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Authors: Walker, Lauren | Attems, Johannes

Article Type: Review Article

Abstract: Pathologies characteristic of Alzheimer’s disease (i.e., hyperphosphorylated tau and amyloid-β (Aβ) plaques), cardiovascular disease, and limbic predominant TDP-43 encephalopathy (LATE) often co-exist in patients with Parkinson’s disease (PD), in addition to Lewy body pathology (α-synuclein). Numerous studies point to a putative synergistic relationship between hyperphosphorylation tau, Aβ, cardiovascular lesions, and TDP-43 with α-synuclein, which may alter the stereotypical pattern of pathological progression and accelerate cognitive decline. Here we discuss the prevalence and relationships between common concomitant pathologies observed in PD. In addition, we highlight shared genetic risk factors and developing biomarkers that may provide better diagnostic accuracy for patients with …PD that have co-existing pathologies. The tremendous heterogeneity observed across the PD spectrum is most likely caused by the complex interplay between pathogenic, genetic, and environmental factors, and increasing our understanding of how these relate to idiopathic PD will drive research into finding accurate diagnostic tools and disease modifying therapies. Show more

Keywords: Parkinson’s disease, co-pathology, α-synuclein, tau, amyloid-β, TDP-43, cerebrovascular disease

DOI: 10.3233/JPD-230154

Citation: Journal of Parkinson's Disease, vol. 14, no. 1, pp. 35-52, 2024

Authors: Jellinger, Kurt A. | Attems, Johannes

Article Type: Research Article

Abstract: The prevalence of both Alzheimer's disease (AD) and vascular dementia (VaD) increase with advancing age, but epidemiologic data above age 85 are imprecise and inconsistent. A retrospective hospital-based study of the prevalence and pathology of VaD was performed in 1700 consecutive autopsy cases of demented elderly in Vienna, Austria (mean age 84.3 ± 5.4 SD; 90% over age 70). It assessed clinical and general autopsy data and neuropathology including immunohistochemistry. Neuropathologic diagnosis followed current consensus criteria. Four age groups (7th to 10th decade) were evaluated. “Pure” VaD (due to cerebrovascular disease without other pathologies; neuritic Braak stages 1.2–1.6) was observed …in 12.3% of the total cohort, decreasing between age 60 and 90+ from 15.0 to 8.7%. Morphologic subtypes (subcortical arteriosclerotic encephalopathy, multi-infarct encephalopathy, and strategic infarct dementia) showed no age-related differences. By contrast, AD (without concomitant pathologies; 45.6% of total), mixed dementia (AD + cerebrovascular encephalopathy; 5.5%), and AD with minor cerebrovascular lesions (22.3%) increased with age. The relative prevalence of AD + Lewy pathology (9.3%) remained fairly stable, whereas other dementias (5.0%) decreased significantly over age 90. 85% of the patients with "pure" VaD had histories of diabetes, 75% of stroke(s), 95% morphologic signs of hypertension, 65% myocardial infarction (recent and old ones), 97% cerebral hypertonic-arteriosclerotic microangiopathy (associated with cerebral amyloid angiopathy in 23%) and 90% severe atherosclerosis of large cerebral arteries. Similar autopsy findings were seen in mixed dementia (MIX) and in AD + minor cerebrovascular lesions. Major vascular lesions differed between VaD and MIX, VaD showing more than 60% subcortical infarcts, MIX only 43% such lesions. This retrograde hospital-based study using strict morphologic diagnostic criteria confirmed the existence of “pure” VaD in old age, with a tendency to decline after age 90, while AD and AD + cerebrovascular pathologies showed considerable age-related increase, and "pure" AD slightly decreasing after age 90. Show more

Keywords: Autopsy study, cerebral amyloid angiopathy, mixed dementia, multi-infarct dementia, subcortical arteriosclerotic encephalopathy, vascular dementia

DOI: 10.3233/JAD-2010-100603

Citation: Journal of Alzheimer's Disease, vol. 21, no. 4, pp. 1283-1293, 2010

Authors: Thal, Dietmar Rudolf | Attems, Johannes | Ewers, Michael

Article Type: Research Article

Abstract: Primary pathologies including amyloid-β (Aβ) plaques and neurofibrillary tangles (NFT) develop many years before the onset of dementia symptoms in Alzheimer's disease (AD). Age-related small vessel disease (SVD) is common in elderly subjects and may contribute to the clinical syndrome of AD. Each type of pathology shows a specific spatio-temporal sequence of spreading in the brain. Here, we review neuropathological and neuroimaging findings (PET tracers of Aβ and NFT, MRI markers of SVD) to assess whether staging of these primary pathologies is useful to predict clinical symptoms in AD. On the basis of neuropathological data, early stages of Aβ plaque …and NFT pathology distribution occur in preclinical AD, but advanced stages with spreading into further brain regions are associated with dementia symptoms. Amyloid PET presumably detects Aβ in advanced neuropathological Aβ stages, and increased global amyloid PET uptake is associated with clinical worsening in non-demented subjects. Tau PET may provide additional predictive value by detecting NFT in the allocortex. There is weak evidence that SVD is related to amyloid or NFT pathology. Global volume of MRI-assessed white matter hyperintensities (WMH) contribute in addition to biomarker levels of Aβ to predict cognitive decline. Regional differences of the effect of WMH on cognition have been demonstrated but are not yet established as a biomarker in AD. In conclusion, biomarkers for amyloid and tau pathology allow a distinction between early and advanced stages of AD, but a subgroup of pathologically identified preclinical AD cases is not identified by the currently available biomarkers. Show more

Keywords: Alzheimer's disease, amyloid-β, biomarker, diagnosis, early detection, magnetic resonance imaging, neurofibrillary tangles, plaques, positron emission tomography, small vessel disease

DOI: 10.3233/JAD-141461

Citation: Journal of Alzheimer's Disease, vol. 42, no. s4, pp. S421-S429, 2014

Authors: Attems, Johannes | Lintner, Felix | Jellinger, Kurt. A.

Article Type: Research Article

Abstract: Olfactory dysfunction and tau pathology in the olfactory bulb increase with the severity of Alzheimer's disease. We report data of a postmortem study in the aged. 130 autopsy cases (81 female, 49 male, aged 61–102, mean 82.48 ± 4.35 SD) years, underwent a standardized neuropathological assessment with immunohistochemical study of tau pathology in the olfactory bulb and nerve and of Alzheimer's disease using established criteria including Braak staging. All cases of definite Alzheimer's disease (Braak stages 5 and 6) (n = 40) showed large numbers of neuropil threads and neurofibrillary tangles, with amyloid deposits in 32.5% and neuritic plaques in …one single case in the olfactory system. Braak stage 4 (n = 27) was associated with mild to moderate tau pathology in 85.2%, and amyloid plaques in 1.1%, Braak stage 3 (n = 28) with olfactory tau lesions in 37.0% and amyloid deposits in one single case, Braak stages 3 and 4 with olfactory tau lesions in 61.1%. Braak stage 2 (n = 15) showed olfactory tau pathology in 31.2%, whereas Braak stages 0 and 1 (n = 15) were all negative. The olfactory system tau score showed highly significant correlations with neuritic Braak stages in the brain, while both scores showed significant but low correlations with age. These data confirm previous studies demonstrating abundant tau pathology in the olfactory system in all definite Alzheimer's disease cases, in two-thirds of limbic Alzheimer's disease, and in almost one-third of non-demented elderly persons with Braak stage 2. There are strong correlations between tau pathology in the olfactory and limbic systems, both with similar increase in severity. Clinical dementia correlated with both Braak and olfactory system tau scores. Since the involvement of both systems is associated with a high risk of cognitive decline, future studies should validate the sensitivity of olfactory mucosa biopsies in the diagnosis of Alzheimer's disease. Show more

Keywords: olfactory system, tau pathology, Alzheimer disease, dementia

DOI: 10.3233/JAD-2005-7208

Citation: Journal of Alzheimer's Disease, vol. 7, no. 2, pp. 149-157, 2005

Authors: Attems, Johannes | König, Claudia | Huber, Monika | Lintner, Felix | Jellinger, Kurt A.

Article Type: Research Article

Abstract: Few studies evaluated cause of death (COD) in elderly demented and non-demented people, the majority based on death certificates alone. The present study is based on autopsy reports with neuropathological examination of 308 inpatients (58.1% female) over age 60 years (mean: 83.5, SD: +/−8.6). CODs were classified into seven groups. The most common were bronchopneumonia (n=117; 38%) and cardiovascular disease (n=116, 37.7%). In 176 patients (57.1%) neuropathology was indicative for dementia: 76.7% Alzheimer disease (AD), 4.5% vascular dementia, 4.0% mixed type dementia (AD + vascular dementia), and 14.8% other dementias. Main COD significantly differed in demented and non-demented patients: bronchopneumonia …(45.5% in demented versus 28.0% in non-demented), cardiovascular disease (46.2% in non-demented versus 31.3% in demented). Whereas there were significant differences in COD between AD patients and non-demented ones (bronchopneumonia versus cardiovascular disease), no differences were seen between the latter and patients with other types of dementia than AD. Our data emphasize the high incidence of bronchopneumonia as a COD in patients suffering from AD Show more

Keywords: Cause of death, dementia, Alzheimer disease, autopsy, bronchopneumonia, cardiovascular disease

DOI: 10.3233/JAD-2005-8107

Citation: Journal of Alzheimer's Disease, vol. 8, no. 1, pp. 57-62, 2005

Authors: Chong, Joyce R. | Chai, Yuek Ling | Lee, Jasinda H. | Howlett, David | Attems, Johannes | Ballard, Clive G. | Aarsland, Dag | Francis, Paul T. | Chen, Christopher P. | Lai, Mitchell K.P.

Article Type: Research Article

Abstract: Background: Of the three transforming growth factor (TGF)-β isoforms known, TGFβ1 deficits have been widely reported in Alzheimer’s disease (AD) and studied as a potential therapeutic target. In contrast, the status of TGFβ2, which has been shown to mediate amyloid-β (Aβ)-mediated neuronal death, are unclear both in AD and in Lewy body dementias (LBD) with differential neuritic plaque and neurofibrillary tangle burden. Objective: To measure neocortical TGFβ2 levels and their correlations with neuropathological and clinical markers of disease severity in a well-characterized cohort of AD as well as two clinical subtypes of LBD, dementia with Lewy bodies (DLB) and Parkinson’s …disease dementia (PDD), known to manifest relatively high and low Aβ plaque burden, respectively. Methods: Postmortem samples from temporal cortex (BA21) were measured for TGFβ2 using a Luminex-based platform, and correlated with scores for neuritic plaques, neurofibrillary tangles, α-synuclein pathology, dementia severity (as measured by annual decline of Mini-Mental State Examination scores) as well as soluble and total fractions of brain Aβ42 . Results: TGFβ2 was significantly increased in AD and DLB, but not in PDD. TGFβ2 also correlated with scores for neurofibrillary tangles, Lewy bodies (within the LBD group), dementia severity, and soluble Aβ42 concentration, but not with neuritic plaque scores, total Aβ42 , or monomeric α-synuclein immunoreactivity. Conclusions: TGFβ2 is increased in the temporal cortex of AD and DLB, and its correlations with neuropathological and clinical markers of disease severity as well as with soluble Aβ42 load suggest a potential pathogenic role in mediating the neurotoxicity of non-fibrillar Aβ. Our study also indicates the potential utility of targeting TGFβ2 in pharmacotherapeutic approaches to AD and DLB. Show more

Keywords: Alzheimer’s disease, amyloid-β, dementia with Lewy bodies, Parkinson’s disease dementia, transforming growth factor β2

DOI: 10.3233/JAD-160781

Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 157-166, 2017

Authors: Schreiber, Stefanie | Drukarch, Benjamin | Garz, Cornelia | Niklass, Solveig | Stanaszek, Luiza | Kropf, Siegfried | Bueche, Celine | Held, Friederike | Vielhaber, Stefan | Attems, Johannes | Reymann, Klaus G. | Heinze, Hans-Jochen | Carare, Roxana O. | Wilhelmus, Micha M.M.

Article Type: Research Article

Abstract: Background: Accumulation of amyloid-β (Aβ) and hyperphosphorylated tau (ptau) accompany cerebral small vessel disease (CSVD) in the aging brain and in Alzheimer’s disease. CSVD is characterized by a heterogeneous spectrum of histopathological features possibly initiated by an endothelial dysfunction and blood-brain barrier (BBB) breakdown. Objective: We test the hypothesis that characteristic features of CSVD are associated with the accumulation of Aβ and ptau in non-transgenic spontaneously hypertensive stroke-prone rats (SHRSP). Methods: Amyloid-β protein precursor (AβPP) and tau were investigated by western blotting (n = 12 SHRSP, age 20 weeks). Lectin staining and plasma protein immunocytochemistry for BBB examination were performed …in 38 SHRSP (age 12–44 weeks) and Aβ (n = 29) and ptau (n = 17) immunocytochemistry in 20–44 week-old SHRSP. We assessed the correlation between extracellular amyloid deposits and features of CSVD (n = 135, 12–44 weeks). Results: In 20 week-old SHRSP, cortical AβPP expression was significantly increased compared to Wistar controls but tau levels were unchanged. At ages of 20–44 weeks, SHRSP exhibited an age-dependent increase in extracellular Aβ. Ptau was observed in 26–44 week-old SHRSP. Distinct features of CSVD pathology developed from the age of 12 weeks on. Conclusion: We demonstrate that in a hypertensive rat model that displays features of CSVD from 12 weeks, there is an age-dependent extracellular deposition of Aβ observed from 20 weeks onwards, increased AβPP expression at 20 weeks and ptau accumulation from 26 weeks on. This study suggests that CSVD associated with hypertension results in an age-related failure of Aβ clearance, increase in AβPP expression, and intraneuronal tau hyperphosphorylation. Show more

Keywords: Amyloid-β, amyloid-β protein precursor, cerebral small vessel disease, hyperphosphorylated tau, spontaneously hypertensive stroke-prone rats

DOI: 10.3233/JAD-132618

Citation: Journal of Alzheimer's Disease, vol. 42, no. s3, pp. S205-S215, 2014

Authors: Alghamdi, Amani | Vallortigara, Julie | Howlett, David R. | Broadstock, Martin | Hortobágyi, Tibor | Ballard, Clive | Thomas, Alan J. | O’Brien, John T. | Aarsland, Dag | Attems, Johannes | Francis, Paul T. | Whitfield, David R.

Article Type: Research Article

Abstract: Lewy body dementia is the second most common neurodegenerative dementia and is pathologically characterized by α-synuclein positive cytoplasmic inclusions, with varying amounts of amyloid-β (Aβ) and hyperphosphorylated tau (tau) aggregates in addition to synaptic loss. A dysfunctional ubiquitin proteasome system (UPS), the major proteolytic pathway responsible for the clearance of short lived proteins, may be a mediating factor of disease progression and of the development of α-synuclein aggregates. In the present study, protein expression of a key component of the UPS, the RPT6 subunit of the 19S regulatory complex was determined. Furthermore, the main proteolytic-like (chymotrypsin- and PGPH-) activities have …also been analyzed. The middle frontal (Brodmann, BA9), inferior parietal (BA40), and anterior cingulate (BA24) gyrus’ cortex were selected as regions of interest from Parkinson’s disease dementia (PDD, n  = 31), dementia with Lewy bodies (DLB, n  = 44), Alzheimer’s disease (AD, n  = 16), and control (n  = 24) brains. Clinical and pathological data available included the MMSE score. DLB, PDD, and AD were characterized by significant reductions of RPT6 (one-way ANOVA, p  < 0.001; Bonferroni post hoc test) in prefrontal cortex and parietal cortex compared with controls. Strong associations were observed between RPT6 levels in prefrontal, parietal cortex, and anterior cingulate gyrus and cognitive impairment (p  = 0.001, p  = 0.001, and p  = 0.008, respectively). These findings highlight the involvement of the UPS in Lewy body dementia and indicate that targeting the UPS may have the potential to slow down or reduce the progression of cognitive impairment in DLB and PDD. Show more

Keywords: Alzheimer’s disease, amyloid-beta, cognitive impairment, dementia with Lewy bodies, Parkinson’s disease with dementia, RPT6, tau, ubiquitin proteasome system

DOI: 10.3233/JAD-160946

Citation: Journal of Alzheimer's Disease, vol. 57, no. 2, pp. 373-386, 2017

Authors: Vallortigara, Julie | Whitfield, David | Quelch, William | Alghamdi, Amani | Howlett, David | Hortobágyi, Tibor | Johnson, Mary | Attems, Johannes | O’Brien, John T. | Thomas, Alan | Ballard, Clive G. | Aarsland, Dag | Francis, Paul T.

Article Type: Research Article

Abstract: Alpha-synuclein (α -syn) aggregations are the key pathological hallmark of dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD), but are also frequently present in Alzheimer’s disease (AD). Much remains unknown about the role of α -syn in the synapse and the wider role of synaptic dysfunction in these dementias. Changes in concentrations of key ‘SNAP (Soluble N-ethylmaleimide Sensitive Factor Attachment Protein) Receptor’ (SNARE) proteins as a consequence of alterations in the aggregation state of α -syn may contribute to synaptic dysfunction in patients with DLB, PDD, and AD and result in impaired cognition. We have studied a large …cohort (n  = 130) of autopsy confirmed DLB, PDD, AD, and control brains. Using semi-quantitative western blotting, we have demonstrated significant changes across the diagnostic groups of DLB, PDD, and AD in the SNARE and vesicle proteins syntaxin, Munc18, VAMP2, and monomeric α -syn in the prefrontal cortex, with a significant reduction of Munc18 in AD patients (p  <  0.001). This correlated to the final MMSE score before death (p  = 0.016). We also identified a significant negative correlation between the duration of dementia and the levels of the binding partners VAMP2 (p  = 0.0004) and monomeric α -syn (p  = 0.0002). Our findings may indicate that an upregulation of SNARE complex related proteins occurs in the early stages of disease as an attempt at compensating for failing synapses, prior to widespread deposition of pathological α -syn. Show more

Keywords: Alpha-synuclein, Alzheimer’s disease, dementia with lewy bodies, munc18, Parkinson’s disease dementia, SNARE process, synaptic dysfunction, VAMP2

DOI: 10.3233/JAD-150707

Citation: Journal of Alzheimer's Disease, vol. 50, no. 1, pp. 101-110, 2016