Epidemiology, pathology, and pathogenesis of dementia with Lewy bodies
- Martin R Farlow, MD
Martin R Farlow, MD
- Professor of Neurology
- Indiana University School of Medicine
Dementia with Lewy bodies (DLB) is increasingly recognized clinically as the second most common type of degenerative dementia after Alzheimer disease (AD). In addition to dementia, distinctive clinical features include: visual hallucinations, parkinsonism, cognitive fluctuations, dysautonomia, sleep disorders, and neuroleptic sensitivity.
First described in the 1960s, DLB has a varied clinical presentation that shares features with other degenerative dementias. It was often overlooked pathologically because of the difficulty in identifying cortical Lewy bodies with routine cellular stains. With the advent of immunohistochemical stains for constituents of Lewy bodies, the prevalence of this disorder began to be recognized. However, challenges remain in defining this as an entity distinct from other degenerative dementias.
DLB may represent several diseases with the shared common finding of cortical Lewy bodies, or it may be a single disease with a spectrum of additional pathological features. This is reflected by the varied names by which it has been called, including diffuse Lewy body disease, Lewy body dementia, Lewy body variant of Alzheimer disease, cortical Lewy body disease, and senile dementia of the Lewy body type.
This topic will describe the epidemiology, neuropathologic findings, and potential pathogenic mechanisms of dementia with Lewy bodies. The clinical features, diagnosis, prognosis, and treatment are discussed separately. (See "Clinical features and diagnosis of dementia with Lewy bodies" and "Prognosis and treatment of dementia with Lewy bodies".)
In population-based and clinic-based studies, dementia with Lewy bodies (DLB) accounts for approximately 4 to 30 percent of dementia cases [1,2]. DLB was likely underrepresented in many of these studies, however, most of which were not specifically designed to identify the prevalence of DLB and did not mention the methods of the evaluation of signs and symptoms, such as extrapyramidal signs or fluctuations in cognition, that would have increased the likelihood of diagnosing DLB . Autopsy series have also found DLB to represent a greater percentage of dementia cases than is typically reported in clinical series, with DLB comprising as much as 31 percent of cases in one study [3,4].
- Vann Jones SA, O'Brien JT. The prevalence and incidence of dementia with Lewy bodies: a systematic review of population and clinical studies. Psychol Med 2014; 44:673.
- Zaccai J, McCracken C, Brayne C. A systematic review of prevalence and incidence studies of dementia with Lewy bodies. Age Ageing 2005; 34:561.
- Barker WW, Luis CA, Kashuba A, et al. Relative frequencies of Alzheimer disease, Lewy body, vascular and frontotemporal dementia, and hippocampal sclerosis in the State of Florida Brain Bank. Alzheimer Dis Assoc Disord 2002; 16:203.
- Fujimi K, Sasaki K, Noda K, et al. Clinicopathological outline of dementia with Lewy bodies applying the revised criteria: the Hisayama study. Brain Pathol 2008; 18:317.
- McKeith IG. Dementia with Lewy bodies. Br J Psychiatry 2002; 180:144.
- Klatka LA, Louis ED, Schiffer RB. Psychiatric features in diffuse Lewy body disease: a clinicopathologic study using Alzheimer's disease and Parkinson's disease comparison groups. Neurology 1996; 47:1148.
- Olichney JM, Galasko D, Salmon DP, et al. Cognitive decline is faster in Lewy body variant than in Alzheimer's disease. Neurology 1998; 51:351.
- Papka M, Rubio A, Schiffer RB. A review of Lewy body disease, an emerging concept of cortical dementia. J Neuropsychiatry Clin Neurosci 1998; 10:267.
- Boot BP, Orr CF, Ahlskog JE, et al. Risk factors for dementia with Lewy bodies: a case-control study. Neurology 2013; 81:833.
- Savica R, Grossardt BR, Bower JH, et al. Incidence of dementia with Lewy bodies and Parkinson disease dementia. JAMA Neurol 2013; 70:1396.
- Woodruff BK, Graff-Radford NR, Ferman TJ, et al. Family history of dementia is a risk factor for Lewy body disease. Neurology 2006; 66:1949.
- Galvin JE, Lee SL, Perry A, et al. Familial dementia with Lewy bodies: clinicopathologic analysis of two kindreds. Neurology 2002; 59:1079.
- Tsuang DW, Dalan AM, Eugenio CJ, et al. Familial dementia with lewy bodies: a clinical and neuropathological study of 2 families. Arch Neurol 2002; 59:1622.
- Brett FM, Henson C, Staunton H. Familial diffuse Lewy body disease, eye movement abnormalities, and distribution of pathology. Arch Neurol 2002; 59:464.
- Bonner LT, Tsuang DW, Cherrier MM, et al. Familial dementia with Lewy bodies with an atypical clinical presentation. J Geriatr Psychiatry Neurol 2003; 16:59.
- Bogaerts V, Engelborghs S, Kumar-Singh S, et al. A novel locus for dementia with Lewy bodies: a clinically and genetically heterogeneous disorder. Brain 2007; 130:2277.
- Meeus B, Theuns J, Van Broeckhoven C. The genetics of dementia with Lewy bodies: what are we missing? Arch Neurol 2012; 69:1113.
- Nervi A, Reitz C, Tang MX, et al. Familial aggregation of dementia with Lewy bodies. Arch Neurol 2011; 68:90.
- Goker-Alpan O, Giasson BI, Eblan MJ, et al. Glucocerebrosidase mutations are an important risk factor for Lewy body disorders. Neurology 2006; 67:908.
- Mata IF, Samii A, Schneer SH, et al. Glucocerebrosidase gene mutations: a risk factor for Lewy body disorders. Arch Neurol 2008; 65:379.
- Nalls MA, Duran R, Lopez G, et al. A multicenter study of glucocerebrosidase mutations in dementia with Lewy bodies. JAMA Neurol 2013; 70:727.
- Clark LN, Kartsaklis LA, Wolf Gilbert R, et al. Association of glucocerebrosidase mutations with dementia with lewy bodies. Arch Neurol 2009; 66:578.
- Shiner T, Mirelman A, Gana Weisz M, et al. High Frequency of GBA Gene Mutations in Dementia With Lewy Bodies Among Ashkenazi Jews. JAMA Neurol 2016; 73:1448.
- Leverenz JB, Fishel MA, Peskind ER, et al. Lewy body pathology in familial Alzheimer disease: evidence for disease- and mutation-specific pathologic phenotype. Arch Neurol 2006; 63:370.
- Nishioka K, Wider C, Vilariño-Güell C, et al. Association of alpha-, beta-, and gamma-Synuclein with diffuse lewy body disease. Arch Neurol 2010; 67:970.
- Bras J, Guerreiro R, Darwent L, et al. Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies. Hum Mol Genet 2014; 23:6139.
- Berge G, Sando SB, Rongve A, et al. Apolipoprotein E ε2 genotype delays onset of dementia with Lewy bodies in a Norwegian cohort. J Neurol Neurosurg Psychiatry 2014; 85:1227.
- Wang CS, Burke JR, Steffens DC, et al. Twin pairs discordant for neuropathologically confirmed Lewy body dementia. J Neurol Neurosurg Psychiatry 2009; 80:562.
- Lewy, FH. Paralysis agitans. In: Handbuch der Neurologie, Lawandowsky, M (Eds), Springer-Verlag, Berlin 1912. p.920.
- OKAZAKI H, LIPKIN LE, ARONSON SM. Diffuse intracytoplasmic ganglionic inclusions (Lewy type) associated with progressive dementia and quadriparesis in flexion. J Neuropathol Exp Neurol 1961; 20:237.
- Zaccai J, Brayne C, McKeith I, et al. Patterns and stages of alpha-synucleinopathy: Relevance in a population-based cohort. Neurology 2008; 70:1042.
- McKeith I, Mintzer J, Aarsland D, et al. Dementia with Lewy bodies. Lancet Neurol 2004; 3:19.
- Duda JE, Giasson BI, Mabon ME, et al. Novel antibodies to synuclein show abundant striatal pathology in Lewy body diseases. Ann Neurol 2002; 52:205.
- Barber R, Panikkar A, McKeith IG. Dementia with Lewy bodies: diagnosis and management. Int J Geriatr Psychiatry 2001; 16 Suppl 1:S12.
- Rowe CC, Ng S, Ackermann U, et al. Imaging beta-amyloid burden in aging and dementia. Neurology 2007; 68:1718.
- Gomperts SN, Rentz DM, Moran E, et al. Imaging amyloid deposition in Lewy body diseases. Neurology 2008; 71:903.
- Edison P, Rowe CC, Rinne JO, et al. Amyloid load in Parkinson's disease dementia and Lewy body dementia measured with [11C]PIB positron emission tomography. J Neurol Neurosurg Psychiatry 2008; 79:1331.
- Harrington CR, Perry RH, Perry EK, et al. Senile dementia of Lewy body type and Alzheimer type are biochemically distinct in terms of paired helical filaments and hyperphosphorylated tau protein. Dementia 1994; 5:215.
- Strong C, Anderton BH, Perry RH, et al. Abnormally phosphorylated tau protein in senile dementia of Lewy body type and Alzheimer disease: evidence that the disorders are distinct. Alzheimer Dis Assoc Disord 1995; 9:218.
- Imamura T, Ishii K, Hirono N, et al. Visual hallucinations and regional cerebral metabolism in dementia with Lewy bodies (DLB). Neuroreport 1999; 10:1903.
- Hansen LA, Masliah E, Terry RD, Mirra SS. A neuropathological subset of Alzheimer's disease with concomitant Lewy body disease and spongiform change. Acta Neuropathol 1989; 78:194.
- Haroutunian V, Serby M, Purohit DP, et al. Contribution of Lewy body inclusions to dementia in patients with and without Alzheimer disease neuropathological conditions. Arch Neurol 2000; 57:1145.
- Nelson PT, Kryscio RJ, Jicha GA, et al. Relative preservation of MMSE scores in autopsy-proven dementia with Lewy bodies. Neurology 2009; 73:1127.
- Ballard CG, Jacoby R, Del Ser T, et al. Neuropathological substrates of psychiatric symptoms in prospectively studied patients with autopsy-confirmed dementia with lewy bodies. Am J Psychiatry 2004; 161:843.
- Harding AJ, Broe GA, Halliday GM. Visual hallucinations in Lewy body disease relate to Lewy bodies in the temporal lobe. Brain 2002; 125:391.
- Nagahama Y, Okina T, Suzuki N, Matsuda M. Neural correlates of psychotic symptoms in dementia with Lewy bodies. Brain 2010; 133:557.
- Benarroch EE, Schmeichel AM, Sandroni P, et al. Involvement of vagal autonomic nuclei in multiple system atrophy and Lewy body disease. Neurology 2006; 66:378.
- Hake, AM, Farlow, E, Farlow, MR, et al. Diffuse Lewy body disease clinically resembling multiple system atrophy. Poster session; Saturday, March 12, 2005. Program and abstracts of the 7th International Conference AD/PD 2005; March 9-13, 2005; Sorrento, Italy.
- Benarroch EE, Schmeichel AM, Dugger BN, et al. Dopamine cell loss in the periaqueductal gray in multiple system atrophy and Lewy body dementia. Neurology 2009; 73:106.
- Gómez-Isla T, Growdon WB, McNamara M, et al. Clinicopathologic correlates in temporal cortex in dementia with Lewy bodies. Neurology 1999; 53:2003.
- Merdes AR, Hansen LA, Jeste DV, et al. Influence of Alzheimer pathology on clinical diagnostic accuracy in dementia with Lewy bodies. Neurology 2003; 60:1586.
- Weisman D, Cho M, Taylor C, et al. In dementia with Lewy bodies, Braak stage determines phenotype, not Lewy body distribution. Neurology 2007; 69:356.
- Harding AJ, Halliday GM. Cortical Lewy body pathology in the diagnosis of dementia. Acta Neuropathol 2001; 102:355.
- Cercy SP, Bylsma FW. Lewy bodies and progressive dementia: a critical review and meta-analysis. J Int Neuropsychol Soc 1997; 3:179.
- Del Ser T, Hachinski V, Merskey H, Munoz DG. Clinical and pathologic features of two groups of patients with dementia with Lewy bodies: effect of coexisting Alzheimer-type lesion load. Alzheimer Dis Assoc Disord 2001; 15:31.
- Holtzer R, Irizarry MC, Sanders J, et al. Relation of quantitative indexes of concurrent alpha-synuclein abnormalities to clinical outcome in autopsy-proven Alzheimer disease. Arch Neurol 2006; 63:226.
- Lopez OL, Becker JT, Sweet RA, et al. Lewy bodies in the amygdala increase risk for major depression in subjects with Alzheimer disease. Neurology 2006; 67:660.
- McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 2005; 65:1863.
- Perry EK, Haroutunian V, Davis KL, et al. Neocortical cholinergic activities differentiate Lewy body dementia from classical Alzheimer's disease. Neuroreport 1994; 5:747.
- Perry EK, Marshall E, Perry RH, et al. Cholinergic and dopaminergic activities in senile dementia of Lewy body type. Alzheimer Dis Assoc Disord 1990; 4:87.
- Ballard C, Piggott M, Johnson M, et al. Delusions associated with elevated muscarinic binding in dementia with Lewy bodies. Ann Neurol 2000; 48:868.
- Sabbagh MN, Corey-Bloom J, Tiraboschi P, et al. Neurochemical markers do not correlate with cognitive decline in the Lewy body variant of Alzheimer disease. Arch Neurol 1999; 56:1458.
- Samuel W, Alford M, Hofstetter CR, Hansen L. Dementia with Lewy bodies versus pure Alzheimer disease: differences in cognition, neuropathology, cholinergic dysfunction, and synapse density. J Neuropathol Exp Neurol 1997; 56:499.
- Shimada H, Hirano S, Shinotoh H, et al. Mapping of brain acetylcholinesterase alterations in Lewy body disease by PET. Neurology 2009; 73:273.
- Bohnen NI, Kaufer DI, Ivanco LS, et al. Cortical cholinergic function is more severely affected in parkinsonian dementia than in Alzheimer disease: an in vivo positron emission tomographic study. Arch Neurol 2003; 60:1745.
- Bohnen NI, Kaufer DI, Hendrickson R, et al. Cognitive correlates of cortical cholinergic denervation in Parkinson's disease and parkinsonian dementia. J Neurol 2006; 253:242.
- Perry EK, Irving D, Kerwin JM, et al. Cholinergic transmitter and neurotrophic activities in Lewy body dementia: similarity to Parkinson's and distinction from Alzheimer disease. Alzheimer Dis Assoc Disord 1993; 7:69.
- Piggott MA, Marshall EF, Thomas N, et al. Striatal dopaminergic markers in dementia with Lewy bodies, Alzheimer's and Parkinson's diseases: rostrocaudal distribution. Brain 1999; 122 ( Pt 8):1449.
- Piggott MA, Perry EK, McKeith IG, et al. Dopamine D2 receptors in demented patients with severe neuroleptic sensitivity. Lancet 1994; 343:1044.
- Sweet RA, Hamilton RL, Healy MT, et al. Alterations of striatal dopamine receptor binding in Alzheimer disease are associated with Lewy body pathology and antemortem psychosis. Arch Neurol 2001; 58:466.
- Cheng AV, Ferrier IN, Morris CM, et al. Cortical serotonin-S2 receptor binding in Lewy body dementia, Alzheimer's and Parkinson's diseases. J Neurol Sci 1991; 106:50.
- Mori T, Ikeda M, Fukuhara R, et al. Correlation of visual hallucinations with occipital rCBF changes by donepezil in DLB. Neurology 2006; 66:935.
- Devos D, Tir M, Maurage CA, et al. ERG and anatomical abnormalities suggesting retinopathy in dementia with Lewy bodies. Neurology 2005; 65:1107.