Cognitive decline is faster in Lewy body variant than in Alzheimer's disease

Department of Neurosciences, University of California, San Diego and San Diego Veteran's Affairs Medical Center, 92161, USA.
Neurology (Impact Factor: 8.29). 08/1998; 51(2):351-7. DOI: 10.1212/WNL.51.2.351
Source: PubMed

ABSTRACT To quantify the rate of cognitive decline on the Mini-Mental State Examination (MMSE) in autopsy-diagnosed Lewy body variant (LBV) of Alzheimer's disease (AD) cases. We hypothesized that LBV patients would have a faster cognitive decline and shorter survival compared with patients with pure AD.
Prior reports have shown extrapyramidal signs to be associated with a poorer prognosis in AD. It has been suggested that LBV is often characterized by a rapidly progressive course. Few data are available regarding the rate of cognitive decline in autopsy-confirmed LBV dementia cases.
We searched the databases of the University of California-San Diego Alzheimer's Disease Research Center and the Consortium to Establish a Registry in Alzheimer's Disease (CERAD) for dementia cases with 1) an autopsy diagnosis of definite or probable AD (CERAD criteria) with concomitant Lewy bodies and 2) longitudinal MMSE assessments. This resulted in a series of 40 LBV cases and 148 AD cases without Lewy bodies, with comparable baseline MMSE scores, age, and education. The rate of cognitive decline was calculated as the baseline MMSE -- final MMSE. Methods were devised to reduce floor effects on the MMSE.
The average rate of cognitive decline was -5.8 +/- 4.5 points/y in LBV and -4.1 +/- 3.0 points/y in AD (t-test, p < 0.01). The LBV group declined a similar amount on the MMSE (means, -10.0 versus -9.6 points) over a significantly shorter time interval (1.9 versus 2.7 years; p = 0.005) than did AD patients. At baseline, the mean MMSE scores were nearly identical (18.2 in LBV; 17.8 in AD), but on follow-up examinations approximately 1, 2, and 3 years later, there were intergroup mean differences of 1.8 points (two-tailed p = 0.19), 4.2 points (p = 0.04), and 5.6 points (p = 0.03), respectively. The LBV cases had shorter survival time from the onset of cognitive symptoms (7.7 +/- 3.0 years versus 9.3 +/- 3.5 years; p = 0.007) and a shorter mean survival after entry/baseline, which was of marginal significance (3.6 versus 4.1 years; p = 0.11).
This study demonstrates that LBV is characterized by a faster cognitive decline and accelerated mortality compared with AD.

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    • "While these criteria improve classification, there is still considerable misdiagnosis compared to autopsy, particularly early in the disease course [4,5]. More accurate differentiation of these two conditions could provide clinically relevant prognostic information [6,7] and influence treatment decisions [8-10]. "
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    ABSTRACT: Biomarkers based on the underlying pathology of Alzheimer's disease (AD) and Dementia with Lewy Bodies (DLB) have the potential to improve diagnosis and understanding of the substrate for cognitive impairment in these disorders. The objective of this study was to compare the patterns of amyloid and dopamine PET imaging in patients with AD, DLB and Parkinson's disease (PD) using the amyloid imaging agent florbetapir F 18 and 18F-AV-133 (florbenazine), a marker for vesicular monamine type 2 transporters (VMAT2). Patients with DLB and AD, Parkinson's disease (PD) and healthy controls (HC) were recruited for this study. On separate days, subjects received intravenous injections of florbetapir, and florbenazine. Amyloid burden and VMAT2 density were assessed quantitatively and by binary clinical interpretation. Imaging results for both tracers were compared across the four individual diagnostic groups and for combined groups based on underlying pathology (AD/DLB vs. PD/HC for amyloid burden and PD/DLB vs. AD/HC for VMAT binding) and correlated with measures of cognition and parkinsonism. 11 DLB, 10 AD, 5 PD, and 5 controls participated in the study. Amyloid binding was significantly higher in the combined AD/DLB patient group (n = 21) compared to the PD/ HC groups (n = 10, mean SUVr: 1.42 vs. 1.07; p = 0.0006). VMAT2 density was significantly lower in the PD/DLB group (n = 16) compared to the AD/ HC group (n = 15; 1.83 vs. 2.97; p < 0.0001). Within the DLB group, there was a significant correlation between cognitive performance and striatal florbenazine binding (r = 0.73; p = 0.011). The results of this study show significant differences in both florbetapir and florbenazine imaging that are consistent with expected pathology. In addition, VMAT density correlated significantly with cognitive impairment in DLB patients ( identifier: NCT00857506, registered March 5, 2009).
    BMC Neurology 04/2014; 14(1):79. DOI:10.1186/1471-2377-14-79 · 2.04 Impact Factor
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    • "Les perspectives d'une telle e ´ chelle sont multiples. Dans la MA, les ré percussions de la pathologie de Lewy associé e sur le phé notype clinique (Johnson et al., 2005) et le pronostic (Kraybill et al., 2005 ; Olichney et al., 1998) restent mé connues. Le dé ficit cholinergique pré coce et sé vè re des maladies a ` corps de Lewy interroge e ´ galement sur l'influence de la pathologie de Lewy sur la ré ponse thé rapeutique aux inhibiteurs de l'acé tylcholinesté rase dans la MA (Samuel et al., 2000 ; Touchon et al., 2006). "
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    ABSTRACT: Dementia with Lewy bodies (DLB) is the second cause of degenerative dementia in autopsy studies. In clinical pratice however, the prevalence of DLB is much lower with important intercenter variations. Among the reasons for this low sensitivity of DLB diagnosis are (1) the imprecision and subjectivity of the diagnostic criteria; (2) the underestimation of non-motor symptoms (REM-sleep behavior disorder, dysautonomia, anosmia); mostly (3) the nearly constant association of Lewy bodies with Alzheimer's disease pathology, which dominates the clinical phenotype. With the avenue of targeted therapies against the protein agregates, new clinical scales able to apprehend the coexistence of Lewy pathology in Alzheimer's disease are expected.
    Revue Neurologique 11/2013; 169(11):844–857. DOI:10.1016/j.neurol.2013.05.004 · 0.66 Impact Factor
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    • "However, 30–40% of AD cases present with additional signs of proteinopathies, including intracellular inclusions composed of α-synuclein (αSyn) known as Lewy bodies and Lewy neurites (LB/LN)(Hamilton, 2000; Trojanowski, 2002). The presence of these additional lesions does not appear to be innocuous, as subjects presenting with the LB variant of AD generally display a more rapid rate of cognitive decline than subjects with AD alone (Olichney et al., 1998). Studies using experimental models have proposed that Aβ, tau and αSyn may have synergistic adverse effects (Giasson et al., 2003a; Lee et al., 2004). "
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    ABSTRACT: Recent evidence has emphasized soluble species of amyloid-β (Aβ) and tau as pathogenic effectors in Alzheimer's disease (AD). Despite the fact that Aβ, tau, and α-synuclein (αSyn) can promote each other's aggregation, the potential contribution of soluble αSyn to AD pathogenesis is unknown. Here, we found an approximate twofold increase over controls in soluble αSyn levels in AD brains in the absence of Lewy body cytopathology. Importantly, soluble αSyn levels were a quantitatively stronger correlate of cognitive impairment than soluble Aβ and tau levels. To examine a putative role for αSyn in modulating cognitive function, we used the Barnes circular maze to assess spatial reference memory in transgenic mice overexpressing human wild-type αSyn. The results revealed that an approximate threefold elevation of αSyn in vivo induced memory deficits similar to those observed in AD mouse models. The neurobiological changes associated with this elevation of soluble αSyn included decreases in selected synaptic vesicle proteins and an alteration of the protein composition of synaptic vesicles. Finally, a synergism between Aβ/APP and human tau seems to be responsible for the abnormal elevation of soluble αSyn in transgenic mice. Altogether, our data reveal an unexpected role for soluble, intraneuronal αSyn in AD pathophysiology.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 07/2012; 32(30):10253-66. DOI:10.1523/JNEUROSCI.0581-12.2012 · 6.34 Impact Factor
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