Dementia with Lewy Bodies¶

Chapter 445 | Part 13: Neurologic Disorders · Part 13 – Neurologic Disorders · Chapter 445

Key Clinical Points¶

DLB is the second most common cause of neurodegenerative dementia, following Alzheimer's disease (AD).
Core diagnostic features include well-formed visual hallucinations, fluctuating cognition, REM sleep behavior disorder (RBD), and parkinsonism.
RBD is a characteristic, often prodromal, feature that may precede clinical symptoms by many years.
Lewy bodies are alpha-synuclein aggregates containing neurofilaments 7–20 nm long; they are the pathognomonic hallmark of LBD.
Fluctuating attention and concentration can manifest as marked periods of confusion or severe lethargy.
Patients with DLB are highly sensitive to infectious or metabolic disturbances, often presenting first with delirium.
Episodic memory impairment is a specific indicator of comorbid AD pathology rather than pure DLB.
Anosmia is more characteristic of LBD than multiple system atrophy (MSA).
Differentiation from MSA: MSA presents with earlier and more severe autonomic dysfunction; LBD has more prominent anosmia.
Pharmacotherapy includes cholinesterase inhibitors for mild-to-moderate impairment and high-dose donepezil or memantine for moderate-to-severe cases.

DEFINITION & OVERVIEW¶

• Definition (Harrison's 22e): - The Lewy body disease (LBD), manifesting as Parkinson's disease dementia (PDD) or dementia with Lewy bodies (DLB), is the second most common cause of neurodegenerative dementia, after Alzheimer's disease (AD). • Clinical Spectrum: - PDD and DLB are viewed as points on a spectrum of LBD pathology. - Differentiation based on timing: - PDD: Patients have long-standing PD; dementia develops later, often with visual hallucinations, fluctuating attention/alertness, and RBD. - DLB: Dementia and neuropsychiatric symptoms precede or co-emerge with parkinsonism. - Note: Patients with DLB more frequently than those with PDD have AD co-pathology. • Pathologic Stages: - Stage 1: Brainstem predominant. - Stage 2: Transitional limbic. - Stage 3: Diffuse neocortical. - Note: Neuronal and synaptic loss, rather than Lewy pathology per se, best predicts clinical deficits.

EPIDEMIOLOGY¶

• Incidence: ~7 per 100,000 person-years. • Prevalence: Increases with aging; affects men more often than women. • Prodromal Phase: RBD may precede the development of an LBD-related syndrome by many years, usually evolving into either PD or DLB.

ETIOLOGY & PATHOPHYSIOLOGY¶

• Pathognomonic Feature: Presence of Lewy bodies and Lewy neurites in brainstem nuclei, substantia nigra, amygdala, cingulate gyrus, and neocortex. • Composition: - Intraneuronal cytoplasmic inclusions. - Stain with periodic acid–Schiff (PAS) and ubiquitin. - Identified by antibodies to the presynaptic protein α-synuclein. - Contain neurofilaments 7–20 nm long and various proteins (ubiquitin, phosphorylated/nonphosphorylated neurofilament proteins). • Classification: Synucleinopathies due of α-synuclein aggregates. • Mechanism of Spread: - Potential prion-like mechanism where abnormally folded α-synuclein aggregates propagate transneuronally. - Pathological progression from periphery to brain correlates with clinical symptoms. - Pathway: Enteric nervous system → vagus nerve → heart → lower brainstem → substantia nigra → limbic system → cerebral cortex. • Clinical Correlation: - Neuronal/synaptic loss predicts clinical deficits. - PD progression: nonmotor features (constipation, hyposmia) → anxiety, depression, RBD, parkinsonism → dementia.

CLINICAL FEATURES¶

• Cognitive Profile: - Severe executive, attentional, and visuospatial deficits. - Often preserved episodic memory (unless comorbid AD is present). • Neuropsychiatric Symptoms: - Well-formed visual hallucinations (may be preceded by a 'sense of presence'). - Delusions: Less frequent than hallucinations; usually related to misidentification, infidelity, theft, or persecution. - Fluctuating cognition: Marked variations in attention/concentration → short periods of confusion or severe lethargy. • Motor & Autonomic Features: - Parkinsonism: Usually associated with early postural instability. - RBD: Patients enact dreams (often violently) due to lack of muscle paralysis during REM sleep. - Anosmia, constipation, depression, and anxiety are common in both PDD and DLB. - Orthostatic hypotension/syncope may occur early → can mimic MSA. • Prodromal Features: - RBD, hallucinations unrelated to medications, fluctuations in attention, or parkinsonism.

DIFFERENTIAL DIAGNOSIS¶

• DLB vs. MSA: - Autonomic symptoms: Earlier and more severe in MSA; cognition relatively preserved. - Anosmia: More characteristic of LBD than MSA. - Potential for differentiation: Skin biopsy and serum with biomarkers for α-synuclein oligomers may eventually differentiate these conditions. • DLB vs. AD: - Episodic memory disturbance → suggests comorbid AD. - MCI-LB vs. MCI-AD (Table 445-1): - MCI: LB affects executive/attention/visuospatial; AD affects memory and semantic naming. - Sleep: LB has RBD; AD has insomnia, frequent awakenings. - Polysomnogram: LB shows RBD without atonia; AD is normal. - CSF: LB shows decreased α-synuclein (RT-QuIC); AD shows decreased β-amyloid (RT-QuIC) and increased phospho-tau. - MRI: LB shows amygdala atrophy; AD shows parahippocampal/hippocampal atrophy. - Amyloid PET: LB is normal (unless comorbid AD); AD shows abnormal parietotemporal areas. - DAT Scan: LB shows reduced dopamine transporter in basal ganglia (putamen); AD is normal. - MIBG Scintigraphy: LB shows postganglionic sympathetic denervation; AD is normal.

INVESTIGATIONS & DIAGNOSIS¶

Clinical Assessment: Identify core features (fluctuating cognition, well-formed hallucinations, RBD, parkinsonism).
Biomarker Screening:
Polysomnogram: Detect RBD without atonia (indicative of LB).
CSF Analysis: Measure α-synuclein by RT-QuIC (decreased = LB) vs. β-amyloid/phospho-tau (AD).
MRI Imaging: Assess amygdala atrophy (LB) vs. parahippocampal/hippocampal atrophy (AD).
PET Imaging:
Amyloid PET: Normal in LB; Abnormal parietotemporal areas in AD.
DAT Scan or PET dopamine scan: Reduced dopamine transporter in basal ganglia (putamen) in LB.
Cingulate Island Sign: Hypometabolism in occipital lobe and increased in posterior cingulate (indicative of LB).
MIBG Myocardial Scintigraphy: Identify postganglionic sympathetic denervation in LB.

MANAGEMENT & TREATMENT¶

Pharmacologic Treatment for Cognitive Impairment:
Mild to moderate impairment → Cholinesterase inhibitors (Donepezil, Rivastigmine, or Galantamine).
Moderate to severe impairment → High-dose Donepezil OR Memantine (NMDA receptor antagonist).
Stroke Prevention (Standard of Care):
Blood pressure management:
Target <140/90 mmHg for all.
Target <130/80 mmHg for those with estimated 10-year CVD risk ≥ 10% (common in patients with imaging evidence of stroke).
Other AHA Life's Essential 8 components:
Cholesterol control, blood sugar reduction, active lifestyle, heart-healthy diet, weight loss, smoking cessation, and healthy sleep.
Secondary Prevention Considerations:
Antiplatelet or statin therapy: Consider if imaging suggests embolism or large-vessel-related strokes.
Screening: All patients with asymptomatic infarcts must be screened for atrial fibrillation; consider prolonged cardiac monitoring for embolic-appearing infarcts.

PROGNOSIS & COMPLICATIONS¶

• Sensitivity to Systemic Stress: Patients are highly sensitive to infectious or metabolic disturbances. • Delirium: Often the first manifestation of DLB, precipitated by infection, new medication, or other systemic disturbance.

SPECIAL CONSIDERATIONS¶

• Prodromal Phase (MCI-LB): - Characterized by executive, attention, and visuospatial deficits. - Distinguished from PD-MCI by the presence of hallucinations (unrelated to meds), RBD, fluctuations in attention, or parkinsonism.

KEY PEARLS & CLINICAL TRAPS¶

• RBD as a Sentinel: RBD often precedes clinical symptoms by years; its presence is highly suggestive of LBD. - Hallucination Quality: Look for "well-formed" visual hallucinations; sense of presence may precede them. - Delirium Warning: High sensitivity to metabolic/infectious triggers means delirium is a common first presentation. - Differentiation Rule: - Episodic memory loss → think comorbid AD. - Early/severe autonomic failure → think MSA. - Prominent anosmia → more likely LBD than MSA.

Reference Tables¶

TABLE 445-1 Distinguishing MCI Due to Lewy Body Disease or Alzheimer’s Disease¶

Harrison's 22e, p.3492

CLINICAL FEATURES	PRODROMAL MCI-LB PATHOLOGY	PRODROMAL MCI-AD PATHOLOGY
MCI	MCI usually affecting executive, attention, and/or visuospatial functions	MCI with impaired memory and semantic naming
	Frequent and severe
Sleep	REM sleep behavior disorder	Insomnia, frequent awakenings
	Frequent
Biomarkers
Polysomnogram	REM sleep behavior disorder without atonia	Normal
	Decreased CSF α-synuclein by RT-QuIC
MRI	Atrophy of the amygdala	Atrophy of the parahippocampal/ hippocampal areas
	Hypometabolism in occipital lobe and increased in posterior cingulate (cingulate island sign)
Amyloid PET scan	Normal, unless associated with AD	Abnormal parietotemporal areas
	Postganglionic sympathetic denervation
DAT scan or PET dopamine scan	Reduced dopamine transporter in the basal ganglia, particularly putamen	Normal