Johannes Attems's research while affiliated with Newcastle University and other places
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Publications (351)
An international consensus report in 2019 recommended a classification system for limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC). The suggested neuropathologic staging system and nomenclature have proven useful for autopsy practice and dementia research. However, some issues remain unresolved, such as cases w...
Age-related cognitive impairment is multifactorial, with numerous underlying and frequently co-morbid pathological correlates. Amyloid beta (Aβ) plays a major role in Alzheimer’s type age-related cognitive impairment, in addition to other etiopathologies such as Aβ-independent hyperphosphorylated tau, cerebrovascular disease, and myelin damage, whi...
Background
The molecular drivers of early sporadic Parkinson’s disease (PD) remain unclear, and the presence of widespread end stage pathology in late disease masks the distinction between primary or causal disease-specific events and late secondary consequences in stressed or dying cells. However, early and mid-stage Parkinson’s brains (Braak stag...
Chronic traumatic encephalopathy (CTE) is a tauopathy associated with repetitive mild head impacts characterized by perivascular hyperphosphorylated tau (p-tau) in neurofibrillary tangles (NFTs) and neurites in the depths of the neocortical sulci. In moderate to advanced CTE, NFTs accumulate in the hippocampus, potentially overlapping neuroanatomic...
Importance:
The behavioral and cognitive symptoms of severe psychotic disorders overlap with those seen in dementia. However, shared brain alterations remain disputed, and their relevance for patients in at-risk disease stages has not been explored so far.
Objective:
To use machine learning to compare the expression of structural magnetic resona...
Background:
Multiple System Atrophy is a rare neurodegenerative disease with alpha-synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome-wide association study in mainly clinically diagno...
Dementia with Lewy bodies (DLB) is pathologically defined by the cytoplasmic accumulation of alpha-synuclein (aSyn) within neurons in the brain. Predominately pre-synaptic, aSyn has been reported in various subcellular compartments in experimental models. Indeed, nuclear alpha-synuclein (aSyn Nuc ) is evident in many models, the dysregulation of wh...
Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) and Alzheimer’s disease neuropathologic change (ADNC) are each associated with substantial cognitive impairment in aging populations. However, the prevalence of LATE-NC across the full range of ADNC remains uncertain. To address this knowledge gap, neuropathologic...
Age-related cognitive impairment is multifactorial, with numerous underlying and frequently co-morbid pathological correlates. Amyloid beta plays a major role in Alzheimers type age-related cognitive impairment, in addition to other etiopathologies such as Amyloid beta-independent hyperphosphorylated tau, cerebrovascular disease, and myelin damage,...
The APOE locus is strongly associated with risk for developing Alzheimer's disease and dementia with Lewy bodies. In particular, the role of the APOE ϵ4 allele as a putative driver of α-synuclein pathology is a topic of intense debate. Here, we performed a comprehensive evaluation in 2466 dementia with Lewy bodies cases versus 2928 neurologically h...
Significance
Converging evidence points to the build-up of phosphorylated α-synuclein (α-syn) at residue serine 129 (pS129) in Lewy body disease, suggesting its central role in the regulation of α-syn aggregation and neuronal degeneration. However, a comprehensive understanding of the role of α-syn phosphorylation at pS129 in α-synuclenopathies pat...
Krabbe disease is an infantile neurodegenerative disorder resulting from pathogenic variants in the GALC gene which causes accumulation of the toxic sphingolipid psychosine. GALC variants are also associated with Lewy body diseases, an umbrella term for age-associated neurodegenerative diseases in which the protein α-synuclein aggregates into Lewy...
Primary age-related tauopathy (PART) is a neurodegenerative pathology with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-β (Aβ) plaques. The pathogenesis of PART is n...
Socioeconomic disadvantage is associated with greater risk of dementia. This has been theorised to reflect inequalities in cognitive reserve, healthcare access, lifestyle, and other health factors which may contribute to the clinical manifestation of dementia. We aimed to assess whether area deprivation in the United Kingdom was associated with gre...
Cerebral white matter lesions (WML) encompass axonal loss and demyelination and are assumed to be associated with small vessel disease (SVD)-related ischaemia. However, our previous study in the parietal lobe white matter revealed that WML in Alzheimer’s disease (AD) are linked with degenerative axonal loss secondary to the deposition of cortical A...
Multiple System Atrophy is a rare neurodegenerative disease with alpha-synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome-wide association study in mainly clinically diagnosed patients...
Background
Dementia with Lewy bodies (DLB) is pathologically-defined by the cytoplasmic accumulation of alpha-synuclein (aSyn) within neuronal cells in the brain. aSyn is predominately pre-synaptic, but has been reported present in various subcellular compartments in cell and animal models. In particular, nuclear aSyn (aSyn Nuc ) is evident in-vitr...
Krabbe disease (KD) is an infantile neurodegenerative disorder resulting from pathogenic variants in the GALC gene which causes accumulation of the toxic sphingolipid psychosine. GALC variants are associated with increased risk of Lewy body diseases (LBD), an umbrella term for age-associated neurodegenerative diseases in which the protein α-synucle...
Professor Kurt Jellinger is well known for his seminal work on the neuropathology of age-associated neurodegenerative disorders, particularly Lewy body diseases. However, it is less well known that he also contributed important insights into the neuropathological features of several paediatric neurometabolic diseases, including Alpers–Huttenlocher...
Primary age-related tauopathy (PART) is a neurodegenerative tauopathy with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-β (Aβ) deposition in plaques. The pathogenesi...
With Alzheimer's disease (AD) exhibiting reduced ability of neural stem cell renewal, we hypothesized that de novo mutations controlling embryonic development, in the form of brain somatic mutations instigate the disease. A leading gene presenting heterozygous dominant de novo autism-intellectual disabilities (ID) causing mutations is activity-depe...
![ShinyGO [38] analysis demonstrated three broad clusters into which...](publication/348908700/figure/fig2/AS:985919695908866@1612072981994/ShinyGO-38-analysis-demonstrated-three-broad-clusters-into-which-enriched-biological_Q320.jpg)
Accumulation of the protein α-synuclein into insoluble intracellular deposits termed Lewy bodies (LBs) is the characteristic neuropathological feature of LB diseases, such as Parkinson’s disease (PD), Parkinson’s disease dementia (PDD) and dementia with LB (DLB). α-Synuclein aggregation is thought to be a critical pathogenic event in the aetiology...
The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identifi...
The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identifi...
Introduction:
The aged brain frequently exhibits multiple pathologies, rather than a single hallmark pathology (pure pathology [PurP]), ranging from low/intermediate levels of additional pathology (LowP) to mixed severe pathology (mixed SevP). We investigated the frequency of PurP, LowP, and mixed SevP, and the impact of additional LowP on cogniti...
Introduction:
Radiolabeled ligands for fibrillar amyloid beta (Aβ) peptides are used in positron emission tomography (PET) for dementia diagnosis. Current ligands do not discriminate parenchymal amyloid plaques from cerebral amyloid angiopathy (CAA).
Methods:
We undertook neuropathological examination of 65 older people (81.6 ± 7.96 (mean ± SD)...
Purpose
The aim of this study was to re-evaluate the differentiation of patients with dementia with Lewy bodies (DLB) from Alzheimer’s disease (AD) and Parkinson’s disease (PD) using a quantitative analysis of ¹²³ I-FP-CIT SPECT scans.
Methods
Thirty-six patients with in vivo ¹²³ I-FP-CIT SPECT and neuropathological diagnoses were included. Based...
Currently, the neuropathological diagnosis of Lewy body disease (LBD) may be stated according to several staging systems, which include the Braak Lewy body stages (Braak), the consensus criteria by McKeith and colleagues (McKeith), the modified McKeith system by Leverenz and colleagues (Leverenz), and the Unified Staging System by Beach and colleag...
Primary age-related tauopathy (PART) is a neurodegenerative entity defined as Alzheimer-type neurofibrillary degeneration primarily affecting the medial temporal lobe with minimal to absent amyloid-β (Aβ) plaque deposition. The extent to which PART can be differentiated pathoanatomically from Alzheimer disease (AD) is unclear. Here, we examined the...
Lewy body diseases (LBD) are characterised by Lewy body pathology, cell loss and mitochondrial dysfunction, but the overlap between these three features is not well understood. We have explored the hypothesis that neurodegeneration in LBD is the result of energy failure in cells with high energy demands, such as cortical fast‐spiking interneurons a...
Cerebral small vessel disease (SVD) encompasses progressive fibrosis/hyalinosis of the small arteries (lipohyalinosis) and arterioles (arteriolosclerosis) of the white matter (WM) resulting in ischemic WM damage. SVD is commonly assessed using a broad semi‐quantitative (SQ) criterion. We implemented sclerotic index (SI) assessment to quantitatively...
Hallmark lesions observed Alzheimer’s disease (AD) include neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein (HP‐ T ) and amyloid β plaques. Pyroglutamylated Aβ (pAβ) is a sub‐species of Aβ, and we have previously demonstrated an association between (pAβ) and HP‐T in human post‐mortem brains, and observed that pAβ predicts...
In addition to the well‐established risk associated with the APOE locus, there has been considerable success in identifying additional genetic variants associated with Alzheimer’s disease (AD). Individually these variants confer only a small increase on an individual’s overall risk; however, combined into a polygenic risk score (PRS), they represen...
Limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC) is present in approximately 57% of Alzheimer’s disease (AD) cases and is associated with accelerated cognitive decline and accelerated disease progression. Hyperphosphorylated tau (HP‐τ) burden in AD is associated with cognitive deficits; it is unknown if LATE‐N...
Cerebral small vessel disease (SVD) encompasses progressive fibrosis/hyalinosis of the small arteries and arterioles of the white matter (WM) resulting in ischemic WM damage. Few studies have compared SVD between different cohorts. Using a sclerotic index (SI) measurement, we quantitatively assessed vessel wall fibrosis in the frontal and parietal...
Senile plaques frequently contain pyroglutamate amyloid β (Aβ‐pE(3)), a N‐terminally truncated Aβ species that is more closely linked to Alzheimer’s Disease (AD) compared to other Aβ species. Tau protein is highly phosphorylated at several residues in AD, specifically tau protein phosphorylated (ptau) at Ser202/Thr205 is known to be increased in AD...
Many studies have provided strong evidence to support JNK3 isoform‐specific involvement in several processes underlying Alzheimer’s Disease (AD) pathogenesis including dysfunction of synaptic plasticity and cognition, phosphorylation of tau and amyloidogenic processing of the amyloid precursor protein. Moreover, the tissue‐specific expression of JN...
Inflammation is usually terminated by resolution, mediated by pro‐resolving mediators including Annexin A1 (AnxA1) which is known to be involved in granulocyte trafficking as well as efferocytosis of apoptotic neutrophils. Failure in resolution may lead to chronic inflammation, which has been considered a pathological hallmark of neurodegenerative...
Using the UK's Brains for Dementia Research (BDR) program, we investigated the frequency of neuropathological dementia diagnosis, the proportion of pure, mixed or concomitant pathologies and the pathological substrates for cognitive impairment. All cases (n = 673) underwent standardised neuropathological assessment outlined in [1]. Cases were class...
We have previously shown that the pathogenesis of parietal white matter lesions (WML) seen in Alzheimer’s disease (AD) can be associated with degenerative loss as a result of Wallerian degeneration activated by hyperphosphorylated tau (HPτ) [1]. In a subset of these cases, we investigated the the pathological composition and aetiology of WML from t...
Cellular senescence, the irreversible arrest of the cell cycle, is a common occurrence in ageing. Astrocytes have been shown to demonstrate a senescent phenotype, which is increased in ageing, and in Alzheimer’s disease (AD) (as evidenced by p16INK4a expression). Recently, a causal link was established between p16INK4a expression and hyperphosphory...
There is clinical overlap between presentations of dementia due to limbic-predominant age-related TDP-43 encephalopathy (LATE) and Alzheimer’s disease. It has been suggested that the combination of Alzheimer’s disease neuropathological change (ADNC) and LATE neuropathological changes (LATE-NC) is associated with greater neuropsychiatric symptom bur...
Drainage of interstitial fluid from the brain occurs via the intramural periarterial drainage (IPAD) pathways along the basement membranes of cerebral capillaries and arteries against the direction of blood flow into the brain. The cerebrovascular smooth muscle cells (SMCs) provide the motive force for driving IPAD, and their decrease in function m...
Aims:
Limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is present in approximately 50% of Alzheimer's disease (AD) cases and is associated with accelerated cognitive decline. Studies indicate a potential synergistic relationship between LATE-NC and hyperphosphorylated-tau. It is unknown if LATE-NC is an indep...
Abstract Leukotrienes (LTs) contribute to the neuropathology of chronic neurodegenerative disorders including Alzheimer’s Disease (AD), where they mediate neuroinflammation and neuronal cell-death. In consequence, blocking the action of Leukotrienes (LTs) ameliorates pathologies and improves cognitive function in animal models of neurodegeneration....
Loss of function mutations within the vesicular trafficking protein Ras analogy in brain 39B (RAB39B) are associated with rare X‐linked Parkinson’s disease (PD). Physiologically, RAB39B is localised to Golgi vesicles and recycling endosomes and is required for glutamatergic receptor maturation but also for alpha‐Synuclein (aSyn) homeostasis and the...
We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian populat...
Alzheimer's disease is a highly heritable, common neurodegenerative disease characterised neuropathologically by the accumulation of β-amyloid plaques and tau-containing neurofibrillary tangles. In addition to the well-established risk associated with the APOE locus, there has been considerable success in identifying additional genetic variants ass...
Neurons of the nucleus basalis of Meynert (nbM) are vulnerable to Lewy body formation and neuronal loss, which is thought to underlie cognitive dysfunction in Lewy body dementia (LBD). There is continued debate about whether Lewy bodies exert a neurodegenerative effect by affecting mitochondria, or whether they represent a protective mechanism. The...
Senile plaques frequently contain Aβ-pE(3), a N-terminally truncated Aβ species that is more closely linked to AD compared to other Aβ species. Tau protein is highly phosphorylated at several residues in AD, and specifically phosphorylation at Ser202/Thr205 is known to be increased in AD. Several studies suggest that formation of plaques and tau ph...
The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia and to generate a resource for the scientific community. Genome-wide association analysis identifie...
Alzheimer’s disease is a highly heritable, common neurodegenerative disease characterized neuropathologically by the accumulation of β-amyloid plaques and tau-containing neurofibrillary tangles. In addition to the well-established risk associated with the APOE locus, there has been considerable success in identifying additional genetic variants ass...
Neuroinflammation is a major contributor to disease progression in Alzheimeŕs disease (AD) and is characterized by the activity of brain resident glial cells, in particular microglia cells. However, there is increasing evidence that peripheral immune cells infiltrate the brain at certain stages of AD progression and shape disease pathology. We rece...
Aims
Neuroferritinopathyor Hereditary Ferritinopathy (HF)is an autosomal dominant movement disorder due to mutation in the light chain of the iron storage protein ferritin (FTL).HF is the only late‐onset neurodegeneration with brain iron accumulation disorder andstudy of HF offers a unique opportunity to understand the role of iron in more common n...
Aggregation of the protein α‐synuclein (α‐syn) into insoluble intracellular assemblies termed Lewy bodies (LBs) is thought to be a critical pathogenic event in LB diseases such as Parkinson’s disease and dementia with LBs. In LB diseases, the majority of α‐syn is phosphorylated at serine 129 (pS129), suggesting this is an important disease‐related...
Corticobasal degeneration typically progresses gradually over 5–7 years from onset till death. Fulminant corticobasal degeneration cases with a rapidly progressive course were rarely reported (RP-CBD). This study aimed to investigate their neuropathological characteristics. Of the 124 autopsy-confirmed corticobasal degeneration cases collected from...
Dementia with Lewy bodies (DLB) represents a huge medical need as it accounts for up to 30% of all dementia cases, and there is no cure available. The underyling spectrum of pathology is complex and creates a challenge for targeted molecular therapies. We here tested the hypothesis that leukotrienes are involved in the pathology of DLB and that blo...
Abstract Dementia with Lewy bodies (DLB) is an age-associated neurodegenerative disorder producing progressive cognitive decline that interferes with normal life and daily activities. Neuropathologically, DLB is characterised by the accumulation of aggregated α-synuclein protein in Lewy bodies and Lewy neurites, similar to Parkinson’s disease (PD)....
Introduction:
The role of TOMM40-APOE 19q13.3 region variants is well documented in Alzheimer's disease (AD) but remains contentious in dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD).
Methods:
We dissected genetic profiles within the TOMM40-APOE region in 451 individuals from four European brain banks, including DLB and P...
Aims:
Galanin is a highly inducible neuroprotective neuropeptide and in Alzheimer's disease (AD), a network of galaninergic fibres has been reported to hypertrophy and hyperinnervate the surviving cholinergic neurons in the basal forebrain. We aimed to determine a) the extent of galanin hyperinnervation in patients with AD and Lewy body disease an...
Highlights
- aSyn sequesters HSP10 in the cytosol and prevents it from acting in the mitochondria
- Overexpression of HSP10 delays aSyn pathology in vitro and in vivo
- HSP10 modulates aSyn pathology in synaptic terminals
In Brief, Szego et al. identify HSP10 as a modulator of alpha-synuclein-induced mitochondrial impairment in striatal synapto...
The cingulate island sign (CIS) refers to the relative sparing of metabolism in the posterior cingulate cortex (PCC) and represents an important biomarker in distinguishing dementia with Lewy bodies (DLB) from Alzheimer disease (AD). The underlying basis of the CIS is unknown; therefore, our aim was to investigate which neurodegenerative changes un...
This chapter describes the main neuropathological features of the most common age associated neurodegenerative diseases including Alzheimer’s disease, Lewy body diseases, vascular dementia and the various types of frontotemporal lobar degeneration. In addition, the more recent concepts of primary age-related tauopathy and ageing-related tau astrogl...
Lewy body diseases (LBDs) share clinical, pathological, genetic, and biochemical signatures, and are regarded as a highly heterogeneous group of neurodegenerative disorders. Inclusive of Parkinson's disease (PD), Parkinson's disease dementia (PDD), and dementia with Lewy bodies (DLB), controversy still exists as to whether they should be considered...
Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare neurodegenerative disease that can mimic other neurological disorders. We present a case of sCJD in a 64-year-old man that presented with corticobasal syndrome and survived for 3 years. He presented initially with dementia, hemiparkinsonism and alien limb phenomenon and was diagnosed with corticob...