Low sensitivity in clinical diagnoses of dementia with Lewy bodies

Nelson, Peter T.; Jicha, Gregory A.; Kryscio, Richard J.; Abner, Erin L.; Schmitt, Frederick A.; Cooper, Gregory; Xu, Li; Smith, Charles D.; Markesbery, William R.

doi:10.1007/s00415-009-5324-y

Cited by 229 publications

(207 citation statements)

References 37 publications

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“…They were established in 1995 and revised in both 1999 and 2005, with estimated sensitivity of 32% and specificity of 95%. 45 The criteria are depicted in the ►Table 1 and are adapted from McKeith et al 15 Definitive diagnosis, as in all neurodegenerative diseases, is by brain autopsy and pathologic confirmation. 15,16,22 Mandatory criteria for diagnosis of probable DLB include dementia plus two out of three core features: fluctuation of cognition or alertness, visual hallucinations, or parkinsonian features.…”

Section: Diagnostic Criteriamentioning

confidence: 99%

Dementia with Lewy Bodies

Mayo

Bordelon

2014

Semin Neurol

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).Dementia with Lewy bodies (DLB) is an atypical parkinsonian disorder characterized as a synucleinopathy based on the cardinal pathologic finding, the Lewy body, a neuronal inclusion comprised of aggregated α-synuclein. Lewy bodies are found in brainstem nuclei in both Parkinson disease (PD) as well as in DLB, though in DLB there is a concomitant presence of Lewy bodies in the cortex and subcortical white matter. The cortical Lewy bodies may not demonstrate the classic structure of an eosinophilic core with surrounding halo; however, they contain α-synuclein. Clinically, DLB manifests with fluctuating alertness, visual hallucinations, and parkinsonian motor symptoms, and has features of both a cortical and a subcortical dementia. EpidemiologyDementia with Lewy bodies is the second most common pathologic diagnosis of dementia, next to Alzheimer disease (AD) and accounts for 25% of all dementias. 1 The prevalence of DLB is estimated to be 0.7% of the population over 65 years of age. 2 Given the challenge of clinical diagnostic accuracy in dementia, there is a wide variation in estimates of the prevalence among dementia patients, ranging from 3 to 26.3% in those over the age of 65 years. 3,4 The incidence of DLB is 3.5 per 100,000 person years and this increases with age. 5 There is a slightly greater male predominance of 1.9:1. 6 Risk factors of DLB include advanced age, hypertension, hyperlipidemia, and carriers of one or more APOE ε4 alleles. 7-9 As in PD, there is overrepresentation of the CYP2D6B allele, and a greater heterozygous frequency of glucocerebrosidase 1 (GBA1) estimated at 3.5% versus 2.9% in Parkinson disease dementia (PDD) and 0.4% in the general population. 10 A separate study also found a significant association between GBA1 mutation carrier status and DLB with an odds ratio of 8.28 versus 6.48 in PDD. 11 PathophysiologyDementia with Lewy bodies is considered a synucleinopathy, along with PD and multiple system atrophy (MSA). It is distinguished pathologically by the presence of Lewy bodies, which are intracellular inclusions with an eosinophilic core Keywords ► dementia with Lewy bodies ► Lewy body ► synucleinopathy ► dementia ► parkinsonism AbstractDementia with Lewy bodies (DLB) is the second most common diagnosis of dementia after Alzheimer disease (AD). The essential pathologic feature is the Lewy body, a neuronal inclusion containing α-synuclein, found in brainstem nuclei and the neocortex. Clinical features include early fluctuations in attention, hallucinations, and parkinsonism, with progression to a combined cortical and subcortical dementia. To distinguish it from Parkinson disease dementia, a time course of one year from cognitive changes to motor feature onset has been established. There is more severe impairment of verbal fluency, executive function, and visuospatial abilities in DLB patients. Both rapid eye movement sleep behavior disorder and neuroleptic sensitivity are notable in this patient group. Treatment is aimed at symptom management. Cholinesterase inhibitors can be bene...

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Section: Diagnostic Criteriamentioning

confidence: 99%

Dementia with Lewy Bodies

Mayo

Bordelon

2014

Semin Neurol

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“…A review of 2,861 neurodegenerative disease cases of the National Alzheimer's Coordinating Center Registry (NACCR) showed high diagnostic accuracy for AD (85% sensitivity, 51.1% specificity) and low sensitivity for DLB (32% for pure AD and 12% for AD+DLB) with a specificity over 58% [70]. Evaluation of the accuracy of current clinical diagnostic methods for AD in 919 autopsy cases from the database of the NACC (2005-2010) revealed a sensitivity from 70.9 to 87.3% and a specificity of 44.3 to 70.8%.…”

Section: Introductionmentioning

confidence: 99%

“…Demonstration that SDS-soluble Aβ measured by immunoassay was better than post mortem PiB binding has important implications for imaging-based biomarkers [66]. In some PiB-negative cases, a combination of pre-existent non-AD pathology and tau-mediated neurodegeneration may be present prior to Aβ pathology [67].Hippocampal atrophy in the elderly, demonstrated by modern imaging methods and confirmed by postmortem diagnosis of AD [44,68], has been shown to be an important and under-appreciated brain lesion of aging [69].A review of 2,861 neurodegenerative disease cases of the National Alzheimer's Coordinating Center Registry (NACCR) showed high diagnostic accuracy for AD (85% sensitivity, 51.1% specificity) and low sensitivity for DLB (32% for pure AD and 12% for AD+DLB) with a specificity over 58% [70]. Evaluation of the accuracy of current clinical diagnostic methods for AD in 919 autopsy cases from the database of the NACC (2005-2010) revealed a sensitivity from 70.9 to 87.3% and a specificity of 44.3 to 70.8%.…”

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confidence: 99%

Neuropathology of Dementia Disorders

Jellinger¹

2014

J Alzheimers Dis Parkinsonism

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IntroductionDementia, encompassing deficits in several cognitive domains that are severe enough to interfere with daily functioning [1], in the new DSM V classification is classified within the broad category of major neurocognitive disorders, proposing specific criteria for the various etiologies [2]. Previously defined as the manifestation of deteriorating brain functions over time due to cell deaths in the brain caused by neurodegeneration or any other disease [3], according to recent research dementia is not primarily caused by neuronal cell death/loss, but by dysfunction and loss of synapses [4] in AD [5] and in α-synucleinopathies [6]. Other causes include cholinergic neuronal and axonal abnormalities [7,8], as well as pre-and postsynaptic cortical cholinergic deficits also occurring in early AD [9]. These changes due to disconnection of major nervous circuitries causing default networks [10][11][12][13] have been demonstrated in vivo in early AD [14], suggesting that disease progress is transmitted by neuronal pathways [15]. A prionlike spread of misfolded protein aggregates in the pathogenesis and progression of neurodegeneration is a hot spot of discussion [16][17][18][19][20][21].Both the prevalence and incidence of dementia increase exponentially with age. In 2010, 35.6 million people worldwide lived with dementia, with around 8 million new cases every year. Numbers are expected to double or triple every 5-10 years, to 135 millions in 2050, 16 millions in Europe. In 2010, 58% of all demented people lived in low-cost countries, with their proportion anticipated to rise to 71% in 2050 [22]. According to recent data from China the incidence of dementia was 9.87/1000 person years and the median standardised mortality ratio was 1.94:1 [23]. With the disproportional growth of the elderly population, dementia has become a major public health and socio-economic problem that threatens to become the scourge of our century. The total costs for dementia were US$ 604 billion in 2010 worldwide, up to 70% for social care alone [24], total payments for AD for 2013 were expected to be $ 203 billion in USA alone, not included contributions of unpaid caregivers [25]. Neuropathology of Dementia DisordersKurt A Jellinger* Institute of Clinical Neurobiology, Kenyongasse 18, A 1070, Vienna, Austria AbstractDementia, being not a specific disease but a syndrome characterized by deficits in several cognitive domains, is a major public health and socio-economic problem of our century. It is caused by dysfunction/loss of synapses and neurons inducing default neuronal networks. Despite updated concensus criteria for the clinical diagnosis of the major neurodegenerative disorders and new biomarkers, the diagnostic accuracy ranges from 65 to 96% (for Alzheimer's disease /AD), with a sensitivity versus other dementias of around 85.4% and a specificity of up to 77.7%. Pathologic assessment, using genetic and molecular biological methods, based on homogenous definitions, harmonized interlaboratory and assessment standards, can achiev...

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“…The clinical criteria for the diagnosis of DLB are criticized for having low sensitivity. 28,29 Moreover, patients who fulfill the clinical criteria for probable DLB may have additional AD pathology and Lewy body disease pathology may be present in Figure 2 Cumulative incidences of progression to dementia with Lewy bodies (DLB) and Alzheimer disease (AD)…”

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confidence: 99%

IC‐02‐05: Hippocampal volumes predict risk of dementia with lewy bodies in mild cognitive impairment

Kantarci

Lesnick

Przybelski

et al. 2015

Alzheimer's & Dementia

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Objective: To predict the risk of probable dementia with Lewy bodies (DLB) competing with Alzheimer disease (AD) dementia by hippocampal volume (HV) in patients with mild cognitive impairment (MCI) with impairments in amnestic or nonamnestic cognitive domains.Methods: Patients with MCI (n 5 160) from the Mayo Clinic Alzheimer's Disease Research Center, who participated in an MRI study at baseline from 2005 to 2014, were followed with approximately annual clinical evaluations. HVs were analyzed from 3T MRIs using FreeSurfer (5.3). Hippocampal atrophy was determined from the most normal 10th percentile of the measurement distributions in a separate cohort of clinically diagnosed patients with AD dementia. The subdistribution hazard ratios for progression to probable DLB and AD dementia were estimated by taking into account the competing risks.Results: During a median (range) follow-up of 2.0 (0.7-8.1) years, 20 (13%) patients with MCI progressed to probable DLB, and 61 (38%) progressed to AD dementia. The estimated subdistribution hazard ratio (95% confidence interval) for normal HV relative to hippocampal atrophy for progression to AD dementia was 0.56 (0.34-0.91; p 5 0.02) after taking into account the competing risks. The estimated hazard ratio for normal HV relative to hippocampal atrophy for progression to probable DLB was 4.22 (1.42-12.6; p 5 0.01) after adjusting for age and after including the MCI subtype in the model. Identifying patients with mild cognitive impairment (MCI) who are at risk for dementia with Lewy bodies (DLB) is critical for early interventions. Amnestic subtype of MCI has been established on clinical grounds in order to identify individuals who are at risk for Alzheimer disease (AD) dementia.1,2 Patients with MCI who have impairments in nonamnestic cognitive domains may be at an increased risk of DLB. 3,4 We have previously demonstrated that the competing risk of progression to probable DLB vs AD is higher in patients with nonamnestic MCI compared to amnestic MCI. 5Hippocampal volumes on antemortem MRI are preserved in patients with DLB who have little or no additional AD pathology at autopsy.6-8 Hippocampal volumes are lower in patients with DLB with increasing Braak neurofibrillary tangle stage regardless of the severity of Lewy

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Low sensitivity in clinical diagnoses of dementia with Lewy bodies

Cited by 229 publications

References 37 publications

Dementia with Lewy Bodies

Dementia with Lewy Bodies

Neuropathology of Dementia Disorders

IC‐02‐05: Hippocampal volumes predict risk of dementia with lewy bodies in mild cognitive impairment

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