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Alzheimer Disease
Address correspondence to
Dr Liana G. Apostolova,
Indiana Alzheimers Disease
Center, 355 W 16th St, Suite
Liana G. Apostolova, MD, MS, FAAN 4700, Indianapolis, IN 46202,
lapostol@iu.edu.
Relationship Disclosure:
Dr Apostolova serves as senior
ABSTRACT associate editor of Alzheimers
Purpose of Review: This article discusses the recent advances in the diagnosis and & Dementia: Diagnosis,
Assessment & Disease
treatment of Alzheimer disease (AD). Monitoring and receives
Recent Findings: In recent years, significant advances have been made in the fields personal compensation for
of genetics, neuroimaging, clinical diagnosis, and staging of AD. One of the most serving on the speakers bureau
of Eli Lilly and Company and
important recent advances in AD is our ability to visualize amyloid pathology in the GE Healthcare Worldwide.
living human brain. The newly revised criteria for diagnosis of AD dementia embrace Dr Apostolova receives grant
the use for biomarkers as supportive evidence for the underlying pathology. Guide- support from the Jim Easton
Consortium for Alzheimers
lines for the responsible use of amyloid positron emission tomography (PET) have Drug Discovery and Biomarker
been developed, and the clinical and economic implications of amyloid PET imaging Development and the National
are actively being explored. Institute on Aging.
Unlabeled Use of
Summary: Our improved understanding of the clinical onset, progression, neuroim- Products/Investigational
aging, pathologic features, genetics, and other risk factors for AD impacts the Use Disclosure:
approaches to clinical diagnosis and future therapeutic interventions. Dr Apostolova discusses the
unlabeled/investigational use
of antidepressant and
Continuum (Minneap Minn) 2016;22(2):419434. antipsychotic medications for
behavioral management as
well as antidementia therapy
in mild cognitive impairment.
INTRODUCTION United States.1 Although there is in- * 2016 American Academy
of Neurology.
Alzheimer disease (AD) is a neuro- creasing evidence that AD pathology
degenerative disorder featuring grad- starts depositing in the brain in midlife,
ually progressive cognitive and the first clinical symptoms usually occur
functional deficits as well as behavioral after the age of 65.2,3
changes and is associated with accu- AD prevalence is rapidly increasing
mulation of amyloid and tau deposi- in large part because the proportion
tions in the brain. Cognitive symptoms of people 65 years and older is grow-
of AD most commonly include deficits ing faster than any other age sector
in short-term memory, executive and of the population worldwide. Between
visuospatial dysfunction, and praxis. 1997 and 2050, the elderly popula-
Several rarer variants of AD with relative tion, defined as subjects 65 years of
preservation of memory have been age and older, will increase from 63 to
recognized. Clinical assessment, includ- 137 million in the Americas, from 18
ing cognitive testing, remains critical to 38 million in Africa, from 113 to
for the diagnosis and staging of AD, 170 million in Europe, and from 172
although recent advances in amyloid to 435 million in Asia.4 One nationally
imaging and genetics show great representative US data set, the Aging,
promise for facilitating early and Demographics, and Memory Study
presymptomatic diagnosis of AD and (ADAMS), estimated that in the
its discrimination from other neuro- United States, 14% of people 71 years
degenerative disorders. and older have dementia. AD demen-
tia accounted for 70% of the dementia
EPIDEMIOLOGY cases across the age spectrum in this
AD is the most common neurode- cohort.5 In a subsequent publication,
generative disorder and the sixth the ADAMS investigators reported that
most common cause of death in the an additional 22% (or 5.4 million
KEY POINTS
h Alzheimer disease Americans) 71 years or older have cog- to the clinical diagnosis and staging of
prevalence is nitive impairment in the absence of patients with AD.
rapidly increasing. overt dementia.6
Although age is the greatest risk Cognitive Decline
h Although age is the
greatest risk factor for
factor for the development of AD, in Memory impairment is the most per-
the development of and of itself, old age is not sufficient vasive feature of AD. Although non-
Alzheimer disease, old to cause AD. Other major risk factors memory cognitive deficits (eg, aphasia,
age is not sufficient, in include the presence of one or more executive dysfunction, apathy, or per-
and of itself, to cause apolipoprotein gene E4 alleles (APOE4), sonality change) can manifest early and
Alzheimer disease. low educational and occupational at- even be the presenting feature, in
h Memory impairment tainment, family history of AD, moder- general, memory decline is considered
is the most pervasive ate or severe traumatic brain injuries, the leading symptom. Early in the
feature of and cardiovascular risk factors. disease course, recent episodic mem-
Alzheimer disease. Gender modulates the prevalence ories are most affected, while memo-
of AD. Nearly two-thirds of all patients ries from the distant past are usually
diagnosed with AD are women.7 Ac- spared. As the disease progresses, all
cording to ADAMS, 16% of women, but aspects of episodic memory become
only 11% of men, live with dementia affected. In contrast to episodic mem-
after 71 years of age.5 While it is true ory, working memory and semantic
that women live longer than men, this memory are preserved until later in the
alone does not explain the discrepancy. disease course.
Genetic, hormonal, and societal factors Language disturbance, especially
(eg, lower education and occupational word-finding difficulties, is a com-
attainment among women currently in mon early symptom in AD but is
their 70s and 80s compared to men) generally mild. Subtle decline in visuo-
likely play a significant role as well. spatial skills likewise occurs in the
Racial disparities in AD prevalence mild dementia stages and progresses
have also been reported. Older African throughout the course of the disease.
Americans and Hispanics have a higher Executive dysfunction, on the other
prevalence of AD relative to older hand, begins even earlierVin the
Caucasians in part because of lower predementia stagesVand, similar to all
education levels and higher preva- other cognitive domains, worsens over
lence of cardiovascular comorbid- the disease course.
ities,8Y10 although other genetic and
societal factors likely play a role as well. Neuropsychiatric Symptoms
Patients with AD exhibit a variety of
CLINICAL PRESENTATION neuropsychiatric symptoms. Behavioral
Recognition of the clinical features and symptoms, once manifest, tend to
presenting symptoms of AD remains worsen over the course of the disease;
essential for the diagnosis and manage- however, these symptoms often fluctu-
ment of patients, even as biomarker ate and are not consistently present at
tests such as amyloid positron emis- each visit. Attention to these treatable
sion tomography (PET) imaging that components of excess morbidity is im-
detect the underlying neuropathology portant as they have a profound im-
of AD are increasingly available for pact on caregiver burden and are the
patient care. Ascertainment of symp- leading cause of institutionalization.11
toms of cognitive decline, behavioral The earliest AD-associated neuro-
symptoms, functional decline, and cog- psychiatric symptoms are apathy, anx-
nitive testing remain the cornerstones iety, and irritability. The latter two
420 www.ContinuumJournal.com April 2016
KEY POINTS
h The Diagnostic and interfere with activities of daily living ciation (AA).14Y16 Similarly to the DSM-5
Statistical Manual of and is not caused by delirium or criteria, the NIA-AA criteria for de-
Mental Disorders, Fifth another neurologic, medical, or psy- mentia of any cause no longer explicitly
Edition criteria no chiatric disorder. Patients with mild require memory impairment to be
longer require the neurocognitive impairment have present, but rather, for the diagnosis
presence of memory milder cognitive decline that does of dementia to be established, call for
impairment for the not yet deprive them of the ability to documentation of impairment in two
diagnosis of lead an independent lifestyle and cognitive domains or one cognitive
neurodegenerative perform complex daily activities such and one behavioral domain in addition
dementia to as managing finances or driving a car. to significant decline in day-to-day
be established.
It should be noted that the DSM-5 functioning (Table 3-2). For the first
h The National Institute introduces a major change in terms of time, the NIA-AA criteria for probable
on Aging and diagnostic criteria for cognitive disor- Alzheimer dementia as a subtype of
Alzheimers Association ders. The criteria no longer require the dementia recognized the diagnostic
criteria for probable
presence of memory impairment for utility of disease biomarkers that
Alzheimer dementia
the diagnosis of neurodegenerative de- have proven sensitivity, specificity,
recognize the
diagnostic utility of
mentia to be established, as was the and pathologic validity (Table 3-2).
disease biomarkers. case in all previous DSM editions. At the present time, two types of
DSM-5 thus recognizes that for some biomarkers meet these criteria. Two
dementing disorders such as vascular neurodegenerative biomarkersV
and frontotemporal dementia, for in- mesial temporal lobe atrophy on
stance, memory impairment is not an structural imaging (Figure 3-1) and
early symptom and may never mani- posterior predominant hypometabo-
fest (Table 3-1). lism with involvement of the posterior
Another set of diagnostic criteria cingulate gyrus on fluorodeoxyglu-
spanning all three major stages of AD cose positron emission tomography
(ie, the preclinical, the prodromal, and (FDG-PET) (Figure 3-2)Vhave already
the overt dementia stages) were recently received wide acceptance. However,
developed by the National Institute on neither of these are exclusively seen
Aging (NIA) and the Alzheimers Asso- in AD dementia. Hippocampal atrophy
b Dementia Syndrome
Objective cognitive or behavioral impairment in at least two of the following
Memory
Reasoning and handling complex tasks
Visuospatial abilities
Language functions
Personality, behavior, or comportment
Decline from previous level of functioning
Functional impairment
b Probable Alzheimer Disease Dementia
Criteria for dementia are met
Insidious onset
Gradual progression
Initial symptoms
Amnestic
Nonamnestic (language, executive)
No other neurologic, psychiatric, or general medical disorders of severity
that can interfere with cognition
Positive biomarkers (eg, CSF amyloid-" [A"]/tau, amyloid positron emission
tomography [PET], hippocampal atrophy on MRI) increase diagnostic certainty
CSF = cerebrospinal fluid; MRI = magnetic resonance imaging.
a
Data from McKhann GM, et al, Alzheimer Dement.15 www.alzheimersanddementia.com/
article/S1552-5260(11)00101-4/fulltext.
occurs in normal aging,17,18 and both played an important role in the workup
hippocampal atrophy and FDG-PET of patients with dementia. The American
abnormalities occur in other demen- Academy of Neurology (AAN) guidelines
ting conditions.19,20 On the other hand, for the diagnostic evaluation of de-
amyloid proteinYbased biomarkers such mentia require physicians to obtain
as a low CSF level of "-amyloid or a a structural imaging scan in every pa-
positive amyloid PET scan have been tient with objective cognitive decline.23
shown to be highly sensitive and spe- This recommendation follows the re-
cific in their ability to detect amyloid view of the evidence presented in a
pathology in the brain.21,22 Class II study showing that 5% of all
patients with cognitive complaints har-
Current Role of Biomarkers in bored a causative nondegenerative
Alzheimer Disease Diagnosis lesion, such as a slow-growing brain
In addition to supporting clinical diag- neoplasm (most commonly of the fron-
nosis, biomarkers have historically tal lobes), subdural hematoma, or
FIGURE 3-2 Temporal (thick arrows) and parietal (thin arrows) hypometabolism on
fluorodeoxyglucose positron emission tomography (FDG-PET) is often seen in
patients with Alzheimer disease dementia.
FIGURE 3-3 Cortico-subcortical microhemorrhages are often found on gradient echo MRI
sequences and are suggestive of the presence of vascular amyloidosis.
KEY POINTS
h Amyloid positron of age). At present, the impact of in the brain tissue begins early in the
emission tomography amyloid PET imaging on clinical prac- disease course and is associated with
scans are only tice and health outcomes is not yet decline in CSF A".35 CSF total and
appropriate if the scan known. Given the lack of disease- phosphorylated tau levels rise in AD
results are expected to modifying drugs for AD, the rationale secondary to neurodegeneration of
alter clinical management. for the use of amyloid PET imaging in tau-containing neurons.36Y39 CSF tau
h The APOE4 genotype clinical practice includes: (1) helping changes occur later in the disease
should be considered a the practitioner to select appropriate course and are associated with cognitive
risk factor that is neither treatments and avoid unnecessary in- decline.40Y43 CSF A" and tau mea-
sufficient nor necessary terventions and to aid in accurate surements are covered by most insur-
for Alzheimer disease diagnosis, (2) improving diagnostic ac- ance companies in the United States
development. curacy, (3) advising patients and fami- as part of the workup for AD. Despite
lies on the clinical course and prognosis, this, they are not routinely used due
and (4) educating patients and families to relative invasiveness of the lumbar
on community services and resources puncture procedure and the risk for
for medical, financial, and legal plan- side effects such as back discomfort,
ing.34 Case 3-1 and Case 3-2 describe headache, and, in rare cases, iatrogenic
exemplary scenarios. meningitis. However, CSF A" and tau
The Appropriate Use Criteria also testing can be quite useful in diag-
define the inappropriate uses of amy- nostically challenging cases as well as
loid PET imaging. Patients who should in those with early disease onset or an
not be scanned include those lacking unusual clinical course. CSF A" level is
objective cognitive decline. Scanning highly correlated with the presence
solely on the basis of family history or of amyloid deposition in the cor-
APOE4 status was likewise determined tex. 44 Thus, CSF A" levels can be
to be inappropriate. Furthermore, amy- used in lieu of an amyloid PET scan
loid PET scans cannot be used for de- as a reliable proxy measure of the
termining dementia severity, as this is presence of brain amyloidosis.
not feasible with this technology.
Another important suggestion of the GENETICS OF ALZHEIMER
Appropriate Use Criteria for amyloid PET DISEASE
imaging is the recommendation that Although the APOE4 gene variant is
the responsibility for determining pa- the most established genetic risk fac-
tients eligibility (ie, appropriateness for tor for sporadic AD, screening for
imaging) should lie with medical pro- APOE4 is not recommended on a rou-
fessionals with significant expertise in tine basis. While it has been estimated
evaluating and treating patients with that one copy of this genetic variant
dementia (defined as 25% or greater increases the odds for developing
proportion of clinical practice devoted AD threefold and two copies increase
to cognitive disorders of the elderly).33 the odds 15-fold,45 a large multicenter
Last but not least, the committee rec- study demonstrated that the presence
ommended that amyloid PET scans of the APOE4 allele increased the
are only appropriate if the scan results positive predictive value of diagnos-
are expected to alter clinical manage- ing AD by only 4% over diagnoses made
ment (see Case 3-1 and Case 3-2 on clinical grounds alone (from 90%
for examples). to 94%).46 The APOE4 genotype should
CSF amyloid-" (A") and tau protein be considered a risk factor that is
levels are the most established AD fluid neither sufficient nor necessary for dis-
biomarkers. Pathologic A" deposition ease development.
426 www.ContinuumJournal.com April 2016
KEY POINT
h The search for other
gene variants that may
Case 3-2
A 59-year-old woman with 12 years of education presented to the memory
affect risk of Alzheimer
disorder clinic because of memory difficulties for the past 1 to 2 years. Her
disease is ongoing.
husband reported that for the past few months they had the same conversation
multiple times a day. She misplaced items more often. Her recall of distant
memories and visuospatial function were preserved. She was also becoming
more distractible. She managed their household without a problem and
safely operated a motor vehicle. On a few occurrences, she reportedly paid
some bills twice while being on time with the rest. She was still able to
manage her appointments and medications with occasional reminders.
She had become quieter in social situations and more reluctant to go out.
She was no longer interested in volunteering at their church.
On bedside cognitive testing the patient scored 22 out of 30 on the
Mini-Mental State Examination (MMSE). She showed relatively preserved
encoding, impaired delayed recall, and endorsed multiple false-positive
items on recognition testing. Her language and visuospatial skills were
preserved. She made a few errors on frontal executive tasks. On formal
neuropsychological testing, additional deficits in category fluency and
nonverbal memory were noted.
The patients MRI revealed mild global atrophy with medial temporal lobe
predominance and hippocampal atrophy. An amyloid PET scan was performed
and showed diffusely increased tracer uptake throughout the cortical cerebral
gray matter with loss of the normal gray-white matter contrast consistent with
the presence of moderate to severe amyloid pathology. A diagnosis of mild
neurocognitive disorder (ie, mild cognitive impairment) due to early-onset AD
was made. The patient was started on donepezil.
Comment. This patient presented with early-onset prodromal AD. The
patient met the Diagnostic and Statistical Manual of Mental Disorders, Fifth
Edition (DSM-5)13 criteria for mild neurocognitive disorder (ie, mild cognitive
impairment) and met the Appropriate Use Criteria for amyloid PET imaging
by virtue of early disease onset. The amyloid PET scan was considered
beneficial in assisting the physicians therapeutic decisions and counseling
of the patient.
KEY POINTS
h Memantine is US Food one agent causes intolerable side ef- support or refute use of memantine in
and Drug Administration fects, another AChEI should be tried. moderate to severe AD.59
approved for the
moderate to Glutamate Receptor Medications for Behavioral
severe stages of Modulators Symptoms
Alzheimer disease. Memantine is a low to moderate affin- The first line of treatment for behav-
h The first line of ity NMDA receptor antagonist that is ioral symptoms of AD are nonpharma-
treatment for behavioral used as an add-on to ongoing AChEI cologic techniques. A quiet, familiar
and neuropsychiatric therapy. A recent meta-analysis of nine environment with labels on doors and
symptoms of Alzheimer trials with a combined sample size of sufficient lighting in all rooms is im-
disease are
2433 revealed that memantine had a portant to reduce disorientation. Ag-
nonpharmacologic
modalities. beneficial effect on cognition, behavior, gressive behavior should always be
activities of daily living, and global addressed with positive and clear
function.52 Memantine is approved by language to reassure and distract
the US Food and Drug Administration the patient.
(FDA) for the moderate to severe AD Depressive symptoms are treated
stages (Mini-Mental State Examination with selective serotonin reuptake in-
[MMSE] score of 5 to 15) in the United hibitors (SSRIs) due to their low pro-
States. The main side effects of con- pensity to cause anticholinergic effects.
fusion and dizziness occur only rarely. SSRIs may also ease anxiety, irritability,
The timing of initiation of cholines- or other nonspecific symptoms that
terase inhibitors and memantine ther- may accompany depression. The SSRI
apy is an area of some controversy.53
citalopram may be useful for agitation.
Cholinesterase inhibitors and meman-
Agitation or disruptive behavior
tine are frequently prescribed off-label
may require a neuroleptic for optimal
for mild cognitive impairment in the
therapeutic response. The newer
United States.54 Recent meta-analyses
atypical antipsychotic medications
have not demonstrated a benefit of
cholinesterase inhibitors in mild cogni- (quetiapine, risperidone, olanzapine)
tive impairment, although a benefit for are often used in low doses with
subgroups of patients remain unde- careful titration. Typical and atypical
termined.55,56 A separate meta-analysis antipsychotic agents, however, carry a
suggests there is not a benefit of black box warning label due to an
memantine in patients with mild AD.57 association with increased cardiovas-
While the 2001 AAN practice parame- cular morbidity and mortality (higher
ter for treatment of dementia is cur- for the typical compared to atypical
rently under revision, 2011 guidelines antipsychotics) and cerebrovascular
from the National Institute for Health adverse events in the elderly with
and Clinical Excellence now recommend dementia-related psychosis.60Y62 In
memantine as an option for managing addition, these medications have ad-
moderate AD for people who cannot ditional adverse effects: anticholiner-
take AChEIs and as an option for man- gic adverse events and orthostatic
aging severe AD.58 In contrast, Canadian and metabolic disturbances. Tradi-
Consensus guidelines on dementia from tional neuroleptics are more likely to
2013 state that, while combination ther- produce extrapyramidal symptoms,
apy of a cholinesterase inhibitor and which may worsen cognitive function.
memantine is rational and appears to All antipsychotics, typical as well as
be safe, there is insufficient evidence to atypical, when used in older adults with
430 www.ContinuumJournal.com April 2016
11. Kaufer DI, Cummings JL, Christine D, et al. 21. Faull M, Ching SY, Jarmolowicz AI, et al.
Assessing the impact of neuropsychiatric Comparison of two methods for the analysis
symptoms in Alzheimers disease: the of CSF A$ and tau in the diagnosis of
Neuropsychiatric Inventory Caregiver Alzheimers disease. Am J Neurodegener Dis
Distress Scale. J Am Geriatr Soc 1998;46(2): 2014;3(3):143Y151.
210Y215. doi:10.1111/j.1532-5415.
22. Beach TG, Schneider JA, Sue LI, et al. Theoretical
1998.tb02542.x.
impact of Florbetapir (18F) amyloid imaging on
12. Johnson JK, Head E, Kim R, et al. Clinical and diagnosis of alzheimer dementia and detection
pathological evidence for a frontal variant of of preclinical cortical amyloid. J Neuropathol
Alzheimer disease. Arch Neurol 1999;56(10): Exp Neurol 2014;73(10):948Y953. doi:10.1097/
1233Y1239. doi:10.1001/archneur.56.10.1233. NEN.0000000000000114.
13. American Psychiatric Association. Diagnostic 23. Knopman DS, DeKosky ST, Cummings JL, et al.
and statistical manual of mental disorders, Practice parameter: diagnosis of dementia
fifth edition. Washington, DC: American (an evidence-based review). Report of the
Psychiatric Publishing, 2013. Quality Standards Subcommittee of the American
14. Albert MS, DeKosky ST, Dickson D, et al. The Academy of Neurology. Neurology 2001;56(9):
diagnosis of mild cognitive impairment due 1143Y1153. doi:10.1212/WNL.56.9.1143.
to Alzheimers disease: recommendations from 24. Chui H, Zhang Q. Evaluation of dementia: a
the National Institute on Aging-Alzheimers systematic study of the usefulness of the
Association workgroups on diagnostic American Academy of Neurologys practice
guidelines for Alzheimers disease. Alzheimers parameters. Neurology 1997;49(4):925Y935.
Dement 2011;7(3):270Y279. doi:10.1016/ doi:10.1212/WNL.49.4.925.
j.jalz.2011.03.008.
25. Apostolova LG, Dutton RA, Dinov ID, et al.
15. McKhann GM, Knopman DS, Chertkow H, Conversion of mild cognitive impairment to
et al. The diagnosis of dementia due to Alzheimer disease predicted by hippocampal
Alzheimers disease: recommendations from atrophy maps. Arch Neurol 2006;63(5):
the National Institute on Aging-Alzheimers 693Y699. doi:10.1001/archneur.63.5.693.
Association workgroups on diagnostic
26. Apostolova LG, Thompson PM, Green AE,
guidelines for Alzheimers disease.
et al. 3D comparison of low, intermediate,
Alzheimers Dement 2011;7(3):263Y269.
and advanced hippocampal atrophy in MCI.
doi:10.1016/j.jalz.2011.03.005.
Hum Brain Mapp 2010;31(5):786Y797.
16. Sperling RA, Aisen PS, Beckett LA, et al. doi:10.1002/hbm.20905.
Toward defining the preclinical stages of
Alzheimers disease: recommendations from 27. Jack CR Jr, Shiung MM, Gunter JL, et al.
the National Institute on Aging-Alzheimers Comparison of different MRI brain
Association workgroups on diagnostic atrophy rate measures with clinical
guidelines for Alzheimers disease. disease progression in AD. Neurology
Alzheimers Dement 2011;7(3):280Y292. 2004;62(2):591Y600. doi:10.1212/
doi:10.1016/j.jalz.2011.03.003. 01.WNL.0000110315.26026.EF.
17. Apostolova LG, Green AE, Babakchanian S, 28. Apostolova LG, Steiner CA, Akopyan GG,
et al. Hippocampal atrophy and ventricular et al. Three-dimensional gray matter atrophy
enlargement in normal aging, mild cognitive mapping in mild cognitive impairment and
impairment (MCI), and Alzheimer disease. mild Alzheimer disease. Arch Neurol 2007;64(10):
Alzheimer Dis Assoc Disord 2012;26(1):17Y27. 1489Y1495. doi:10.1001/archneur.64.10.1489.
doi:10.1097/WAD.0b013e3182163b62. 29. Thompson PM, Hayashi KM, de Zubicaray G,
18. De Leon MJ, George AE, Golomb J, et al. et al. Dynamics of gray matter loss in
Frequency of hippocampal formation atrophy Alzheimers disease. J Neurosci 2003;23(3):
in normal aging and Alzheimers disease. 994Y1005.
Neurobiol Aging 1997;18(1):1Y11. doi:10.1016/
30. Kilroy E, Apostolova L, Liu C, et al. Reliability
S0197-4580(96)00213-8.
of two-dimensional and three-dimensional
19. Cerami C, Della Rosa PA, Magnani G, et al. pseudo-continuous arterial spin labeling
Brain metabolic maps in Mild Cognitive perfusion MRI in elderly populations:
Impairment predict heterogeneity of comparison with 15O-water positron emission
progression to dementia. Neuroimage Clin tomography. J Magn Reson Imaging
2014;7:187Y194. doi:10.1016/j.nicl.2014.12.004. 2014;39(4):931Y939. doi:10.1002/jmri.24246.
20. Zarow C, Weiner MW, Ellis WG, Chui HC. 31. Silverman DH. Brain 18F-FDG PET in the
Prevalence, laterality, and comorbidity of diagnosis of neurodegenerative dementias:
hippocampal sclerosis in an autopsy sample. comparison with perfusion SPECT and with
Brain Behav 2012;2(4):435Y442. doi:10.1002/ clinical evaluations lacking nuclear imaging.
brb3.66. J Nucl Med 2004;45(4):594Y607.
51. Doody RS, Stevens JC, Beck C, et al. Practice technology appraisal guidance (TA217).
parameter: management of dementia www.nice.org.uk/guidance/ta217. Updated
(an evidence-based review). Report of the March 2011. Accessed February 5, 2016.
Quality Standards Subcommittee of the
American Academy of Neurology. 59. Gauthier S, Patterson C, Chertkow H,
Neurology 2001;56(9):1154Y1166. et al. Recommendations of the 4th Canadian
doi:10.1212/WNL.56.9.1154. consensus conference on the diagnosis
and treatment of dementia (CCCDTD4). Can
52. Matsunaga S, Kishi T, Iwata N. Memantine Geriatr J 2012;15(4):120Y126. doi:10.
monotherapy for Alzheimers disease: a 5770/cgj.15.49.
systematic review and meta-analysis. PLoS
One 2015;10(4):e0123289. doi:10.1371/ 60. Schneider LS, Tariot PN, Dagerman KS, et al.
journal.pone.0123289. CATIE-AD Study Group. Effectiveness of
53. Ehret MJ, Chamberlin KW. Current practices atypical antipsychotic drugs in patients with
in the treatment of Alzheimer disease: Alzheimers disease. N Engl J Med
Where is the evidence after the phase III 2006;355(15):1525Y1538.
trials? Clin Ther 2015;37(8):1604Y1616.
61. Steinberg M, Lyketsos CG. Atypical
doi:10.1016/j.clinthera.2015.05.510.
antipsychotic use in patients with dementia:
54. Roberts JS, Karlawish JH, Uhlmann WR, et al. Managing safety concerns. Am J Psychiatry
Mild cognitive impairment in clinical care: a 2012;169(9):900Y906. doi:10.1176/
survey of American Academy of Neurology appi.ajp.2012.12030342.
members. Neurology 2010;75(5):425Y431.
doi:10.1212/WNL.0b013e3181eb5872. 62. Schneeweiss S, Setoguchi S, Brookhart A,
et al. Risk of death associated with the
55. Kelley BJ. Treatment of mild cognitive
use of conventional versus atypical
impairment. Curr Treat Options Neurol 2015;
antipsychotic drugs among elderly patients.
17(9):372. doi: 10.1007/s11940-015-0372-3.
CMAJ 2007;176(5):627Y632. doi:10.
56. Russ TC, Morling JR. Cholinesterase inhibitors 1503/cmaj.061250.
for mild cognitive impairment. Cochrane
Database Syst Rev 2012;9:CD009132. 63. Masliah E, Hansen L, Adame A, et al.
doi:10.1002/14651858.CD009132.pub2. Abeta vaccination effects on plaque
57. Schneider LS, Dagerman KS, Higgins JP, pathology in the absence of encephalitis
McShane R. Lack of evidence for the efficacy in Alzheimer disease. Neurology
of memantine in mild Alzheimer disease. 2005;64(1):129Y131. doi:10.1212/01.WNL.
Arch Neurol 2011;68(8):991Y998. 0000148590.39911.DF.
doi:10.1001/archneurol.2011.60. 64. Nicoll JA, Wilkinson D, Holmes C, et al.
58. National Institute for Health and Clinical Neuropathology of human Alzheimer
Excellence. Donepezil, galantamine, disease after immunization with amyloid-beta
rivastigmine, and memantine for the peptide: a case report. Nat Med
treatment of Alzheimers disease. NICE 2003;9(4):448Y452. doi:10.1038/nm840.