CSF diagnosis of Alzheimer’s disease and dementia with Lewy bodies

Summary. Differential diagnosis of Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) is often crucial. CSF Tau protein and Amyloid-beta (Aβ) peptides have shown diagnostic value for the diagnosis of AD, but discrimination from DLB was poor. Herein, we investigate CSF of 18 patients with probable AD, 25 with probable DLB and 14 non-demented disease controls (NDC) by Aβ-SDS-PAGE/immunoblot and commercially available ELISAs for Aβ1-42 and tau. CSF Aβ peptide patterns and tau exhibited disease specific alterations among AD and DLB. The ratio of Aβ1-42 to Aβ1-38 and Aβ1-42 to Aβ1-37, respectively, in combination with absolute tau, yielded a sensitivity and specificity of 100 and 92%, respectively. We conclude that CSF Aβ peptide patterns and tau levels reflect disease-specific pathophysiological pathways of these dementias as distinct neurochemical phenotypes. Combined evaluation of these biomarkers provides a reasonable accuracy for differential diagnosis of AD and DLB.     

Motor cortex inhibitory circuits in dementia with Lewy bodies and in Alzheimer’s disease

Summary. To determine whether a peculiar neurophysiological profile may contribute to characterize dementia with Lewy bodies (DLB) vs. Alzheimer disease (AD), we used transcranial magnetic stimulation to examine the excitability of two different inhibitory systems of the motor cortex, short latency intracortical inhibition (SICI) and short latency afferent inhibition (SAI) in 10 patients with DLB, in 13 patients with AD and in 15 healthy subjects. SICI and SAI were significantly reduced in AD patients, while both were not significantly different from the controls in DLB patients. The differential pattern of SICI and SAI exhibited by AD vs. DLB may have diagnostic significance in discriminating DLB from AD. Furthermore, this technique may help to clarify the pathophysiological entity of DLB; since SAI is a cortical phenomenon that depends on central cholinergic activity, our findings suggest that the mechanisms of cholinergic depletion in DLB may be different from that in AD, while normal SICI may reflect a less pronounced dysregulation of the intracortical GABAergic inhibitory circuitries in DLB.     

Atrophy of the cholinergic basal forebrain in dementia with Lewy bodies and Alzheimer’s disease dementia

Similar to Alzheimer’s disease (AD), dementia with Lewy bodies (DLB) is characterized by a profound degeneration of cortically-projecting cholinergic neurons of the basal forebrain (BF) and associated depletion of cortical cholinergic activity. We aimed to investigate subregional atrophy of the BF in DLB in vivo and compare it to the pattern of BF atrophy in AD. Structural MRI scans of 11 patients with DLB, 11 patients with Alzheimer’s disease, and 22 healthy controls were analysed using a recently developed technique for automated BF morphometry based on high-dimensional image warping and cytoarchitectonic maps of BF cholinergic nuclei. For comparison, hippocampus volume was assessed within the same morphometric framework using recently published consensus criteria for the definition of hippocampus outlines on MRI. The DLB group demonstrated pronounced and subregion-specific atrophy of the BF which was comparable to BF atrophy in AD: volume of the nucleus basalis Meynert was significantly reduced by 20–25 %, whereas rostral BF nuclei were only marginally affected. By contrast, hippocampus volume was markedly less affected in DLB compared to AD. Global cognition as determined by MMSE score was associated with BF volume in AD, but not in DLB, whereas visuoperceptual function as determined by the trail making test was associated with BF volume in DLB, but not in AD. DLB may be characterized by a more selective degeneration of the cholinergic BF compared to AD, which may be related to the differential cognitive profiles in both conditions.     

Eyelid retraction in dementia with Lewy bodies and Parkinson’s disease

Journal of Neurology -     

Follow-up investigations in cerebrospinal fluid of patients with dementia with Lewy bodies and Alzheimer’s disease

Summary. Measuring proteins in cerebrospinal fluid (CSF) has gained wide acceptance for the differential diagnosis of dementia. Some groups have already extended these investigations in Alzheimers disease (AD) by asking how stable these markers are in follow-up analysis, if they depend on the stage of disease and whether they can be used to monitor the progression and biological effects of treatment. We evaluated 21 patients with dementia with Lewy bodies (DLB) and 19 patients with AD, on two occasions, with regard to levels of tau protein, tau protein phosphorylated at threonine 181 (p-tau), A42, A40 and S-100B protein, using a set of commercially available assays.Tau protein levels were lower in DLB in first and second LP compared to AD and decreased during course of both groups. P-tau levels were increased in AD and DLB and decreased during follow-up. A42 and A40 remained relatively stable during follow-up but we found a slight increase of the median A42 level in DLB, whereas in AD, A42 tends to decrease during follow-up. S-100B protein increased during follow-up in both diseases.The protein dynamics in DLB and AD are relatively similar. S-100B protein may be a useful marker for follow-up in neurodegenerative diseases but has to be analysed in longer follow-up periods. Tau protein may be used to differentiate between DLB and AD.Follow-up CSF analyses are of limited value for the differentiation of AD and DLB. We conclude that more specific markers have to be established for the differentiation and follow-up of these diseases.     

Pathological entity of dementia with Lewy bodies and its differentiation from Alzheimer’s disease

We reclassified the pathological subtypes of dementia with Lewy bodies (DLB), based on both Lewy pathology and Alzheimer pathology, to clarify the pathological entity of DLB and the boundary between DLB and Alzheimers disease (AD) in autopsied cases, using both pathological and immunohistochemical methods. DLB was classified as either limbic type or neocortical type according to the degree of Lewy pathology including Lewy bodies (LB) and LB-related neurites by our staging, and was classified as pure form, common form or AD form according to the degree of Alzheimer pathology including neurofibrillary tangles (NFT) and amyloid deposits by Braak staging. These combined subtypes were lined up on a spectrum, not only with Lewy pathology but also with other DLB-related pathologies including Alzheimer pathology, neuronal loss in the substantia nigra, spongiform change in the transentorhinal cortex and LB-related neurites in the CA2–3 region. In contrast, the Lewy pathology of AD did not meet the stages of Lewy pathology in DLB, and there were scarcely any similarities in other DLB-related pathologies between AD and DLB. In addition, the Lewy pathology of AD had characteristics different from that of DLB, including the coexistence rate of LB with NFT, and the immunohistochemical and immunoelectron microscopic findings of LB and LB-related neurites. These findings suggest that DLB is a distinctive pathological entity that can be differentiated from AD, although it shows some pathological subtypes.     

Fluctuating cognition and different cognitive and behavioural profiles in Parkinson’s disease with dementia: comparison of dementia with Lewy bodies and Alzheimer’s disease

To examine the occurrence of fluctuating cognition (FC) in a group of patients with Parkinson’s disease with dementia (PDD), and to determine whether the presence of FC in PDD is associated with a pattern of cognitive and behavioural disturbances similar to the one shown by patients affected by dementia with Lewy bodies (DLB), a cluster analysis was carried out on the scores obtained by 27 PDD patients on the Clinician Assessment of Fluctuation Scale (CAF). The analysis separated the PDD patients into two subgroups, called PDD non-fluctuators (PDDNF; CAF ≤ 2) and PDD fluctuators (PDDF; CAF > 2). The two groups underwent a cognitive and behavioural evaluation. Their scores were compared with those obtained by DLB and Alzheimer’s disease (AD) patients. When exploring the cognitive performance of the patients with the Dementia Rating Scale-2 (DRS-2), PDDF had a similar pattern of impairments compared to DLB, which involved prevalently the attention and initiation/perseveration domains, and which was significantly more pronounced compared to that shown by PDDNF. The main behavioural finding of the study was the similar incidence of visual hallucinations in the PDDF and DLB groups, which was significantly higher compared to PDDNF and AD. Our results confirmed the hypothesis that subgroups with different cognitive profiles exist within PDD and that the occurrence of FC is the clinical variable associated with a DLB pattern of impairment in PDD. In conclusion, our study suggests that when FC occurs in PDD this syndrome becomes clinically undistinguishable from DLB.     

Alzheimer’s disease pathology in motor cortex in dementia with Lewy bodies clinically mimicking corticobasal degeneration

We report here a 70-year-old woman whose initial clinical presentation suggested corticobasal degeneration, but autopsy revealed dementia with Lewy bodies (DLB) with severe Alzheimer’s disease (AD)-type pathology accentuated in the motor cortex, in conjunction with a high burden of both cortical and brain stem LB. Review of the literature disclosed four patients with AD whose peri-Rolandic region was particularly involved by the disease and who exhibited similar clinical and neuropathological findings as in our patient except they lacked LB. It appears that DLB if associated with severe AD-type pathology can, like some unusual cases of AD, mimic corticobasal degeneration. Received: 20 October 1998 / Revised, accepted: 15 February 1999     

Staging TDP-43 pathology in Alzheimer’s disease

TDP-43 immunoreactivity occurs in 19–57 % of Alzheimer’s disease (AD) cases. Two patterns of TDP-43 deposition in AD have been described involving hippocampus (limbic) or hippocampus and neocortex (diffuse), although focal amygdala involvement has been observed. In 195 AD cases with TDP-43, we investigated regional TDP-43 immunoreactivity with the aim of developing a TDP-43 in AD staging scheme. TDP-43 immunoreactivity was assessed in amygdala, entorhinal cortex, subiculum, hippocampal dentate gyrus, occipitotemporal, inferior temporal and frontal cortices, and basal ganglia. Clinical, neuroimaging, genetic and pathological characteristics were assessed across stages. Five stages were identified: stage I showed scant-sparse TDP-43 in the amygdala only (17 %); stage II showed moderate-frequent amygdala TDP-43 with spread into entorhinal and subiculum (25 %); stage III showed further spread into dentate gyrus and occipitotemporal cortex (31 %); stage IV showed further spread into inferior temporal cortex (20 %); and stage V showed involvement of frontal cortex and basal ganglia (7 %). Cognition and medial temporal volumes differed across all stages and progression across stages correlated with worsening cognition and medial temporal volume loss. Compared to 147 AD patients without TDP-43, only the Boston Naming Test showed abnormalities in stage I. The findings demonstrate that TDP-43 deposition in AD progresses in a stereotypic manner that can be divided into five distinct topographic stages which are supported by correlations with clinical and neuroimaging features. Given these findings, we recommend sequential regional TDP-43 screening in AD beginning with the amygdala.     

Quantification of myelin loss in frontal lobe white matter in vascular dementia, Alzheimer’s disease, and dementia with Lewy bodies

The aim of this study was to characterize myelin loss as one of the features of white matter abnormalities across three common dementing disorders. We evaluated post-mortem brain tissue from frontal and temporal lobes from 20 vascular dementia (VaD), 19 Alzheimer’s disease (AD) and 31 dementia with Lewy bodies (DLB) cases and 12 comparable age controls. Images of sections stained with conventional luxol fast blue were analysed to estimate myelin attenuation by optical density. Serial adjacent sections were then immunostained for degraded myelin basic protein (dMBP) and the mean percentage area containing dMBP (%dMBP) was determined as an indicator of myelin degeneration. We further assessed the relationship between dMBP and glutathione S-transferase (a marker of mature oligodendrocytes) immunoreactivities. Pathological diagnosis significantly affected the frontal but not temporal lobe myelin attenuation: myelin density was most reduced in VaD compared to AD and DLB, which still significantly exhibited lower myelin density compared to ageing controls. Consistent with this, the degree of myelin loss was correlated with greater %dMBP, with the highest %dMBP in VaD compared to the other groups. The %dMBP was inversely correlated with the mean size of oligodendrocytes in VaD, whereas it was positively correlated with their density in AD. A two-tier regression model analysis confirmed that the type of disorder (VaD or AD) determines the relationship between %dMBP and the size or density of oligodendrocytes across the cases. Our findings, attested by the use of three markers, suggest that myelin loss may evolve in parallel with shrunken oligodendrocytes in VaD but their increased density in AD, highlighting partially different mechanisms are associated with myelin degeneration, which could originate from hypoxic–ischaemic damage to oligodendrocytes in VaD whereas secondary to axonal degeneration in AD.     

The synaptic pathology of α-synuclein aggregation in dementia with Lewy bodies, Parkinson’s disease and Parkinson’s disease dementia

Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are usually associated with loss of dopaminergic neurons. Loss of substantia nigra neurons and presence of Lewy body inclusions in some of the remaining neurons are the hallmark pathology seen in the final stages of the disease. Attempts to correlate Lewy body pathology to either cell death or severity of clinical symptoms, however, have not been successful. While the pathophysiology of the neurodegenerative process can hardly be explained by Lewy bodies, the clinical symptoms do indicate a degenerative process located at the presynapse resulting in a neurotransmitter deficiency. Recently it was shown that 90% or even more of α-synuclein aggregates in DLB cases were located at the presynapses in the form of very small deposits. In parallel, dendritic spines are retracted, whereas the presynapses are relatively preserved, suggesting a neurotransmitter deprivation. The same α-synuclein pathology can be demonstrated for PD. These findings give rise to the notion that not cell death but rather α-synuclein aggregate-related synaptic dysfunction causes the neurodegeneration. This opens new perspectives for understanding PD and DLB. If presynaptic α-synuclein aggregation, not neuronal loss, is the key issue of the neurodegenerative process, then PD and DLB may eventually be treatable in the future. The disease may progress via trans-synaptical spread, suggesting that stem cell transplants are of limited use. Future therapies may focus on the regeneration of synapses.     

Striatal β-amyloid in dementia with Lewy bodies but not Parkinson’s disease

Professor Jellinger first identified that striatal Aβ deposition at postmortem seemed to differentiate cases of dementia with Lewy bodies (DLB) from those with Parkinson’s disease dementia (PDD), a finding subsequently questioned. Our replication study in 34 prospectively studied cases assessed the ability of striatal Aβ deposition to differentiate DLB from PDD, and also assessed the relationship between striatal and cortical Aβ deposition and α-synuclein-immunoreactive pathologies, using previously published protocols. Cases with DLB had significantly shorter durations and greater dementia severities compared with cases with PDD. Striatal Aβ-immunoreactive plaques were only consistently found in cases with DLB and correlated with both the severity (positive correlation) and duration (negative correlation) of dementia. Striatal Aβ-immunoreactive plaques also positively correlated with the severity of α-synuclein-immunoreactive pathologies as well as cortical Aβ-positive plaques. Striatal Aβ deposition positively predicted dementia in Lewy body cases with high specificity and had the greatest sensitivity to differentiate DLB from PDD with 100% negative predictive value. These data suggest that striatal Aβ deposition in Lewy body diseases contributes to early dementia and in these cases may impact on the efficacy of treatments targeting the striatum.     

Dopaminergic degeneration and perfusional impairment in Lewy body dementia and Alzheimer’s disease

Abstract. The clinical differentiation of Lewy body dementia (LBD) from Alzheimers disease (AD) may be difficult. The aim of the present study was to assess the dopamine transporter function and the perfusional pattern in LBD and AD in vivo. Twenty patients with probable LBD and 24 with probable AD underwent on 2 separate days a brain perfusional SPECT with 99mTc-ECD and a SPECT with ¹²³I-FP-CIT, a ligand of dopamine transporter. In LBD a significantly (p<0.0005) lower ratio of specific (bilateral caudate nucleus, putamen) to non-specific (occipital cortex) ¹²³I-FP-CIT binding than in AD was reported. Perfusional data (SPM analysis) showed a significant (p<0.001) decrease of temporo-parietal blood flow in AD versus LBD, whereas in LBD a significant (p<0.001) occipital hypoperfusion with respect to AD was reported. Our findings confirm that dopaminergic nigrostriatal function is impaired in LBD. The selective occipital hypoperfusion in LBD needs to be further investigated.     

Cerebrospinal fluid markers analysis in the differential diagnosis of dementia with Lewy bodies and Parkinson’s disease dementia

European Archives of Psychiatry and Clinical Neuroscience - Dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD) share a couple of clinical similarities that is often a...     

The role of α-synuclein gene multiplications in early-onset Parkinson’s disease and dementia with Lewy bodies

Summary. Background: A triplication of the α-synuclein gene was found to cause autosomal dominant Lewy body disease in two distinct families. Method: We searched for alterations of α-synuclein gene dosage and analysed the entire coding region for point mutations in 54 dementia with Lewy body disease (DLB) and in 103 young onset Parkinson’s disease (PD) patients from Central Europe. Results: We could not detect any quantitative alterations in the gene dosage of α-synuclein. Mutational screening of the entire coding region of α-synuclein revealed only one silent mutation V3V (adenine9guanine) in one case. Conclusions: Thus, this phenomenon appears not to be a major cause in the pathogenesis of sporadic DLB and young onset PD in this European population.     

Does striatal pathology distinguish Parkinson disease with dementia and dementia with Lewy bodies?

The morphological differentiation of Parkinson disease with dementia (PDD) and dementia with Lewy bodies (DLB) is a matter of discussion. The objective of this study was to investigate the regional distribution of beta-amyloid (Abeta) plaques, alpha-synuclein (AS), and pathology in both disorders. The basal ganglia from 17 age-matched patients of PDD and DLB each were immunohistochemically examined with variable degrees of associated Alzheimer pathology using antibodies to Abeta, AS, and tau. DLB brains showed a significantly higher burden of (diffuse) amyloid plaques in the putamen and caudate nucleus and slightly more severe tau pathology than PDD brains despite similar neuritic Braak stages. Phases of Abeta development in DLB brains often, but inconsistently, correlated with both neuritic Braak stages and severity of striatal Abeta load, while these correlations were almost never seen in PDD cases with Alzheimer lesions. They also revealed a higher burden of AS-lesions (both Lewy neurites and Lewy bodies) than PDD cases that commonly had a paucity of all three types of lesion. The globus pallidus was virtually spared in both phenotypes. Differences in AS and Abeta pathologies and much less of tau lesions in the striatum support a morphologic distinction between PDD and DLB, which may be of pathophysiologic importance, but the causes of these differences are unclear.     

Are Parkinson's disease with dementia and dementia with Lewy bodies the same entity?

The diagnosis of Parkinson's disease with dementia (PDD) or dementia with Lewy bodies (DLB) is based on an arbitary distinction between the time of onset of motor and cognitive symptoms. These syndromes share many neurobiological similarities, but there are also differences. Deposition of beta-amyloid protein is more marked and more closely related to cognitive impairment in DLB than PDD, possibly contributing to dementia at onset. The relatively more severe executive impairment in DLB than PDD may relate to the loss of frontohippocampal projections in DLB. Visual hallucinations and delusions associate with more abundant Lewy body pathology in temporal cortex in DLB. The differential involvement of pathology in the striatum may account for the differences in parkinsonism. Longitudinal studies with neuropathological and neurochemical evaluations will be essential to enable more robust comparisons and determine pathological substrates contributing to the differences in cognitive, motor, and psychiatric symptoms.