing. Eventually develop problems with toileting. Emotional changes, such as agitated behavior, may emerge.
7. Very severe cognitive decline		All verbal abilities are lost. Incontinence is present, progressive loss of basic psychomotor skills

REF: Reisberg B, Ferris SH, de Leon MJ, Crook T. The Global Deterioration Scale for assessment of primary degenerative dementia. Am J Psychiatry 1982;139(9):1136–9.

24. Alzheimer’s Disease Cooperative Study – Activities of Daily Living Inventory (ADCS-ADLs)

This hierarchic scale, developed by the ADCS, is commonly used in trials. By interviewing an informant it assesses the following ADLs:

1. Finding belongings at home

2. Selecting clothes for the day

3. Dressing

4. Cleaning a room

5. Balancing checkbook/credit card statement

6. Writing things down

7. Cleaning a load of laundry

8. Keeping appointments

9. Using a telephone

10. Preparing a meal or snack

11. Traveling beyond home

12. Talking about current events

13. Reading

14. Watching television

15. Shopping

16. Left alone

17. Using a household appliance

18. Participating in a pastime or hobby

19. Driving a car

20. Taking medications regularly

21. Carrying out complex activities

22. Initiating complex activities

23. Time to complete complex activities

24. Extenuating circumstances

REF: Galasko D, Bennett D, Sano M, et al. An inventory to assess activities of daily living for clinical trials in Alzheimer’s disease. Alzheimer’s Dis Assoc Disord. 1997;11(Suppl 2):S33–S39.

25. Dependence Scale

1. Does the patient need reminders or advice to manage chores, go shopping, cook, play games, or handle money?

2. Does the patient need help to remember important things such as appointments, recent events, or names of family or friends?

3. Does the patient need frequent (at least once a month) help finding misplaced objects, keeping appointments, or maintaining health or safety (locking doors, taking medication)?

4. Does the patient need household chores done for them?

5. Does the patient need to be watched or kept company when awake?

6. Does the patient need to be escorted when outside?

7. Does the patient need to be accompanied when bathing or eating?

8. Does the patient have to be dressed, washed, and groomed?

9. Does the patient have to be taken to the toilet regularly to avoid incontinence?

10. Does the patient have to be fed?

11. Does the patient need to be turned, moved, or transferred?

12. Does the patient wear a diaper or a catheter?

13. Does the patient need to be tube fed?

Items A and B are coded: no=0; occasionally=1 (at least once a month); frequently=2 (at least once a week).

Items C–M are coded: no = 0; yes = 1.

Derivation of Dependence Level

Level 0 (0 to all items)		0
Level 1 (Either A, B or C=1)		1
Level 2 (2 of A, B or C=1 or A or B=2 or D=1)		2
Level 3 (E, F or G=1)		3
Level 4 (H, I or J =1)		4
Level 5 (K, L or M=1)		5

REF: Stern Y, Albert SM, Sano M, et al. Assessing patient dependence in Alzheimer’s disease. J Gerontol. 1994;49(5):M216–22.

26. Functional Activities Questionnaire

The FAQ is a straightforward instrument. Adding the scores gives the total FAQ score. Scores range from 0 to 30. Scores of 9 or below are normal. Scores of 10 and above indicate reduced functional ability.

Caregivers score each area as follows:

Fully dependent on others: 3

Some assistance needed: 2

Finds it difficult but manages alone: 1

No difficulty: 0

• Dealing with financial matters, paying bills, writing checks

• Keeping records of taxes, business affairs

• Shopping for everyday necessities: groceries, clothes, etc

• Hobbies or playing games

• Making tea, turning the kettle on and off

• Cooking a balanced meal

• Perception of current events

• Level of attention and understanding: books, television

• Memory: remembering appointments and medications

• Getting about: driving or taking public transport

REF: Pfeffer RI, Kurosaki TT, Harrah CH, Chance JM, Filos S. Measurement of functional activities in older adults in the community J Gerontol. 1982;37(3):323–329.

27. Neuropsychological Assessments for Dementia

Major Area		Tests		Comments
Attention		Letter Cancellation Digit Span Continuous Performance Task		Attention must be adequate for performance of other tasks.
Language		Boston Diagnostic Aphasia Western Aphasia Battery Boston Naming Test Reitan Aphasia Screening Controlled Word Association Test		Testing involves naming, fluency, comprehension, repetition, vocabulary, reading, writing. Naming difficulty is age-related and common in dementia.
Memory		Wechsler Memory Scale, Logical Memory I and II New York University Paragraph Recall Rey Auditory Verbal Learning Test Selective Reminding Test California Verbal Learning Test		Must distinguish between immediate and delayed memory. List memory and story memory have different characteristics.
Visuospatial Abilities		Benton Visual Retention Test Block Design Subtest of the WAIS-R		Involves figure copying
Executive Function		Similarities subtest of WAIS-R Proverbs Test Trailmaking Test (A and B) Wisconsin Card Sort Test Stroop Letter number selection		Tests of concept formation, abstraction, set shifting, and maintenance. Affected in depression, most dementia, especially frontotemporal dementia
Dementia Batteries		Mattis Dementia Rating Scale CERAD Battery ADAS-cog RBANS		Potentially clinically useful because they assess a broad range of abilities, and are scaled so that dementia patients are more likely able to complete them without excessive stress

ADAS-cog=Alzheimer’s Disease Assessment Scale (Cognitive Subscale);

WAIS-R=Wechsler Adult Intelligence Scale-Revised;

CERAD=Consortium to Establish a Registry for Alzheimer’s Disease.

28. Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-cog)

The ADAS-cog is a standard primary measure of cognitive outcome in clinical trials of antidementia medications. The average annual deterioration on the ADAS-cog in patients enrolled in trials is approximately 5 points but this depends on severity at baseline. This consideration is useful in determining clinical significance on the ADAS-cog.

Description: Contains items for several cognitive domains impaired in AD including memory, language, praxis and orientation. It was designed specifically as an outcome measure in clinical trials. It consists of 11 items; scores range from 0 for a patient who makes no errors to 70 for a patient who is profoundly demented. The battery itself and its scoring is heavily weighted toward memory

Administration time: 20–45 minutes

ADAS-cog Items.

Test Items:
Word recall task		10-item, 3-trial list learning task
Naming fingers and objects		Patient names each finger, simple items (flower, bed, whistle, pencil), moderate items (rattle, mask, scissors, comb), difficult items (harmonica, stethoscope, wallet, tongs).
Commands		Patient performs 5 basic tasks. For example, “put the pencil on top of the card, then put it back.”
Constructional praxis		Patient copies a circle, two overlapping rectangles, rhombus, and cube.
Ideational praxis		Patient is asked to fold a letter, put it in an envelope, seal it, address it, and identify location to place a postage stamp.
Orientation		Patient is asked to provide name, date, day, month, season, year, location, and time of day.
Word recognition		Patient is shown 12 words, and then has to recognize those words from a set of 12 distractor words. 3 trials are performed.
Spoken language ability		5-point rating of patient’s clarity of speech, without considering word finding.
Comprehension		5-point rating of patient’s ability to comprehend speech, assessed via conversation.
Word finding difficulty		5-point rating of patient’s word finding, assessed via conversation.
Remembering test instructions		Frequency that patient needs re-instruction during word recognition.

REF: Mohs RC, Knopman D, Petersen RC, et al. Development of cognitive instruments for use in clinical trials of antidementia drugs: additions to the Alzheimer’s disease Assessment Scale that broaden its scope. The Alzheimer’s disease Cooperative Study. Alzheimer’s Dis Assoc Disord. 1997;11(Suppl 2):S13–S21.

29. Minimum Clinically Important Differences for Scales Used Both in Research and in the Clinic

Comparison or Reported MCIDs and Placebo-Controlled Outcomes for 10 Mg Donepezil, High-Dose Aducanumab, Solanezumab, and Donanemab.

		Alzheimer's disease population		Endpoint (weeks)		CDR-SB		MMSE		ADAS-Cog11		ADAS-Cog13		ADAS-Cog14
MCID		MCI		..		–0.98		1.26		..		..		..
MCID		Mild		..		–1.63		2.32		–3		..		..
MCID		Moderate-severe		..		–2.30		3.22		..		..		..
10 mg donepezil		Mild-severe		24–26		–0.53		1.05		–2.67*		..		..
High-dose aducanumab (EMERGE)		MCI-mild		78		–0.39		0.6		..		–1.40		..
High-dose aducanumab (ENGAGE)		MCI-mild		78		0.03		–0.1		..		–0.59		..
Solanezumab (EXPEDITION-1)		Mild-moderate		80		–0.3		0.7		–1.5		..		–1.7
Solanezumab (EXPEDITION-3)		Mild		80		–0.34		0.49		..		..		–0.80
Donanemab (TRAILBLAZER-ALZ)		MCI-mild		76		–0.36		0.64		..		–1.86		..

All the listed outcomes for ENGAGE and EXPEDITION 1–3 trials, and outcomes except for ADAS-Cog13 for TRAILBLAZER-ALZ, were not statistically significant (p>0.05). Precision of data are provided as previously published. •Data are a pooled mean across four randomised controlled trails that used ADAS-Cog11 and one that used ADAS-Cog13. MCID=minimal clinically important difference. MCI=mild cognitive impairment. CDR-SB=Clinical Dementia Rating-Sum of Boxes. MMSE=Mini-Mental state Examination. ADAS-Cog=Alzheimer's Disease-Cognitive Subscale.

REF: Liu KY, Schneider LS, Howard R. The need to show minimum clinically important differences in Alzheimer's disease trials. The Lancet Psychiatry 2021(8);11:1013–1016.

D. Clinical Management of AD and Similar Dementia

30. California Wellness Visit/Screening

REF: California Department of Public Health, Alzheimer Disease Resources for Health Professionals. www.cdph.ca.gov/programs/CCDPHP/DCDIC/CDCB/pages/AlzheimersDiseaseResources.aspx

31. California Guidelines for AD Management 2017

About the Guideline: Developed by an ad hoc workgroup. A collaborative effort of health-care providers, consumers, academicians, professional and volunteer organizations, and purchasers. A companion document explains areas of the guideline in detail. www.alzla.org.

Purpose

Provide core recommendations for management that are clear, measurable, practical, and based on evidence. Provision of expert opinion when research evidence is unavailable or inconsistent.

Assessment

1. Conduct and document assessments of:

   • Daily functions, including feeding, bathing, dressing, mobility, toileting, continence, ability to manage finances and medications

   • Cognitive status using a valid instrument (eg, MMSE)

   • Other medical conditions

   • Behavioral problems, psychotic symptoms, or depression

2. Reassess every 6 months or more frequently, as needed.

3. Identify the caregivers, assess family, and support systems.

4. Assess decision-making capacity and if a surrogate is needed

5. Assess the patient’s and family’s culture, values, decision-making process.

Treatment

Develop and implement a treatment plan with defined goals including:

• Cholinesterase inhibitors, if indicated to treat cognitive decline

• Referral to structured activities e.g., recreation, adult day care services

• Appropriate treatment of medical conditions

Treat behavioral problems and mood disorders using:

• Non-pharmacologic approaches, e.g., environmental modification, task simplification, appropriate activities.

• Referral to social service agencies or support organizations, e.g., Alzheimer’s Association’s Safe Return Program for wandering

• Medications, if indicated

Patient and Caregiver Education and Support

Discuss diagnosis, progression with patient and family in a manner consistent with their values, preferences, and patient’s abilities.

Refer to support organizations for materials, community resources, groups, legal, financial issues, respite care, future needs and options

Discuss advance directives, identify surrogates for medical and legal decision-making.

Reporting Requirements in California

Monitor for evidence of abuse and report abuse to Adult Protective Services or police.

Driving: Report diagnosis of AD according to law (Sections 2500 and 2572, Title 17, California Code of Regulations).

REF: 2017 Guidelines for Alzheimer’s Disease Management, www.cdph.ca.gov/programs/CCDPHP/DCDIC/CDCB/pages/AlzheimersDiseaseResources.aspx

32. Approach to Psychosis Symptoms in Dementia

Characterize the behavioral syndrome

Delirium

Psychosis (delirium and hallucinations)

Depression

Characterize symptoms to be treated

Excessive suspiciousness

Delusions

Manifest or apparent hallucinations

Aggression and agitation

Frightened

Bizarre ideation/verbalization

Medical evaluation to identify possible medical disorder

Intercurrent medical problems?

Concurrent medication?

If delusions/hallucinations due to medical disorder or medication, treat and monitor target symptoms (however, psychosis may not improve)

Evaluate psychiatrically, differential diagnosis

If psychiatric disorder, treat and monitor target symptoms

Assess for contributing factors

Concurrent medical illness, medication use Precipitating stress

Safety evaluation prior to prescribing

whole blood count, cardiac evaluation, hepatic screen

Empirical trials of symptomatic pharmacotherapy

Start low, but adjust dosage, dosage individualization

Assess target symptoms

Increase dose until benefit or maximum

If effective, continue for several weeks taper, and reevaluate

If ineffective, taper and reevaluate.

Nonpharmacologic management of psychosis

Ensure sensory input

Enhance and regulate environment

Ensure appropriate environmental cues

Optimize psychosocial milieu:

Maintain special interests, routines, social contacts, familiar objects, maintain religious identity, support, reassurance

Educate/support caregivers, simple, clear communication, distraction, redirection

33. Cohen-Mansfield Agitation Inventory (CMAI)-items

1. Pacing and aimless wandering – constantly walking back and forth, i

2. Inappropriate dressing or disrobing – putting on too many clothes, putting on clothing in a strange manner.

3. Spitting (including while feeding) – spitting onto floor, other people, etc

4. Cursing or verbal aggression – only using words; swearing, use of obscenity, profanity, unkind speech or criticism, verbal anger, combativeness.

5. Constant unwarranted request for attention or help – verbal or nonverbal unreasonable nagging, pleading, demanding

6. Repetitive sentences or questions – repeating the same sentence or question one right after the other, addressed to a particular person or to no one.

7. Hitting (including self) – physical abuse, striking others, pinching others, banging self/furniture.

8. Kicking – striking forcefully with feet at people or objects.

9. Grabbing onto people or things inappropriately – snatching, seizing roughly, taking firmly, or yanking.

10. Pushing – forcefully thrusting, shoving, moving putting pressure against another.

11. Throwing things – hurling objects, violently tossing objects up in air, tipping off surfaces, flinging, dumping food.

12. Making strange noises – including crying, weeping, moaning, weird laughter, grinding teeth, does not include intelligible words.

13. Screaming – shouting, piercing howl, making loud shrills.

14. Biting – chomping, gnashing, gnawing, either other people or self.

15. Scratching – clawing, scraping with fingernails either other people or self.

16. Trying to get to a different place – inappropriately entering or leaving a place.

17. Intentional falling – purposefully falling onto floor, include from wheelchair, chair, or bed.

18. Complaining – whining, complaining about self, somatic complaints, personal gripes or complaining about physical environment or other people.

19. Negativism – bad attitude, doesn’t like anything, nothing is right, does not include overt verbal anger or verbal aggression.

20. Eating or drinking inappropriate substances – putting into mouth and trying to swallow items that are inappropriate.

21. Hurting self or other – burning self or other, cutting self or other, touching self or other with harmful objects, etc.

22. Handling things inappropriately. – picking up things that don’t belong to them,

23. Hiding things – putting objects out of sight, under or behind something.

24. Hoarding things – putting many or inappropriate objects in purse, pockets, or drawers, keeping too many of an item.

25. Tearing things or destroying property – shredding, ripping, breaking, stomping on something.

26. Performing repetitious mannerisms – stereotypic movement, such as patting, tapping, rocking, fiddling or twiddling with something, rubbing self or object, sucking fingers, taking shoes on and off, picking at self, clothing, or objects, picking imaginary things out of air or off floor, manipulation of nearby objects in a repetitious manner, does not include repetitious words or vocalizations.

27. Making verbal sexual advances – sexual propositions, sexual innuendo, or “dirty” talk.

28. Making physical sexual advances or exposing genitals – touching a person in an inappropriate sexual way, rubbing genital area, inappropriate masturbation unwanted fondling or kissing.

29. General restlessness – fidgeting, always moving around in seat, getting up and sitting down inability to sit still.

REF: Cohen-Mansfield J. Instruction Manual For The Cohen-Mansfield Agitation Inventory (CMAI). Rockville, Maryland: The Research Institute of the Hebrew Home of Greater Washington; 1991.

34. Structural and Functional Brain Imaging

Imaging Technique		Description		Typical Findings for dementia/ Alzheimer disease
CT Scanning		X-ray procedure, contrast agent usually not needed; scan time is a few minutes, finer temporal resolution than MRI		Findings: normal for age; mild to moderate generalized atrophy; no space occupying lesions. Uses: Extent of atrophy, white-matter changes; infarction, tumor, subdural hemorrhage
MRI		Non-invasive; detects molecular activation from radio frequency waves; scan time is long, about 30 to 70 minutes depending on number of sequences. More sensitive to small lesions		Normal for age: mild to moderate generalized atrophy; hippocampal atrophy; small vessel changes; periventricular hyperintensities, mild leucoencephalopathy; very few microhemorrhages; no evidence of infarctions
		Used to surveil for vasogenic edema and hemorrhages (ARIA) associated with anti-amyloid antibody treatment.
MRI morphometrics		Careful measurements of brain volumes, or regions of interest such as whole brain, hippocampal, medial temporal cortex, and ventricle volumes		Uses: determination of ventricular size, medial temporal lobe size, decreased hippocampal volumes in AD, and further decrease with disease progression.
FDG-PET		Can assess metabolic activity such as glucose utilization, blood flow, receptor binding, neurotransmitter function.		Typical findings with AD: Biparietal hypometabolism. Clinical use: when an AD diagnosis is uncertain.
Amyloid- PET		18F-labeled radio isotope ligand binds to Aβ fibrils/plaques. Examples are; Florbetapir, Florbetaben, Flutemetamol		Measures of amyloid plaques are useful in the evaluation of patients

CT=Computed Tomography; MRI=magnetic resonance imaging; PET= positron emission tomography.

Indications for structural imaging: Headache, consideration of focal brain lesions, abrupt or rapid cognitive decline, dementia onset earlier than 65 years of age, seizures, gait impairments or motor signs, atypical features of AD.

Note on vascular dementia: Typical changes, white matter changes, multiple cortical infarctions, single cortical infarctions, multiple subcortical infarctions, single lacunar infarction.

E. Medications Used for Alzheimer’s Disease and Dementia

Psychotropic Medications Used with Elderly Patients with Dementia

Listings of medications are for reference only. No recommendations are implied. Many of the medications listed should not be considered first line choices in the elderly. Dosage ranges in the elderly may vary by indication. Consult the prescribing information of individual drugs for more detailed information.

35. FDA Approved and Marketed Cholinesterase Inhibitors and Memantine

Cholinesterase Inhibitors.

Drug		How Supplied		Initial Dosage		Maintenance Dosage		Comments
Donepezil (Aricept) Donepezil transdermal (Adlarity)		5, 10, 23 mg tablets and OD tablets		5 mg/d		5–10 mg/d or 23 mg/d		10 mg is more optimal dose; 5 mg also shows efficacy with fewer adverse events; 23 mg can be used after 3 months at 10 mg/d; not more effective than 10 mg
		Transdermal, 5 or 10 mg/d		5 mg/d weekly patch		5 – 10 mg/d weekly patch
Rivastigmine (Exelon)		1.5, 3, 4.5, 6 mg capsules; oral solution (2 mg/mL)		1.5 mg b.i.d		3, 4.5, or 6 mg b.i.d		Available as a liquid concentrate. Doses of 4.5 mg b.i.d. may be most optimal. May be taken with food. Higher doses of the patch are well-tolerated
		4.6, 9.5, and 13.3 mg transdermal patch		4.6 mg/24 hrs		4.6 mg to 13.3 mg/d
Galantamine (Razadyne)		4, 8, 12 mg capsules		4 mg b.i.d		8 or 12 mg b.i.d		8 mg b.i.d. is a modal optimal dose with fewer adverse effects; 16 mg/d ER is effective as well
		8, 16, 24 mg extended-release capsules		ER: 8 mg/d		ER: 16 or 24 mg/d

Memantine & Combination.

Drug		How Supplied		Initial Dosage		Maintenance Dosage		Comments
Memantine (Namenda)		5, 10 mg tablets; 2 mg/mL solution		5 mg bid		10 mg bid,		10 mg/d effective in nursing home patients.
Memantine- extended release (Namenda XR)		7, 14, 21, 28 mg ER caps		7 mg/d increased by 7 mg/d at weekly intervals		28 mg ER/d		Clinical effects of 28 mg/d like 10 mg/d but hasn’t been directly compared.
Memantine/donepezil combination (Namzaric)		7 memantine/10 donepezil, 14/10, 21/10, 28/10 mg		Must be on 10 mg/d donepezil: then 7/10 mg/d increased every week		28/10 mg/d	Bioequivalence of the combination, co-administration was the basis for marketing approval. Indicated for patients maintained on donepezil, 10 mg/d

For the cholinesterase inhibitors, initial dosages should be maintained for at least 2 weeks and preferably 4–6 weeks before increasing. Adverse events may occur with dosage titration.

The FDA approved indication for these drugs is: “for the treatment of mild to severe dementia of the Alzheimer’s type, and for memantine, for the treatment of moderate to severe dementia of the Alzheimer’s type. Rivastigmine is FDA approved for Parkinson’s disease dementia.

See prescribing information:

https://www.adlarityhcp.com/?utm_medium=ppc&utm_source=google&utm_content=Donepezil+Package+Insert+Prescribing+Info+Guide&utm_term=donepezil%20prescribing%20information&utm_id=PS221121152302

https://www.namzaric.com/?cid=ppc_ppd_ggl_namzaric_branded_prescribinginformation_donepezil_prescribing_information_exact_usnmz210099&gclid=Cj0KCQjwmN2iBhCrARIsAG_G2i6A-snKtJz6d3UG-Y9OD6Yrw7oXQp5lIfAwklfILP4XyXoBFGV99HQaAjr9EALw_wcB&gclsrc=aw.ds

https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=&ved=2ahUKEwisr8TYgeT-AhVIBTQIHZJsAIYQFnoECBEQAQ&url=https%3A%2F%2Fwww.accessdata.fda.gov%2Fdrugsatfda_docs%2Flabel%2F2012%2F020690s035%2C021720s008%2C022568s005lbl.pdf&usg=AOvVaw0-Gy3oSb8cmHKExxI2bx_g

https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=&cad=rja&uact=8&ved=2ahUKEwjGm5KSg-T-AhU0JX0KHTvCDJoQFnoECBAQAQ&url=https%3A%2F%2Fwww.accessdata.fda.gov%2Fdrugsatfda_docs%2Flabel%2F2013%2F021487s010s012s014%2C021627s008lbl.pdf&usg=AOvVaw3w30S-r__fw7qLHAD1xpi3

REF: Schneider LS. Antidementia Drugs. In: Schneider LS. Antidementia drugs. In, Kaplan & Sadock’s Comprehensive Textbook of Psychiatry, Tenth Edition. Edited by BJ Sadock, VA Sadock, P Ruiz. Lippincott, Williams and Wilkins, Wolters Kluwer Health, Philadelphia, 2017; p 4139–4151.

36. Adverse Effects of Cholinesterase Inhibitors

Adverse event estimates vary widely among the cholinesterase inhibitors. Relative adverse event rates among drugs are difficult to estimate. Cholinergic adverse effects generally occur early and are related to initiating or increasing medication. They tend to be mild and self-limited. Medications should be restarted at lowest doses after temporarily stopping.

Summary of Adverse Event Data in Placebo-Controlled, Randomized Clinical Trials. The Method of Obtaining Adverse Events and Their Reporting Vary Among Trials.

Drug		Adverse Events
Donepezil		Nausea, diarrhea, insomnia, vomiting, muscle cramps, fatigue, anorexia, dizziness, abdominal pain, myasthenia, rhinitis, weight loss, anxiety, syncope.
Rivastigmine		Nausea, vomiting, anorexia, dizziness, abdominal pain, diarrhea, malaise, fatigue, asthenia, headache, sweating, weight loss, somnolence, syncope. Rarely: severe vomiting with esophageal rupture.
Galantamine		Nausea, vomiting, diarrhea, anorexia, weight loss, abdominal pain, dizziness, tremor, syncope.

General precautions with cholinesterase inhibitors:

By increasing central and peripheral cholinergic stimulation cholinesterase inhibitors may:

Increase gastric acid secretion, increasing the risk for gastrointestinal bleeding especially in patients with ulcer disease or those taking anti-inflammatories

Vagal effects on the heart may cause bradycardia, especially in patients with sick sinus or other supraventricular conduction delay, leading to syncope, falls, and possible injury

May exacerbate obstructive pulmonary disease

Cause urinary outflow obstruction

May increase risk for seizures

May prolong the effects of succinylcholine-type muscle relaxants

37. Anti-Amyloid Antibodies

The FDA approved anti-amyloid-β antibodies are aducanumab (Aduhelm) and lecanemab (Leqembi). Donanemab is a similar antibody that is under review and appears likely to be approved by the end of 2023.

All are approved for MCI due to AD or mild dementia due to AD when the diagnosis is supported by a positive amyloid biomarker. Exact eligibility criteria vary from trial to trial.

Aducanumab and lecanemab received accelerated approval based on the surrogate endpoint of reduction in amyloid plaques in the brain as determined by amyloid PET. Lecanemab is likely to receive regular approval on July 6, 2023, based on improvement on the CDR-SB in an 1795-patient, 18-month trial.

The importance of amyloid plaques in the development of Alzheimer’s disease and the expression of sympotms is unclear, as is the relevance of plaque reduction.

Medicare and the Centers for Medicare and Medicaid Services (CMS) will reimburse for aducanumab only for patients enrolled in a qualifying clinical trial. Medicare is likely to reimburse for lecanemab based on future FDA regular approval.

Adverse effects of anti-amyloid antibodies – Cerebral edema in 12% to 35%, microhemorrhages in 10 to 19%, and superficial siderosis in up to 15% of patients treated with aducanumab, lecanemab, or donanemab.

Initial up titration of the doses may reduce incidences and severity of vasogenic edema and hemorrhage (ARIA-E and ARIA-H)

Most ARIA is asymptomatic. However, some occurances of ARIA are associated with headache, dizziness, unsteadiness, confusion, visual changes and, rarely, seizures. APOE ε4 carriers are more likely to develop ARIA.

About 1 to 2% of ARIA is serious, requiring hospitalization. Deaths have been associated with anti-amyloid antibodies.

MRIs – It is essential to surveil for ARIA by regular MRI scans to detect and manage ARIA as soon as possible. This often requires temporary or permanent discontinuation of the antibody For lecanemab, obtain an MRI prior to the 5th, 7th, and 14th infusions. If ARIA occurs then treatment recommendations are based on type, severity, and presence of symptoms. See prescribing information.

Anti-Amyloid Antibodies.

Antibody		How Supplied		Initial Dosage		Maintenance Dosage		Comments
Aducanumab (Aduhelm)		170 mg/ 1.7 mL vials, 300 mg/ 3mL vials		1 mg/kg IV q4 wk for 2 infusions; 3 mg/kg, 2 infusions’ 6 mg/kg, 2 infusions		10 mg/kg IV every 4 wks		Slow titration; (microhemorrhage, superficial siderosis, possible large hemorrhage). If ARIA occurs, treatment recommendations are based on type, severity, and presence of symptoms. MRI monitoring essential.
Lecanemab (Leqembi)		200 mg/2 mL and 500 mg/5 mL (100 mg/mL) vials		10 mg/kg IV		10 mg/kg IV every 2 wks		MRI monitoring essential. Obtain an MRI prior to 1st the 5th, 7th, and 14th infusions. High likelihood of vasogenic edema and/or hemorrhage. If ARIA occurs, treatment recommendations are based on type, severity, and presence of symptoms.
Donanemab		TBD						Currently under FDA review, decision expected end of 2023

REF: https://www.aduhelm.com/; https://www.leqembi.com/

F. Pharmacologic Treatment of Behavioral Symptoms

The main behavioral syndromes associated with dementia are depression, psychosis, agitation/aggression, and sleep disorders. Often clinicians, staff, and caregivers notice only agitation. It is useful to try to identify the predominant symptomatology (e.g., depression or delusions) prior to considering treatment. A search for possible antecedents to the behaviors should be made; environmental and behavioral interventions should be considered along with pharmacological interventions.

The following drugs have been variously advocated to treat a range of agitated behaviors in patients with dementia.

38. Antipsychotics

Antipsychotic		How Supplied		Geriatric Dosage Range		Comments
Atypical Antipsychotics
Risperidone (Risperdal)		Tablets: 0.25, 0.5, 1, 2, 3, 4 mg Oral Solution: 1 mg/mL		Starting: 0.5 mg/day Maintenance: 1–3 mg/day		In nursing home patients 1–2 mg/day appears efficacious with 2 mg associated with greater side effects. 3 mg/day may be needed for late onset psychoses.
Quetiapine (Seroquel)		Tablets: 25, 100, 200, 300 mg		Starting: 12.5–25 mg/day Maintenance: 50–100 mg/day		Data from open case series suggests a wide dosage range and need to individualize treatment.
Brexpiprazole (Rexulti)		Tablets: 0.25, 0.5, 1 mg, 2 mg, 3 mg, 4 mg		Starting: 0.5 mg/d Target dose: 2 mg/d Maximum: 3 mg/d		Indicated for adjuctive treatment for antidepressants for major depressive disorder, for schizophrenia, for agitation associated with dementia due to Alzheimer disease; not indicated as a p.r.n for agitation.
Pimavanserin (Nuplazid)		10 mg tablets 34 mg capsules		34 mg/day		Indicated for Parkinson disease psychosis and rejected by FDA for use in hallucinations and delusions associated with Alzheimer’s disease. Associated with QT interval prolongation, peripheral edema, confusional state; interacts with CYP3A4 inhibitors
Aripiprazole (Abilify)		Tablets: 2, 5, 10, 15 mg 1 ml oral 1 mg solution		2-15 mg/day		Not FDA approved for agitation or psychosis in dementia

TD=tardive dyskinesia; EPS=extrapyramidal symptoms; WBC=whole blood count; EKG=electrocardiogram.

39. Adverse Events Associated with Atypical Antipsychotics

Antipsychotics carry a black box warning and other warnings similar to the following for brexpiprazole (Rexulti):

WARNINGS AND PRECAUTIONS

Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in the drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group.

Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.

Cerebrovascular Adverse Reactions Including Stroke in Elderly Patients with Dementia-Related Psychosis

In placebo-controlled trials in elderly patients with dementia, patients randomized to risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and transient ischemic attack, including fatal stroke.

[NOTE: REXULTI is not approved for the treatment of patients with dementia-related psychosis without agitation associated with dementia due to Alzheimer’s disease.]

Other warnings and precautions involving antipsychotics

• Neuroleptic Malignant Syndrome (NMS)

• Tardive Dyskinesia

• Metabolic Changes

• Pathological Gambling and Other Compulsive Behaviors

• Leukopenia, Neutropenia, and Agranulocytosis

• Orthostatic Hypotension and Syncope

• Falls

• Seizures

• Body Temperature Dysregulation

• Dysphagia

• Potential for Cognitive and Motor Impairment

40. Antidepressants

Consultants generally prefer serotonin uptake inhibitors and avoid strongly anticholinergic TCAs for treating older and dementia patients. There is limited information on treating depression occurring after dementia. Dosages listed are based on the treatment of non-demented elderly. SSRIs are sometimes used off-label for treating agitation in dementia.

Medication		How Supplied		Dosage in Elderly for Depression		Hepatic Metabolism		Comments
Serotonin Uptake
Fluoxetine (Prozac, Serafin, others) Fluoxetine ER		Capsules: 10, 20, 40 mg Enteric coated tablet: 90 mg pulvule, Liquid oral solution: 20 mg/5 mL		Starting: 10 mg/day Maintenance: 10–40 mg/day		Strong inhibitor of CYP 2D6, long-acting metabolite		FDA-approved label for late-life depression. May raise levels of other drugs. Enteric coated tablet once weekly use not recommended for elderly.
Paroxetine (Paxil)		Tablets: 10, 20, 30, 40 mg, Oral suspension: 10 mg/5 mL		Starting: 10 mg/day Recommended dose: 10 mg/day		Strong inhibitor of CYP 2D6		Relatively anticholinergic: Increased plasma levels in the elderly
Sertraline (Zoloft)		Tablets: 25, 50, 100 mg Oral concentrate: 20 mg/mL		Starting: 25–50 mg/day Maintenance: 50–100 mg/day		Weak cytochrome inhibitor		50 mg appears as efficacious as higher doses
S-citalopram (Lexapro)		Tablets: 5, 10, 20 mg Oral solution: 1 mg/mL		Starting: 5 mg/day Maximum recommended dose: 10 mg/day		CYP 2C19		Increased risk of falling in the elderly, hyponatremia SIADH
Citalopram (Celexa)		Tablets: 20, 40 mg, oral solution: 10 mg/5 mL		Starting: 10 mg or less Maintenance: 20 mg/day Maximum recommended dose for patients > 60: 20 mg/day		CYP 2C19		Doses greater than 20 mg in elderly not recommended
Other Classes
Trazodone (Desyrel, others)		Tablets: 50, 100 mg		Start: 25 mg Maintenance: 50–150 mg/day in divided doses				Sometimes used to treat agitation and as a hypnotic for dementia patients
Mirtazapine, mirtazapine orally disintegrating tablets (Remeron, Remeron SolTab)		Tablets: 15, 30, 45 mg Orally disintegrating tablets: 15, 30, 45 mg		15–30 mg q. h. s		Extensively metabolized via CYP 2D6, CYP 1A2, CYP 3A3/4		Mixed noradrenergic, serotonergic through alpha-2 presynaptic antagonism, strong H-1 antagonist.
Bupropion, bupropion SR (Wellbutrin, Wellbutrin-SR, Zyban)		Tablets: 75, 100 mg SR Tablets: 100, 150, 174, 200 mg		100–200 mg/day		CYP 2D6		Noradrenegic and dopaminergic uptake in very few; seizures may occur at higher doses
Venlafaxine and venlafaxine-SR (Effexor, Effexor-SR)		Tablets: 25, 37.5, 50, 75, 100 mg XR capsules: 37.5, 75, 150 mg		75–150 mg/day		Weak cytochrome inhibitor		Mixed norepinephrine and serotonin effects.

REF: Schatzberg AF, DeBattista C. The Black Book of Psychotropic Dosing and Monitoring 2018. A supplement to Psychopharmacology Bulletin.

41. Antidepressant Adverse Events

The more typical adverse events of antidepressants are listed. Complete prescribing information should be consulted.

Antidepressant Class		Adverse Events		Comment
SSRIs		Most common: nausea, headache, nervousness or anxiety, insomnia, diarrhea, fatigue, sexual dysfunction, dry mouth, sweating Less common: weight gain, orthostatic hypotension, anticholinergic effects, inappropriate ADH secretion, rashes, bradycardia or tachycardia. Withdrawal effects: dizziness, nausea, paresthesias, tremor, palpitations, anxiety. (Withdraw medications gradually).		Generally mild side effects, nonsedating, not fatal in overdose. Interactions with many others drugs. Should not be used with MAOIs, including selegiline. In general, not cognitive impairing. Some SSRIs are associated with QT prolongation and Torsades de pointes
Tricyclic Antidepressants		Most common: anticholinergic effects, urinary retention, constipation, dry mouth, blurred vision, orthostatic hypotension, weight gain, sedation, increased heart rate. Less common: confusion or delirium, falls, increased intra-ocular pressure in patients with narrow-angle glaucoma, quinidine-like effects. Withdrawal symptoms (with abrupt discontinuation): sleep disturbance, nightmares, irritability, gastrointestinal symptoms.		TCAs have quinidine effects, prolonging repolarization, QT interval. Contraindicated in patients with cardiac arrhythmias or recent myocardial infarction. Nortriptyline is a relatively preferred TCA because of less orthostatic hypotension
Trazodone		Common: sedation, orthostatic hypotension, nausea, GI upset. Less common: ventricular arrhythmias, edema. Rare: priapism		Commonly used to treat agitation and as a hypnotic. Not fatal in overdose
Buproprion		Common: rash, agitation, anxiety, insomnia, anorexia, tremor, dry mouth headache, nausea, weight loss Uncommon: seizures in high doses, confusion.		Generally well tolerated. Should not be used with MAOIs, or in patients with seizures.
Venlafaxine, Venlafaxine-ER		Common: nausea, nervousness, somnolence, dizziness, headache, sweating, anorexia, insomnia. Less common: constipation, weight loss, hypertension, inappropriate ADH secretion		b.i.d or t.i.d schedule. Should not be used with MAOIs.
Mirtazapine		Common: somnolence, dizziness, increased appetite and weight gain, increased cholesterol, triglycerides. Uncommonly: elevated transaminases, agranulocytosis		Decreased clearance in the elderly; may be especially sedating. Should not be used with MAOIs.

REF: Schatzberg AF, DeBattista C. The Black Book of Psychotropic Dosing and Monitoring 2018. A supplement to Psychopharmacology Bulletin.

G. Resources

Administration on Aging

Washington, DC

https://acl.gov/about-acl/administration-aging

Alzheimer’s Association

225 N. Michigan Ave, Floor 17

Chicago, IL 60601

Tel: 800-272-3900

http://www.alz.org

Alzheimer’s Disease Education and Referral Center

Tel: 800-438-4380

http://www.nia.nih.gov/health/about-adear-center

Alzheimer’s Research Forum

www.alzforum.org

contact@alzforum.org

The American Academy of Family Physicians

www.aafp.org/home.html

American Association for Geriatric Psychiatry

Tel: (703)-884-9453

https://www.aagponline.org

info@aagponline.org

American Association of Retired Persons (AARP)

Washington, DC

Tel: 888-687-2277

http://www.aarp.org

American Bar Association Commission on Law and Aging

Washington, DC

Tel: 202-662-8690

www.americanbar.org/groups/law_aging

Family Caregiver Alliance

San Francisco, CA

Tel: 800-445-8106

http://www.caregiver.org

International Psychogeriatric Association

Milwaukee, WI

Tel: 414-918-9889

http://www.ipa-online.org

Medicare Hotline

Medicare contact center operations

Lawrence, KS

Tel: 1-800-MEDICARE (800-633-4227)

www.medicare.gov

Caregiver Action Network

Washington, DC

Tel: (855)-227-3640

http://www.caregiveraction.org

info@caregiveraction.org

Social Security Information

Tel: 800-772-1213

https://www.ssa.gov