Influence of Alzheimer pathology on clinical diagnostic accuracy in dementia with Lewy bodies

Merdes, Annette; Hansen, Lawrence A.; Jeste, D. V.; Galasko, Douglas; Hofstetter, C. Richard; Ho, Gilbert; Thal, Leon J.; Corey–Bloom, Jody

doi:10.1212/01.wnl.0000065889.42856.f2

Cited by 282 publications

(215 citation statements)

References 28 publications

(28 reference statements)

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“…Other studies indicate the existence of alternative mechanisms, including the formation of SDS-stable oligomers (Podlisny et al ., 1995) and chaperone complexes of Aβ peptides with specific carrier proteins (Wiltfang et al ., 2002, 2003; Bibl et al ., 2004). However, misfolding and subsequent deposition of proteins is considered to be a major pathological event in both neurodegenerative diseases and amyloid pathology has also been reported for DLB (Merdes et al ., 2003). …”

Section: Discussionmentioning

confidence: 92%

CSF amyloid-β-peptides in Alzheimer's disease, dementia with Lewy bodies and Parkinson's disease dementia

Bibl¹,

Mollenhauer²,

Esselmann³

et al. 2006

Brain

182

144

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As the differential diagnosis of dementias based on established clinical criteria is often difficult, biomarkers for applicable diagnostic testing are currently under intensive investigation. Amyloid plaques deposited in the brain of patients suffering from Alzheimer's disease, dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) mainly consist of carboxy-terminally elongated forms of amyloid-beta (Aβ) peptides, such as Aβ1–42. Absolute Aβ1–42 levels in CSF have shown diagnostic value for the diagnosis of Alzheimer's disease, but the discrimination among Alzheimer's disease, DLB and PDD was poor. A recently established quantitative urea-based Aβ-sodium-dodecylsulphate–polyacrylamide-gel-electrophoresis with Western immunoblot (Aβ-SDS–PAGE/immunoblot) revealed a highly conserved Aβ peptide pattern of the carboxy-terminally truncated Aβ peptides 1–37, 1–38, 1–39 in addition to 1–40 and 1–42 in human CSF. We used the Aβ-SDS–PAGE/immunoblot to investigate the CSF of 23 patients with Alzheimer's disease, 21 with DLB, 21 with PDD and 23 non-demented disease controls (NDC) for disease-specific alterations of the Aβ peptide patterns in its absolute and relative quantities. The diagnostic groups were matched for age and severity of dementia. The present study is the first attempt to evaluate the meaning of Aβ peptide patterns in CSF for differential diagnosis of the three neurodegenerative diseases—Alzheimer's disease, DLB and PDD. The Aβ peptide patterns displayed disease-specific variations and the ratio of the differentially altered Aβ1–42 to the Aβ1–37 levels subsequently discriminated all diagnostic groups from each other at a highly significant level, except DLB from PDD. Additionally, a novel peptide with Aβ-like immunoreactivity was observed constantly in the CSF of all 88 investigated patients. The pronounced percentage increase of this peptide in DLB allowed a highly significant discrimination from PDD. Using a cut-off point of 0.954%, this marker yielded a diagnostic sensitivity and specificity of 81 and 71%, respectively. From several lines of indication, we consider this peptide to represent an oxidized α-helical form of Aβ1–40 (Aβ1–40*). The increased abundance of Aβ1–40* probably reflects a disease-specific alteration of the Aβ1–40 metabolism in DLB. We conclude that Aβ peptide patterns reflect disease-specific pathophysiological pathways of different dementia syndromes as distinct neurochemical phenotypes. Although Aβ peptide patterns failed to fulfil the requirements for a sole biomarker, their combined evaluation with other biomarkers is promising in neurochemical dementia diagnosis. It is noteworthy that DLB and PDD exhibit distinct clinical temporal courses, despite their similar neuropathological appearance. Their distinct molecular phenotypes support the view of different pathophysiological pathways for each of these neurodegenerative diseases.

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Section: Discussionmentioning

confidence: 92%

CSF amyloid-β-peptides in Alzheimer's disease, dementia with Lewy bodies and Parkinson's disease dementia

Bibl¹,

Mollenhauer²,

Esselmann³

et al. 2006

Brain

182

144

View full text Add to dashboard Cite

show abstract

“…Because clinical assessment alone cannot reliably detect the co‐occurrence of these pathologies,59 an obvious limitation of our study is the lack of autopsy confirmation of most cases we analyzed by chart review or EEG. However, spectral slowing has been documented in autopsy‐confirmed cases of DLB61 and was confirmed here with a different approach to spectral analysis.…”

Section: Discussionmentioning

confidence: 99%

Network dysfunction in α‐synuclein transgenic mice and human Lewy body dementia

Morris

Sanchez

Verret

et al. 2015

Ann Clin Transl Neurol

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ObjectiveDementia with Lewy bodies (DLB) is associated with the accumulation of wild‐type human α‐synuclein (SYN) in neurons and with prominent slowing of brain oscillations on electroencephalography (EEG). However, it remains uncertain whether the EEG abnormalities are actually caused by SYN.MethodsTo determine whether SYN can cause neural network abnormalities, we performed EEG recordings and analyzed the expression of neuronal activity‐dependent gene products in SYN transgenic mice. We also carried out comparative analyses in humans with DLB.ResultsWe demonstrate that neuronal expression of SYN in transgenic mice causes a left shift in spectral power that closely resembles the EEG slowing observed in DLB patients. Surprisingly, SYN mice also had seizures and showed molecular hippocampal alterations indicative of aberrant network excitability, including calbindin depletion in the dentate gyrus. In postmortem brain tissues from DLB patients, we found reduced levels of calbindin mRNA in the dentate gyrus. Furthermore, nearly one quarter of DLB patients showed myoclonus, a clinical sign of aberrant network excitability that was associated with an earlier age of onset of cognitive impairments. In SYN mice, partial suppression of epileptiform activity did not alter their shift in spectral power. Furthermore, epileptiform activity in human amyloid precursor protein transgenic mice was not associated with a left shift in spectral power.InterpretationWe conclude that neuronal accumulation of SYN slows brain oscillations and, in parallel, causes aberrant network excitability that can escalate into seizure activity. The potential role of aberrant network excitability in DLB merits further investigation.

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“…The accuracy of the clinical diagnosis was ensured by clinical follow-up only. However, the histopathologic diagnosis may also be uncertain, as DLB often presents in coexistence with Alzheimer disease and vascular dementia pathology (36). Further, there is an excellent correlation between initial DAT imaging and diagnosis by autopsy in DLB patients (37).…”

Section: Discussionmentioning

confidence: 99%

Striatal Dopamine Transporter Binding Does Not Correlate with Clinical Severity in Dementia with Lewy Bodies

et al. 2013

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Patients who have dementia with Lewy bodies (DLB) show both clinical and histopathologic overlap with Alzheimer disease patients and Parkinson disease patients. In this study, we correlated the core features of DLB (dementia, parkinsonism, hallucinations, and fluctuations) with striatal dopamine transporter (DAT) availability as assessed with SPECT and 123 I-N-(3-iodoprop-2E-enyl)-2-b-carbomethoxy-3b-(4-methylphenyl) nortropane ( 123 I-PE2I) in patients with newly diagnosed DLB. Methods: Two hundred eighty-eight patients were consecutively included in the study as they were referred for diagnostic SPECT scanning of DAT with 123 I-PE2I. Of those patients, 51 had, on the basis of clinical guideline criteria, a probable-DLB diagnosis at follow-up 16 6 11.6 mo later. Before or on the day of the SPECT scan, DLB patients had a routine neurologic examination including Hoehn and Yahr grading and were cognitively evaluated with the Mini Mental State Examination. The central feature in dementia with Lewy bodies (DLB) is progressive dementia, but compared with other forms of dementia it has several additional frequent core features, namely fluctuations, hallucinations, and parkinsonism. Parkinson disease (PD), DLB, and PD dementia are seen as a spectrum of the same condition, "Lewy body diseases" (1). In the clinic, DLB and PD dementia are nosologically differentiated only by the time span between the development of parkinsonism and dementia. In DLB, cognitive problems occur less than a year after the onset of parkinsonism (2). The dopamine system is deeply involved in all Lewy body diseases, and dopamine is reduced in the basal ganglia as a consequence of the aggregation of Lewy bodies in this area of the brain (3,4).Imaging of the dopamine transporter (DAT) with SPECT serves as a surrogate marker of the nerve connection between axons from the substantia nigra and neurons in the striatum (5,6). An in vitro study of brains from monkeys treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, meant as a model of human DLB, suggested that the loss of DAT and the loss of striatal dopamine content are linearly correlated (7).In PD, many studies have shown a clear correlation between DAT binding and core features of parkinsonism (8). We identified only one DAT SPECT imaging study including 15 DLB patients correlating DAT binding (in which 123 I-2-b-carbomethoxy-3b-(4-iodophenyl)-N-(3-fluoropropyl)nortropane [ 123 I-FP-CIT] was used as the radioligand) with parkinsonism. The authors suggested that there might be a difference in the predilection for DAT uptake in PD versus DLB, since the caudate-to-putamen ratio was less reduced in DLB than in PD and, further, no correlation between severity of parkinsonism and DAT binding was found in DLB patients (9).SPECT imaging of cerebral blood flow has demonstrated frontoparietooccipital hypoperfusion patterns in DLB patients (10). The frontal hypoperfusion is interesting, since the dorsolateral circuit involved in planning and attention connects the frontal cortex with the striatum and ...

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Influence of Alzheimer pathology on clinical diagnostic accuracy in dementia with Lewy bodies

Abstract: The degree of concomitant AD tangle pathology has an important influence on the clinical characteristics and, therefore, the clinical diagnostic accuracy of DLB.

Cited by 282 publications

References 28 publications

CSF amyloid-β-peptides in Alzheimer's disease, dementia with Lewy bodies and Parkinson's disease dementia

CSF amyloid-β-peptides in Alzheimer's disease, dementia with Lewy bodies and Parkinson's disease dementia

Network dysfunction in α‐synuclein transgenic mice and human Lewy body dementia

Striatal Dopamine Transporter Binding Does Not Correlate with Clinical Severity in Dementia with Lewy Bodies

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