Dementia

Questions

1. Which of the following choices reflects the most common presentations suggesting a diagnosis of mild cognitive impairment (MCI)?

A. A 75-year-old woman who presents with cognitive decline over 12 months found to have normal performance on standardized testing and is able to complete her functional activities of daily living

B. A 75-year-old woman who presents with cognitive decline over 12 months found to have reduced performance on standardized testing in memory only, although is able to complete her functional activities of daily living

C. A 75-year-old woman who presents with cognitive decline over 12 months found to have reduced performance on standardized testing in multiple cognitive domains including executive function, visuospatial processing, and memory, but she remains independently able to accomplish her instrumental and basic functional activities of daily living

D. A 75-year-old woman who presents with cognitive decline over 12 months found to have reduced performance on standardized testing in multiple cognitive domains including executive function and visuospatial processing, which has impacted her ability to complete her instrumental activities of daily living

E. Choices B and C

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1. Answer E. (MN-50) MCI is best defined as identification of objective evidence of cognitive dysfunction across one or multiple domains as may be determined on neuropsychological testing, along with the preservation of ability to complete essential activities of daily living (Table 6.1.1). Many individuals who meet neuropsychological criteria for MCI are unaware of their impairment, but most will report some sense of declining cognition, most often memory. There are four subtypes of MCI, amnestic single domain (memory alone), amnestic multidomain (memory plus one other domain, ie, language, executive functioning, etc.), nonamnestic single domain, and nonamnestic multidomain (Table 6.1.2). Amnestic single and multidomain are the most common subtypes of MCI, often reflecting the earliest stages of incipient Alzheimer disease, and these are best exemplified in choices B and C. Instrumental activities of daily living reflect activities that typically define adult independence such as the ability to manage one’s finances, appointments, meal preparation, and medications without assistance or errors. In contrast, basic activities of daily living reflect more essential daily routines including dressing, toileting, eating, and related bathroom hygiene; basic ADLs are typically unaffected in early dementia but become more apparently affected in later stages.

TABLE 6.1.1 Broad Definition of Mild Cognitive Impairment

Core Criteria	Examples
Subjective (self-reported or informant-reported) cognitive complaint	Forgetfulness about events, appointments, or items of information Forgetfulness regarding date or time Misplacing or “losing” objects Word-finding problems, such as “forgetting words” Spatial disorientation, such as becoming lost
Objective evidence of cognitive dysfunction on testing	Decreased performance on standardized testing of cognitive domains, including memory, language, visuospatial, attentional, or executive functions or skills^a
Preservation of functional activities	Essentially normal function in living activities^b
Absence of diagnosis of dementia	Diagnosis of dementia is exclusionary^c
^aVarious cutoffs have been used for the objective tests, including 1.5 standard deviations below age- and sex-adjusted norms on one or more tests within a particular cognitive domain.
^bFunctional preservation is the most problematic of the three core inclusionary features because function may depend on living situation and demands.
^cDiagnoses of mild cognitive impairment and dementia are mutually exclusionary, but diagnosis of dementia is not independent from the criteria in the table.
Reprinted with permission from Louis ED, Mayer SA, Noble JM, eds. Merritt’s Neurology. 14th ed. Wolters Kluwer; 2022.

TABLE 6.1.2 Classification of Types of Mild Cognitive Impairment (MCI)^a

MCI Type	Domains Affected	Possible Prodromal Disease
Amnestic single domain	Memory alone	Alzheimer disease
Amnestic multidomain	Memory PLUS one or more other domain: language, attention, executive, or visuospatial dysfunction	Alzheimer disease, dementia with Lewy bodies
Nonamnestic single domain	Language, attention, executive, or visuospatial dysfunction	Frontotemporal dementia, Lewy body dementia (including dementia with Lewy bodies and Parkinson disease dementia), vascular dementia, posterior cortical atrophy, hydrocephalus
Nonamnestic multidomain	Memory not affected but more than one domain affected: language, attention, executive, or visuospatial dysfunction	Frontotemporal dementia, Lewy body dementia, vascular dementia, posterior cortical atrophy, hydrocephalus
^aDifferent types of MCI, leftmost column, may ultimately more likely represent, as shown in rightmost column, prodromal states of different dementia disorders.
Reprinted with permission from Louis ED, Mayer SA, Noble JM, eds. Merritt’s Neurology. 14th ed. Wolters Kluwer; 2022.

2. A 70-year-old man presents with progressive language difficulty and is found to have deficits in naming, comprehension, and attention. His memory is relatively well preserved, and he is able to perform his activities of daily living. How would you classify his mild cognitive impairment (MCI) and what would you expect initial neuroimaging to show?

A. Amnestic multidomain MCI. Brain MRI with bilateral temporal and parietal atrophy

B. Amnestic single-domain MCI. Brain MRI with bilateral temporal and parietal atrophy

C. Nonamnestic multidomain MCI. Brain MRI with focal hippocampal and parietal atrophy

D. Nonamnestic multidomain MCI. Brain MRI with frontal and anterior temporal atrophy

E. Nonamnestic single-domain MCI. Brain MRI with bilateral frontal and anterior temporal atrophy

View Answer

2. Answer D. (MN-50) The patient above has nonamnestic multidomain MCI as evidenced by decline in multiple cognitive domains, including language and attention with preserved memory. Nonamnestic MCI may reflect early stages of non-Alzheimer dementia including frontotemporal dementia (FTD). On MRI, FTD often has atrophy of the frontal and/or temporal lobes or hypometabolism in these regions on fluorodeoxyglucose-PET scan. Hippocampal and parietal atrophy are classically seen in the amnestic MCI groups, as these patients tend to develop Alzheimer disease (Tables 6.1.2 and 6.2.1). Frontal atrophy can also occur in AD, although typically as an atypical nonamnestic presentation of AD or in later stages of disease when there is hippocampal, temporal, and parietal atrophy.

TABLE 6.2.1 Biomarkers Useful in Prognostication for Mild Cognitive Impairment^a

Biomarker	Result	Prognostic Implications
Brian MRI	Focal decreased hippocampal volume, parietal gyral atrophy, or cortical thinning	Likely AD
Fluorodeoxyglucose-PET imaging	Bitemporoparietal hypometabolism Frontal or anterior temporal hypometabolism Occipital hypometabolism	Likely AD Suggestive of FTD Suggestive of PCA or DLB
Florbetapir, florbetaben, or flutemetamol PET imaging	Positive signal for fibrillar amyloid	Suggestive of AD with or without involvement of DLB
Ioflupane SPECT imaging (DAT)	Decreased unilateral or bilateral striatal uptake	Suggestive of DLB
Cerebrospinal fluid biomarker analysis	Low β-amyloid₄₂ High phospho-tau	Suggestive of AD
Apolipoprotein E genotyping	ɛ4 Allele present	Suggestive of underlying AD
AD, Alzheimer disease; DAT, dopamine transporter single-photon emission computed tomography; DLB, dementia with Lewy bodies; FTD, frontotemporal dementia; MRI, magnetic resonance imaging; PCA, posterior cortical atrophy; PET, positron emission tomography; SPECT, single-photon emission computed tomography.
^aThe above-mentioned assessments are useful in research-based studies of MCI and are anticipated to have broader clinical implications should disease-modifying therapies become available.
Reprinted with permission from Louis ED, Mayer SA, Noble JM, eds. Merritt’s Neurology. 14th ed. Wolters Kluwer; 2022.

3. A 55-year-old man presents with chief complaint of short-term memory loss and poor attention. His neurological examination, including standardized cognitive testing and brain MRI, and basic labs for reversible cognitive decline, including syphilis, vitamin B₁₂ level, and HIV, are unremarkable. What would be the most appropriate next step in his workup?

A. Fluorodeoxyglucose-PET imaging to evaluate for subtle signs of reduced cerebral metabolic activity

B. Focused history and examination screening for psychiatric illness such as anxiety and depression, as well as screen for obstructive sleep apnea

C. Lumbar puncture to evaluate CSF biomarkers including tau, phosphor-tau, and β-amyloid

D. Reassurance

E. Choices A and C

View Answer

3. Answer B. (MN-50) This patient does not have any objective evidence of cognitive decline on neurological examination and thus does not meet criteria for mild cognitive impairment, nor requires further dementia workup. Mild cognitive impairment is more common in people over 70 years of age. Adults 60 years or younger presenting with subjective cognitive complaints, without a family history of dementia or objective evidence of cognitive decline, should be screened for an underlying psychiatric basis for their cognitive dysfunction, such as anxiety and depression. In adults of this age who do not otherwise have obvious reversible causes, and with objective decline confirmed by neuropsychological testing, a biomarker-based workup including brain imaging (usually noncontrast MRI brain) and cerebrospinal fluid markers or molecular-PET (amyloid-PET) may be considered. Obstructive sleep apnea (OSA) is common, underdiagnosed, and undertreated; OSA can contribute to daytime vigilance and alertness as revealed in the history as well as cognitive symptoms.

4. A 76-year-old woman is brought in by family for concern over worsening short-term memory and is found to have decreased performance in multiple cognitive domains including memory, attention, and visuospatial organization. The patient has a prior history of depression, although she denies feeling sad or changes to her mood. She is able to perform activities of daily living, and her MRI shows subtle temporal and parietal lobe atrophy. Based on the patient’s most likely diagnosis, what would be the most appropriate next step?

A. Consider a trial of galantamine as this medication has been shown to delay progression to Alzheimer disease in patients with MCI

B. Consider starting serotonin reuptake inhibitor to improve the patient’s mood given her prior history of depression

C. Pursue a biomarker-based workup to possibly diagnose Alzheimer disease

D. Start donepezil as this medication clearly delays progression to dementia in patients with mild cognitive impairment (MCI)

E. Choices B and D

View Answer

4. Answer C. (MN-50) The patient has amnestic multidomain MCI based on her cognitive performance and preserved ability to perform essential activities of daily living. Of the two cholinesterase inhibitors mentioned above, only donepezil showed minimal efficacy in delaying progression of MCI to Alzheimer disease and is not strongly indicated. Although the patient has a history of depression, there is no evidence on examination that this disease is causing her neurological symptoms. With the emergence of new biological agents targeting amyloid pathways implicated in Alzheimer disease and approved for MCI and mild dementia, a biomarker-based workup is strongly favored.

5. An 85-year-old man previously followed in your clinic for cognitive decline recently passed away. Prior to his death, his neurological examination was significant for impairments in memory, language, and executive functioning and 18F-fluorodeoxyglucose-PET scan showed hypometabolic activity in the bilateral parietal and temporal lobes. Based on the constellation of his symptoms and neuroimaging data, what findings would you expect to see on autopsy?

A. Extracellular β-amyloid plaques and intracellular phosphorylated tau tangles

B. Intracellular β-amyloid plaques and extracellular phosphorylated tau tangles

C. Intracellular neuronal inclusions that stain positive for α-synuclein

D. Intraneuronal vacuolar changes and synapse loss

E. Choices A and D

View Answer

5. Answer E. (MN-51) The classic neuropathological findings for Alzheimer disease include extracellular deposition of β-amyloid plaques in addition to intracellular/intracytoplasmic neurofibrillary tangles of phosphorylated tau protein. Histologically brain tissue also shows synaptic loss and granulovacuolar change (Table 6.5.1). Intracellular neuronal inclusions that stain positive for α-synuclein are classic for synucleinopathies, such as Lewy body dementia or Parkinson disease. While multiple pathologies are common in dementia, including Lewy bodies prevalent in about one-third of persons who die with Alzheimer disease, the clinical history is more suggestive of Alzheimer disease.

TABLE 6.5.1 Pathologic Hallmarks of Alzheimer Disease^a

Macroscopic/Regional	Clinical Implications
Hippocampal atrophy	Memory impairment
Parietotemporal atrophy	Dysnomia/visuospatial impairment
Nucleus basalis cell loss	Attentional impairment
Microscopic	Molecular Concomitant
Neuritic plaques	Aβ₄₂ and Aβ₄₀ fibrillar aggregates with associated neuritic changes
Diffuse plaques	Aβ₄₂ and Aβ₄₀ fibrillar aggregates
Neurofibrillary tangles	Paired helical filamentous aggregates of phosphorylated tau protein
Synaptic loss	Not known, but accompanied by decreases in various neurotransmitters
Neuronal loss	Not known
Granulovacuolar degeneration	Intraneuronal vesicular changes
^aList of pathologic hallmarks of Alzheimer disease, including macroscopic/regional changes and microscopic changes and their clinical and molecular correlates.
Reprinted with permission from Louis ED, Mayer SA, Noble JM, eds. Merritt’s Neurology. 14th ed. Wolters Kluwer; 2022.

6. With regards to biomarker-based evaluation, what would be a typical cerebrospinal fluid profile for someone who suffers from Alzheimer disease?

A. Elevated β-amlyoid₄₂, reduced total tau, and elevated phosphorylated tau proteins

B. Elevated β-amlyoid₄₂, total tau, and phosphorylated tau proteins

C. Elevated β-amlyoid₄₂, with reduced total tau and phosphorylated tau proteins

D. Reduced β-amlyoid₄₂ and total tau, with elevated phosphorylated tau proteins

E. Reduced β-amlyoid_42, elevated total tau and phosphorylated tau proteins

View Answer

6. Answer E. (MN-51) Reduced β-amlyoid₄₂ and elevated total tau and phosphorylated tau proteins in the cerebrospinal fluid are consistent with a diagnosis of Alzheimer disease. Combined measures of the concentration of these three biomarkers results in a sensitivity and specificity greater than 90%.

7. Which of the following states is correct with regards to our understanding of the genetic factors associated with Alzheimer disease?

A. Amyloid precursor protein (APP) and presenilin 1 and 2 (PSEN1, PSEN2) are most commonly associated with early-onset Alzheimer disease

B. Amyloid precursor protein (APP) and presenilin 1 and 2 (PSEN1, PSEN2) genes are most commonly associated with late-onset Alzheimer disease

C. APOE e4 allele is associated with an increased risk of late-onset Alzheimer disease

D. Neither first- nor second-degree relatives of persons with Alzheimer disease are at higher risk for developing this disease

E. Choices A and C

View Answer

7. Answer E. (MN-51) Pathogenic variants, also known as mutations, in amyloid precursor protein (APP) and presenilin 1 and 2 (PSEN1, PSEN2) genes result in autosomal dominant forms of early-onset Alzheimer disease. The e4 allele of the APOE gene on chromosome 19 confers a higher risk for development of late-onset Alzheimer especially if the individual has two copies of this allele. Given these genetic risk factors for Alzheimer disease, first-degree relatives of patients with Alzheimer are at a higher risk of developing this disease. Of note, the APP gene is located on chromosome 21; thus, patients with trisomy 21 are at a high risk of developing Alzheimer disease by 50 years.

8. You are caring for an 85-year-old man who presents for several years of cognitive decline. He is oriented to person and place but not time. He needs support in most of his instrumental and basic activities of daily living (ADLs). His neurological examination is significant for deficits in attention, memory, and executive function, in addition to abstract reasoning. MRI shows atrophy in the bilateral parietal and temporal lobes including the hippocampi. Which of the following medication strategies would be most appropriate to improve the patient’s cognition and behavior?

A. Consider a cholinesterase inhibitor first and if the patient fails to improve add a second cholinesterase inhibitor

B. Consider a trial of a cholinesterase inhibitor alone, such as donepezil

C. Consider a trial of memantine, a N-methyl-D-aspartate receptor (NMDA) antagonist alone

D. Consider combining memantine with a cholinesterase inhibitor such as donepezil

E. Continue supportive care as there is no pharmacological treatment for the cognitive and behavioral symptoms of Alzheimer disease

View Answer

8. Answer D. (MN-51) The patient likely suffers from moderate to severe dementia due to Alzheimer disease given his abnormal neurological examination and reliance on others for most ADLs. Both cholinesterase inhibitors and memantine (NMDA receptor antagonist) have been shown to have mild efficacy in improving cognitive symptoms in patients with Alzheimer disease. The cholinesterase inhibitors tend to be used in more mild disease, although they can be used in moderate to severe Alzheimer disease, while memantine is reserved for moderate to severe Alzheimer disease. The cognitive benefit is seen in both monotherapy and concomitant therapies. Given the patient has moderate to severe Alzheimer disease, it is reasonable to try both medications. At present, antiamyloid therapies are only indicated for persons in the MCI or mild dementia stages if the underlying etiology is considered to be Alzheimer disease.

9. A 50-year-old man is working as an accountant and becomes socially inappropriate disinhibited at work, verbally lashing out at colleagues when impatient. He has arrived late to work on several occasions over the last 12 months and shown no concern for this despite having always been punctual. His wife has reported that he is increasingly difficult to be around and has noted that he does not have appropriate emotional reactions. For example, he was observed to laugh when his daughter tripped and fell over. His brother died of amyotrophic lateral sclerosis (ALS) 2 years ago, at age 45 years. On presentation to a neurologist he showed no concern about his family’s reports of inappropriate behavior. Which genetic test is most likely to be positive?

A. Amyloid precursor protein (APP)

B. Chromosome 9 Open Reading Frame 72 (C9ORF72) hexanucleotide repeat expansion

C. Presenilin 1 (PSEN1)

D. Progranulin (GRN)

View Answer

9. Answer B. (MN-52) C9ORF72 hexanucleotide repeat expansion, because this mutation is associated with both FTD and ALS (Figure 6.9.1). The patient reports a family history of ALS and presents with behavioral problems typical of behavioral variant FTD (bvFTD). APP and PSEN1 are genes associated with early-onset Alzheimer disease, not FTD. While GRN mutations can cause FTD, they are not generally associated with ALS and instead are associated motorically with apraxia and focal limb dystonia.

FIGURE 6.9.1 (Reprinted with permission from Louis ED, Mayer SA, Noble JM, eds. Merritt’s Neurology. 14th ed. Wolters Kluwer; 2022.)

10. A 60-year-old recently retired high school English teacher presents to her doctor with prominent word finding difficulties as her primary complaint. She is referred for neuropsychological assessment. On testing, she has severe naming and word comprehension deficits. Her spontaneous speech is fluent with normal rhythm/tempo and contains no phonological paraphasias or grammatical errors, although the neuropsychologist notices that she often uses the word “thing” to refer to specific objects. When asked to read the word “yacht,” she pronounces it “ya-ch-et.” Repetition of both single words and lengthy sentences is intact. Which FTD subtype is this language profile most consistent with?

A. Behavioral variant FTD

B. Logopenic variant PPA

C. Nonfluent variant PPA

D. Semantic variant primary progressive aphasia (PPA)

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10. Answer D. (MN-52) Semantic variant PPA. This patient displays anomia and comprehension difficulties, which are the core diagnostic criteria of semantic variant PPA, sometimes termed semantic dementia. A feature of this examination is that she makes a regularization error often referred to as “surface dyslexia.” When asked to pronounce “yacht,” she instead sounds out portions of the word according to its spelling, an approach that would be particularly unusual given her experience as an English teacher. She does not meet criteria for nonfluent variant PPA as her speech is neither effortful nor dysgrammatic. Moreover, comprehension is generally preserved in nonfluent variant PPA. It is unlikely that she has logopenic PPA as her speech was not observed to be slow or contained no phonological paraphasias or circumlocutions and her repetition of lengthy sentences was intact. While naming deficits may be reported in behavioral variant FTD, language deficits tend to be more subtle and are unlikely to be the prominent complaint.

11. In the scenario above, assume the patient meets clinical criteria for semantic variant PPA. What would you expect to see on her MRI?

A. Bilateral temporal lobe greater than frontal lobe atrophy

B. Left frontal atrophy with sparing of the temporal lobes

C. Left greater than right hemisphere atrophy of the anterior temporal lobes

D. Left posterior temporoparietal atrophy

E. Sparing of the frontal lobes with prominent parietal and occipital atrophy

View Answer

11. Answer C. (MN-52) Left greater than right hemisphere atrophy of the anterior temporal lobes. Semantic variant PPA is associated with a distinct pattern of atrophic anterior temporal lobes, and it is most common to see greater involvement of the left hemisphere (although there are cases of right-dominant temporal atrophy). While frontal atrophy is likely as the disease progresses, you would not expect relative sparing of the temporal lobes. Left posterior temporoparietal atrophy is more likely to be associated with logopenic PPA. It is unlikely that you would see sparing of the frontal lobes with prominent parietal and occipital atrophy in FTD.

12. A 63-year-old farmer reports to a neurologist with his wife. The wife has observed that her husband is increasingly irritable and distant, which is unusual for him. She is worried he might have Alzheimer disease because he is misplacing items and forgets names. The patient is not aware of any cases of dementia in his family. Symptoms started around 2 years ago, at the same time that his son was diagnosed with lymphoma. Although the son fully recovered, the patient’s symptoms continued to progress. He has become obsessed with food, especially sweets, and has gained 40 pounds. Upon neurological examination, no motor signs, such as tremor, were present. Neuropsychological testing revealed executive dysfunction and mild anomia. Memory was found to be poor but within normal limits. The neurologist considers the differential diagnosis as Alzheimer disease (AD) versus behavioral variant FTD (bvFTD). Which diagnostic tests would be most useful here?

A. Brain MRI and CSF for amyloid and tau

B. Clinical genetic testing and brain MRI

C. CT scan of the brain

D. DAT scan and PET scan

E. No further workup is necessary, the diagnosis is clear

View Answer

12. Answer A. (MN-52) Brain MRI and CSF for amyloid and tau. Magnetic resonance imaging (MRI) in FTD often reveals cortical volume loss in the frontal and anterior temporal lobes, while in Alzheimer disease medial temporal (ie, hippocampal) atrophy is more common. CSF phosphorylated tau/total tau, and Aβ42 levels can be useful to distinguish FTD and Alzheimer disease, as patients with AD will usually show elevated levels of t-tau and p-tau and reduced levels of Aβ42 in CSF compared with controls and patients with frontotemporal lobar degeneration. Although PET scans can be used to differentiate between FTD and Alzheimer disease, a DAT would have no role in this scenario, as these scans examine dopamine update in the basal ganglia and thus are used in diagnosing movement disorders. Genetic testing would not necessarily be a primary diagnostic focus as there is no clear family history. Although CT may show radiographic stigmata of FTD versus Alzheimer disease in later stages of disease, it is far less sensitive than MRI imaging. While the clinical signs tentatively suggest bvFTD as opposed to AD, due to the hyperphagia, it is not a clear case and further diagnostic workup is necessary.

13. A 40-year-old woman reports that her father died at age 67 years from dementia and recalls that he lost all the family’s savings in a bad investment decision approximately 12 years prior to his death. Her sister, who is 10 years older than her, has stopped calling their mother and is generally disengaged with the family. This patient has recently undergone clinical genetic testing and found out that she carries an MAPT mutation. Which clinical phenotype is this patient most likely to develop?

A. Alzheimer disease

B. Amyotrophic lateral sclerosis (ALS)

C. Behavioral variant FTD (bvFTD)

D. Nonfluent variant PPA

E. Semantic variant PPA

View Answer

13. Answer C. (MN-52) Behavioral variant FTD (bvFTD). This patient reports a family history of dementia and symptoms/behavioral change consistent with bvFTD in her father and sister. While nonfluent variant PPA has been observed in MAPT mutation carriers, it is a much rarer presentation than bvFTD for this genetic mutation. MAPT mutations are not associated with ALS or Alzheimer disease.

14. A 68-year-old man presents with 2 years of progressive cognitive changes. He has more difficulty with concentration and multitasking. He has gotten lost while driving in familiar areas twice in the past month. He denies visual hallucinations or fluctuations in alertness. He endorses significant constipation. You notice his wife has a bruise on her lip, and she comments that he hit her while he was asleep last week. For the past several years, he occasionally yells and flails his arms while he is asleep. On examination, he has no rigidity, bradykinesia, or tremor. At this point, which of the following is the most appropriate diagnosis?

A. Alzheimer disease

B. Possible dementia with Lewy bodies (DLB)

C. Probable dementia with Lewy bodies

D. Progressive supranuclear palsy

E. Vascular dementia

View Answer

14. Answer B. (MN-53) Possible dementia with Lewy bodies, The patient has had a progressive decline in cognition, with functional impact (driving). He has one McKeith core clinical feature—REM sleep behavior disorder (RBD)—but lacks the other three—visual hallucinations, fluctuations, parkinsonism. Therefore, at this point, he meets criteria for possible DLB. While constipation is a supportive clinical feature, it does not contribute to making a consensus diagnosis of probable (or even possible) DLB (Table 6.14.1). The presence of RBD makes the other potential causes of dementia less likely. Recall RBD is highly specific for synucleinopathies, while progressive supranuclear palsy is a tauopathy.

TABLE 6.14.1 Diagnostic Criteria for Dementia With Lewy Bodies

Clinical Features
Core	Supportive
Fluctuations Recurrent visual hallucinations, usually well formed REM sleep behavior disorder Parkinsonism At least one of bradykinesia, rigidity, or resting tremor	Neuroleptic sensitivity Postural instability, frequent falls Recurrent syncope/transient unresponsiveness Dysautonomia (constipation, orthostatic hypotension, urinary incontinence) Hypersomnia Hyposmia Nonvisual hallucinations Delusions Apathy, depression, anxiety
Biomarkers
Indicative	Supportive
Abnormal DaTscan Abnormal cardiac MIBG scan Polysomnography showing REM sleep without atonia	Lack of medial temporal atrophy on CT/MRI Generalized reduced functional brain activity with reduced occipital activity (SPECT/PET) Cingulate island sign Posterior slowing on EEG
Diagnosis
Probable DLB can be diagnosed when: Two or more core clinical features are present. One core clinical feature and one (or more) indicative biomarker are present.
Possible DLB can be diagnosed when: One core clinical feature is present. One (or more) indicative biomarker is present (without core clinical features).
CT, computed tomography; DLB, dementia with Lewy bodies; EEG, electroencephalography; MIBG, metaiodobenzylguanidine; MRI, magnetic resonance imaging; PET, positron emission tomography; REM, rapid eye movement; SPECT, single-photon emission computed tomography.
Adapted from 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. https://creativecommons.org/licenses/by/4.0/

15. Which of the following studies would provide the strongest evidence in support of your suspected diagnosis?

A. Dopamine transporter imaging

B. EEG

C. FDG-PET brain imaging

D. Lumbar puncture with CSF analysis

E. MRI of the brain

View Answer

15. Answer A. (MN-53) Dopamine transporter imaging. Reduced striatal uptake on dopamine transporter imaging (eg, DaTscan) is a McKeith indicative biomarker and would enable a consensus diagnosis of probable DLB. Brain MRI would likely be included in the workup of the patient but can only provide supportive biomarker evidence for diagnosis of DLB (preservation of medial temporal lobe). Similarly, relative occipital lobe hypometabolism and the related cingulate island sign on brain FDG-PET are supportive biomarkers. Finally, CSF analysis for AD biomarkers, while informative, is not listed as a McKeith biomarker feature. EEG is relatively nonspecific and would not provide strong evidence for dementia with Lewy bodies over another age-related neurological disease (Table 6.14.1).

16. One year later, he passes away unexpectedly from a heart attack. At autopsy, numerous neocortical Lewy bodies are observed. These are best described as intracellular inclusions containing which of the following?

A. Alpha-synuclein

B. ApoE

C. Beta-amyloid

D. Hyperphosphorylated tau

E. Prion protein

View Answer

16. Answer A. (MN-53) Alpha-synuclein. Lewy bodies are intracellular inclusions (Figure 6.16.1A, H&E stain, layer V, precuneus, original magnification 630×) characterized by the presence of alpha-synuclein (Figure 6.16.1C, by immunohistochemical stain against alpha-synuclein shows widespread Lewy bodies within the infragranular layers of the cortex; original magnification 100×. Figure 6.16.1C’, A Lewy neurite within the cortex). While DLB is mostly uniquely defined by the presence of Lewy bodies (and the closely related Lewy neurites), most cases have coexisting pathology. There is often prominent AD pathology, with intracellular tangles, composed of hyperphosphorylated tau, and extracellular diffuse and neuritic plaques, composed of beta-amyloid. There can also be spongiform changes (Figure 6.16.1B, H&E, anterior temporal pole layers V-VI, original magnification 100×), similar to that seen in prion disease, although prion protein is not involved in DLB . The clinical features of DLB are detailed in Table 6.16.1.

FIGURE 6.16.1 GM, gray matter; WM, white matter. (Reprinted with permission from Louis ED, Mayer SA, Noble JM, eds. Merritt’s Neurology. 14th ed. Wolters Kluwer; 2022.)

TABLE 6.16.1 Pathologic Features Associated With Dementia With Lewy Bodies