Dementia with Lewy Bodies (DLB)

Primer

Dementia with Lewy Bodies (DLB), is a neurodegenerative disorder associated with abnormal deposits of alpha-synuclein in the brain. It is characterized by progressive cognitive impairment (with early changes in complex attention and executive function rather than learning and memory), recurrent complex visual hallucinations, rapid eye movement (REM) sleep behavior disorder, depression, and/or delusions. DLB is one of the most common causes of dementia.

Terminology

What's the Difference Between Lewy Body Dementia and Dementia with Lewy Bodies?

Lewy body dementia (LBD) (more correctly, should be referred to as Lewy Body Dementias) is actually an umbrella term that refers either a diagnosis of Dementia with Lewy bodies (DLB) or Parkinson's disease dementia. The terminology can sometimes be confusing as the terms might be used interchangeably. Both diseases are under this term of LBD because both diagnoses involve the same pathophysiological changes in the brain and over time, individuals develop similar symptoms.
Epidemiology
  • DLB is estimated to account for around 4.2% of all diagnosed dementias in the community.[1]
    • However, the true prevalence is likely to be much higher because DLB diagnoses are often missed.[2]
Prognosis
  • Dementia with Lewy Bodies (DLB) has a very quick progression relative to other dementias such as Alzheimer's, with an average survival time of 3 to 5 years.[3][4][5]
Comorbidity
  • Alzheimer's pathology (i.e - amyloid) is often present in most individuals with DLB, and it is rare to have a “pure” DLB.
    • Conversely, Lewy bodies also occur in up to 2/3 of patients with early-onset familial Alzheimer’s disease caused by mutations of presenilin-1, presenilin-2, or amyloid precursor protein.[6]
  • DLB also shares many of the clinical and pathological characteristics of the dementia that occurs during the course of Parkinson's disease, and both are due to the abnormal aggregation of the synaptic protein alpha-synuclein.
Risk Factors
  • The presence of REM sleep behaviour disorder is a major risk factor for DLB.

DSM-5 Diagnostic Criteria

Criterion A

The criteria are met for major or mild neurocognitive disorder.

Criterion B

The disorder has an insidious onset and gradual progression.

Criterion C

The disorder meets a combination of core diagnostic features and suggestive diagnostic features for either probable or possible neurocognitive disorder with Lewy bodies.

For probable major or mild neurocognitive disorder with Lewy bodies, the individual has 2 core features, or 1 suggestive feature with 1 or more core features.

For possible major or mild neurocognitive disorder with Lewy bodies, the individual has only 1 core feature, or 1 or more suggestive features.

  1. Core diagnostic features:
    • a. Fluctuating cognition with pronounced variations in attention and alertness
    • b. Recurrent visual hallucinations that are well formed and detailed
    • c. Spontaneous features of parkinsonism, with onset subsequent to the development of cognitive decline
  2. Suggestive diagnostic features:
Criterion D

The disturbance is not better explained by cerebrovascular disease, another neurodegenerative disease, the effects of a substance, or another mental, neurological, or systemic disorder.

Specifiers

Specifiers

Specify if:

  • Probable major neurocognitive disorder with Lewy bodies
    • With behavioral disturbance
    • Without behavioral disturbance
  • Possible major neurocognitive disorder with Lewy bodies
  • Mild neurocognitive disorder with Lewy bodies

Signs and Symptoms

  • The feeling of presence (FOP) is defined as a feeling of someone present in the room when no one is actually there, and is a commonly reported symptom in DLB and Parkinsonian disorders.[7][8]

2017 Consensus Criteria

The diagnostic criteria for lewy body dementia continues to evolve, and while the DSM-5 provides a guiding diagnostic framework, it was published in 2013, and many new research findings have occurred. The latest consensus is from the Fourth consensus report of the DLB Consortium, issued in 2017.[9] The diagnostic criteria contains categories of probable and possible DLB, describing the clinical presentations most typical of dementia associated with underlying Lewy-related pathology.

Clinical Features

Revised Criteria for the Clinical Diagnosis of Probable and Possible Dementia with Lewy bodies (DLB)

McKeith, I. G. et al (2017). Diagnosis and management of dementia with Lewy bodies: Fourth consensus report. Neurology, 89(1), 88-100
Essential Essential for a diagnosis of DLB is dementia, defined as a progressive cognitive decline of sufficient magnitude 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 (visuospatial) ability may be especially prominent and occur early.
Core clinical features (The first 3 typically occur early and may persist throughout the course.)
1. Fluctuating cognition with pronounced variations in attention and alertness.
2. Recurrent visual hallucinations that are typically well formed and detailed.
3. REM sleep behavior disorder, which may precede cognitive decline.
4. 1 or more spontaneous cardinal features of parkinsonism: these are bradykinesia (defined as slowness of movement and decrement in amplitude or speed), rest tremor, or rigidity.
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.
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.
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 ± the cingulate island sign on FDG-PET imaging.
• Prominent posterior slow-wave activity on EEG with periodic fluctuations in the pre-alpha/ theta range.

Probable vs. Possible Diagnosis

Probable versus Possible Diagnosis

Probable DLB can be diagnosed if:
a. 2 or more core clinical features of DLB are present, with or without the presence of indicative biomarkers, or

b. Only 1 core clinical feature is present, but with 1 or more indicative biomarkers.
(Probable DLB should not be diagnosed on the basis of biomarkers alone.)
Possible DLB can be diagnosed if:
a. Only 1 core clinical feature of DLB is present, with no indicative biomarker evidence, or

b. 1 or more indicative biomarkers is present but there are no core clinical features.
DLB is less likely:
a. In the presence of any other physical illness or brain disorder including cerebrovascular disease, sufficient to account in part or in total for the clinical picture, although these do not exclude a DLB diagnosis and may serve to indicate mixed or multiple pathologies contributing to the clinical presentation, or

b. If parkinsonian features are the only core clinical feature and appear for the first time at a stage of severe dementia.

REM Sleep Behaviour Disorder

Rapid Eye Movement (REM) Sleep Behaviour Disorder is a sleep disorder characterized by repeated episodes of arousal, often associated with vocalizations and/or complex motor behaviours arising during REM sleep. Almost 90% of patients diagnosed with a REM sleep behaviour disorder will later develop a Parkinson's-plus disorder such as Parkinson's Disease (PD), Dementia with Lewy Bodies (DLB), and Multiple System Atrophy (MSA).[10]

Pathophysiology

  • The underlying pathophysiology of DLB is primarily a synucleinopathy due to alpha-synuclein misfolding and aggregation. Lewy body pathology frequently coexists with Alzheimer's disease and cerebrovascular disease pathology, particularly among the oldest age groups. In Alzheimer's disease, there is concomitant synuclein pathology in 60% of cases.
  • Compared to Alzheimer's dementia, Lewy Body Dementia has even greater cholinergic deficits early in the course of illness.[11]
    • This is also why acetylcholinesterase inhibitors are found to be effective in DLB.

Differential Diagnosis

  • Parkinsons's Disease Dementia (PDD)
  • Alzheimer's Disease
    • Because of considerable pathologic heterogeneity, some dementia presentations associated with Lewy-related pathology are atypical. For example, if abundant neocortical neuritic plaques and tangles are present in addition to Lewy bodies, the clinical profile may more closely resemble AD rather than DLB. Such mixed pathology cases are common, explaining why up to half of carefully research-diagnosed patients with AD may have unsuspected Lewy-related pathology at autopsy.
  • Depression with psychotic features[12]

Lewy Body or Parkinsons's Dementia?

Is It Lewy Body or Parkinsons's Disease Dementia?

Lewy Body Dementia presents with cognitive and/or psychiatric symptoms first, and is followed by the typical symptoms of Parkinson’s within 1 year (or from the very beginning). In Parkinson's Disease Dementia (PDD), the full motor symptoms of Parkinson’s need to be present for a minimum of 1 year, before the onset of cognitive impairment or dementia. PDD should be used to describe dementia that occurs in the context of already well-established Parkinson's disease. In research studies where a distinction needs to be made between DLB and PDD, the “1-year rule” between the onset of dementia and parkinsonism is commonly used.[13]

Neuroleptic Sensitivity

Neuroleptic sensitivity is not a diagnostic marker but does raises suspicion of DLB if it does occur. Additionally, neuroleptic sensitivity is another way to differentiate between Parkinson's and Lewy Body Dementia (more so than visual hallucinations).[14] However, this is not a diagnostic approach.

Investigations

Polysomnography

  • The presence REM sleep behaviour disorder is a highly specific predictor of Lewy-related pathology, and is suggestive of a >90% likelihood of a synucleinopathy.

Cognitive Testing

  • Cognitive tests like the Mini-Mental Status Exam (MMSE) and Montreal Cognitive Assessment (MoCA) are useful to characterize global impairment. Deficits are typically in attention, executive function, and visual processing
    • Measures of processing speed and divided/alternating attention (e.g. - Stroop test, trail-making tasks, phonemic fluency, and computerized tasks of reaction time) can be helpful to reveal disproportionate deficits in these areas
  • The spatial and perceptual difficulties of DLB often occur early
    • Commonly see in figure copying (e.g. - intersecting pentagons, complex figure copy, visual assembly, block design, puzzle tasks, spatial matching, line orientation, size matching tasks, and perceptual discrimination)
  • Memory and object naming tend to be less affected in DLB, and are best evaluated through story recall, verbal list learning, and confrontation naming tasks, although some patients' difficulties may be secondary to speed or retrieval task demands.

Neuroimaging

  • Different types of brain perfusion scans (SPECT) can be done:[15]
    • 123Iodine-metaiodobenzylguanidine myocardial scintigraphy (MIBG) may show low striatal dopamine transporter uptake
    • 123I-ioflupane single-photon emission computed tomography (SPECT), also known as a dopamine transporter (DAT) scan
      • This assesses DAT uptake in the basal ganglia in vivo, and has been shown to be more specific than clinical diagnostic criteria for DLB.
      • It maybe the most reliable imaging modality of choice in differentiating DLB from pure AD.
    • Fluorodeoxyglucose PET (FDG PET) may show occipital hypometabolism
    • Routine brain perfusion SPECT (bp-SPECT) may show occipital hypoperfusion, but sensitivity is around 70% and specificity around 76%.[16][17]
  • On MRI, generalized atrophy can be seen in most dementias.
    • DLB can similarly have such generalized atrophy, but there is more relative sparing of the medial temporal lobes (MTL).[18]

Treatment

Pharmacotherapy

Typical and High Potency Antipsychotics are CONTRAINDICATED in Lewy Body Dementia!

A severe sensitivity reaction occurs in an estimated 25-50% of Dementia with Lewy Bodies (DLB) patients administered typical antipsychotic drugs (especially haloperidol). This results in cognitive impairment, sedation, increased/irreversible acute onset of parkinsonism, or symptoms resembling neuroleptic malignant syndrome. If an antipsychotic must be used, then low potency atypical antipsychotics like clozapine or quetiapine should be used.[19]
  • Acetylcholinesterase inhibitors should be the first medications used to treat hallucinations and agitation in patients with DLB. Both rivastigmine and donepezil are effective in DLB for improving cognition, global function, and activities of living.[20][21] Furthermore, if patients do not improve with treatment, there is a lower likelihood of deterioration. There is less evidence for the efficacy of memantine, but it is well-tolerated and may have benefits, either as monotherapy or as an adjunctive to a acetylcholinesterase inhibitors.[22]
  • Motor symptoms can be treated with low doses of carbidopa-levodopa.
  • Low-dose melatonin or clonazepam can be used to treat REM sleep behaviour disorder. There are no systematic studies of antidepressants for depression in DLB.

Resources

For Patients
Case Reports

References

1) Jones, S. V., & O'brien, J. T. (2014). The prevalence and incidence of dementia with Lewy bodies: a systematic review of population and clinical studies. Psychological medicine, 44(4), 673-683.
2) Jones, S. V., & O'brien, J. T. (2014). The prevalence and incidence of dementia with Lewy bodies: a systematic review of population and clinical studies. Psychological medicine, 44(4), 673-683.
3) Price, A., Farooq, R., Yuan, J. M., Menon, V. B., Cardinal, R. N., & T O’Brien, J. (2017). Mortality in dementia with Lewy bodies compared with Alzheimer’s dementia: a retrospective naturalistic cohort study. BMJ open, 7(11), e017504.
4) Jellinger, K. A., Wenning, G. K., & Seppi, K. (2007). Predictors of survival in dementia with lewy bodies and Parkinson dementia. Neurodegenerative Diseases, 4(6), 428-430.
5) Olichney, J. M., Galasko, D., Salmon, D. P., Hofstetter, C. R., Hansen, L. A., Katzman, R., & Thal, L. J. (1998). Cognitive decline is faster in Lewy body variant than in Alzheimer's disease. Neurology, 51(2), 351-357.
6) McKeith, I., Mintzer, J., Aarsland, D., Burn, D., Chiu, H., Cohen-Mansfield, J., Dickson, D., Dubois, B., Duda, J. E., Feldman, H., Gauthier, S., Halliday, G., Lawlor, B., Lippa, C., Lopez, O. L., Carlos Machado, J., O'Brien, J., Playfer, J., Reid, W., & International Psychogeriatric Association Expert Meeting on DLB (2004). Dementia with Lewy bodies. The Lancet. Neurology, 3(1), 19–28.
7) Nicastro, N., Eger, A. F., Assal, F., & Garibotto, V. (2020). Feeling of presence in dementia with Lewy bodies is related to reduced left frontoparietal metabolism. Brain imaging and behavior, 14(4), 1199-1207.
8) Naasan, G., Shdo, S. M., Rodriguez, E. M., Spina, S., Grinberg, L., Lopez, L., ... & Rankin, K. P. (2021). Psychosis in neurodegenerative disease: differential patterns of hallucination and delusion symptoms. Brain, 144(3), 999-1012.
9) McKeith, I. G., Boeve, B. F., Dickson, D. W., Halliday, G., Taylor, J. P., Weintraub, D., ... & Bayston, A. (2017). Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium. Neurology, 89(1), 88-100.
10) Iranzo, A., Fernández-Arcos, A., Tolosa, E., Serradell, M., Molinuevo, J. L., Valldeoriola, F., Gelpi, E., Vilaseca, I., Sánchez-Valle, R., Lladó, A., Gaig, C., & Santamaría, J. (2014). Neurodegenerative disorder risk in idiopathic REM sleep behavior disorder: study in 174 patients. PloS one, 9(2), e89741.
11) Tiraboschi, P., Hansen, L. A., Alford, M., Merdes, A., Masliah, E., Thal, L. J., & Corey-Bloom, J. (2002). Early and widespread cholinergic losses differentiate dementia with Lewy bodies from Alzheimer disease. Archives of general psychiatry, 59(10), 946-951.
12) Perera, J. K., Rosenblat, J. D., & Flint, A. J. (2017). Dementia with Lewy bodies presenting as psychotic depression. Australian & New Zealand Journal of Psychiatry, 51(11), 1160-1161.
13) Dubois, B., Burn, D., Goetz, C., Aarsland, D., Brown, R. G., Broe, G. A., ... & Korczyn, A. (2007). Diagnostic procedures for Parkinson's disease dementia: recommendations from the movement disorder society task force. Movement disorders, 22(16), 2314-2324.
14) Rapoport, M., Wiens, A., Seitz, D., & Lilly, E. (2016). Geriatric Psychiatry Review and Exam Preparation Guide: A Case-Based Approach (1st ed.). University of Toronto Press, Scholarly Publishing Division.
15) Surendranathan, A. et al. (2018). Clinical imaging in dementia with Lewy bodies. Evidence-based mental health, 21(2), 61-65.
16) Yeo, J. M., Lim, X., Khan, Z., & Pal, S. (2013). Systematic review of the diagnostic utility of SPECT imaging in dementia. European archives of psychiatry and clinical neuroscience, 263(7), 539–552.
17) Kobayashi, S., Makino, K., Hatakeyama, S., Ishii, T., Tateno, M., Iwamoto, T., Tsujino, H., Kawasaki, K., Mikuni, K., Ukai, W., Murayama, T., Hashimoto, E., Utsumi, K., & Kawanishi, C. (2017). The usefulness of combined brain perfusion single-photon emission computed tomography, Dopamine-transporter single-photon emission computed tomography, and 123 I-metaiodobenzylguanidine myocardial scintigraphy for the diagnosis of dementia with Lewy bodies. Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society, 17(4), 247–255. https://doi.org/10.1111/psyg.12227
18) Barber, R., Gholkar, A., Scheltens, P., Ballard, C., McKeith, I. G., & O’Brien, J. T. (1999). Medial temporal lobe atrophy on MRI in dementia with Lewy bodies. Neurology, 52(6), 1153-1153.
19) Lewy Body Dementia Association: Emergency Room Treatment of Psychosis
20) O’Brien, J. T., Holmes, C., Jones, M., Jones, R., Livingston, G., McKeith, I., ... & Sampson, E. L. (2017). Clinical practice with anti-dementia drugs: a revised (third) consensus statement from the British Association for Psychopharmacology. Journal of Psychopharmacology, 31(2), 147-168.
21) Mori, E., Ikeda, M., Nagai, R., Matsuo, K., Nakagawa, M., & Kosaka, K. (2015). Long-term donepezil use for dementia with Lewy bodies: results from an open-label extension of Phase III trial. Alzheimer's research & therapy, 7(1), 5.
22) Wesnes, K. A., Aarsland, D., Ballard, C., & Londos, E. (2015). Memantine improves attention and episodic memory in Parkinson's disease dementia and dementia with Lewy bodies. International journal of geriatric psychiatry, 30(1), 46-54.