Papers by Liisa Myllykangas
Alzheimer's & Dementia, 2015
Acta Neuropathologica, Sep 1, 2021
Annals of clinical and translational neurology, Aug 18, 2015
Objective: Dementia with Lewy bodies is an a-synucleinopathy characterized by neocortical Lewy-re... more Objective: Dementia with Lewy bodies is an a-synucleinopathy characterized by neocortical Lewy-related pathology (LRP). We carried out a genome-wide association study (GWAS) on neocortical LRP in a population-based sample of subjects aged 85 or over. Methods: LRP was analyzed in 304 subjects in the Vantaa 85+ sample from Southern Finland. The GWAS included 41 cases with midbrain, hippocampal, and neocortical LRP and 177 controls without midbrain and hippocampal LRP. The Medical Research Council Cognitive Function and Ageing Study (CFAS) material was used for replication (51 cases and 131 controls). Results: By analyzing 327,010 markers the top signal was obtained at the HLA-DPA1/DPB1 locus (P = 1.29 9 10 À7); five other loci on chromosomes 15q14, 2p21, 2q31, 18p11, and 5q23 were associated with neocortical LRP at P < 10 À5. Two loci were marked by multiple markers, 2p21 (P = 3.9 9 10 À6 , upstream of the SPTBN1 gene), and HLA-DPA1/DPB1; these were tested in the CFAS material. Single marker (P = 0.0035) and haplotype (P = 0.04) associations on 2p21 were replicated in CFAS, whereas HLA-DPA1/DPB1 association was not. Bioinformatic analyses suggest functional effects for the HLA-DPA1/ DPB1 markers as well as the 15q14 marker rs8037309. Interpretation: We identified suggestive novel risk factors for neocortical LRP. SPTBN1 is the candidate on 2p21, it encodes beta-spectrin, an a-synuclein binding protein and a component of Lewy bodies. The HLA-DPA1/DPB1 association suggests a role for antigen presentation or alternatively, cis-regulatory effects, one of the regulated neighboring genes identified here (vacuolar protein sorting 52) plays a role in vesicular trafficking and has been shown to interact with a-synuclein in a yeast model.
Alzheimers & Dementia, Sep 28, 2016
INTRODUCTION: Amyloid imaging has been intergrated into diagnostic criteria for Alzheimer´s disea... more INTRODUCTION: Amyloid imaging has been intergrated into diagnostic criteria for Alzheimer´s disease (AD). How amyloid tracers binding differ for different tracer structure and amyloid-β aggregate in autosomal dominant AD (ADAD) and sporadic AD is unclear. METHODS: Binding properties of different amyloid tracers were examined in(brain homogenates from six ADAD with APPswe, PS1M146V and PS1E∆9 mutations, thirteen sporadic AD and fourteen control cases. RESULTS: 3 H-PIB, 3 H-florbetaben, 3 H-AZD2184 and BTA-1 shared a high-and a varying lowaffinity binding site in the frontal cortex of sporadic AD. AZD2184 detected another binding site (affinity 33 nM) in the frontal cortex of ADAD. The 3 H-AZD2184 and 3 H-PIB binding were significantly higher in the striatum of ADAD compared to sporadic AD and control. Polyphenol resveratrol showed strongest inhibition on 3 H-AZD84 binding followed by 3 H-florbetaben and minimal on 3 H-PIB. DISCUSSION: This study implies amyloid tracers of different structures detect different sites on amyloid-β fibrils or conformations.
Annals of Neurology, Sep 1, 1999
Recently, two studies have reported an association between the ␣ 2-macroglobulin gene on chromoso... more Recently, two studies have reported an association between the ␣ 2-macroglobulin gene on chromosome 12 and late-onset Alzheimer's disease, whereas others have not been able to replicate these findings. By using a prospective populationbased study, we have investigated the relation between two polymorphisms in this gene with the presence of the disease and also with the extent of pathological changes in the cerebral cortex. The Vantaa 85؉ Study includes all 601 persons, at least 85 years of age, who were living in Vantaa, Finland, on April 1, 1991. The neocortical -amyloid protein load and the number of neurofibrillary tangles were determined on tissue sections by using methenamine silver staining and a modified Bielschowsky staining, respectively. The A/A genotype in exon 24 of the ␣ 2-macroglobulin gene was associated with neuropathologically defined diagnosis of Alzheimer's disease according to the CERAD (Consortium to Establish a Registry for Alzheimer's Disease) criteria and with an increase in the neocortical -amyloid protein load. The effect of this association was stronger in the apolipoprotein E 4-negative group. Therefore, genetic variability in the ␣ 2macroglobulin gene is a risk factor associated with neuropathologically defined Alzheimer's disease in our population, as well as with the extent of neocortical -amyloid protein deposition.
Neurobiology of Aging, May 1, 2000
Alzheimers & Dementia, Jul 1, 2010
Neurobiology of Aging, Apr 1, 2018
Biallelic loss-of-function mutations in TYROBP and TREM2 cause a rare disease that resembles earl... more Biallelic loss-of-function mutations in TYROBP and TREM2 cause a rare disease that resembles early-onset frontotemporal dementia with bone lesions (PLOSL). Some PLOSLcausing variants in TREM2 have also been associated with Alzheimer's disease when heterozygous. Here, we studied the PLOSLFIN TYROBP deletion that covers four of the gene's five exons. We genotyped 3220 older Finns (mean age 79, range 58-104) and found 11 deletion carriers (mean age 78, range 60-94). The carrier prevalence was 0.0034 (1 in 293) that matches previous findings in younger cohorts suggesting no significant early mortality. By comparing MMSE scores and diagnoses of dementia we did not find any significant differences between TYROBP deletion carriers and non-carriers (all p-values >0.5). Neuropathological analysis of two deletion carriers (aged 89 and 94) demonstrated only minimal beta-amyloid pathology (CERAD score 0). Collectively these results suggest that heterozygous carriership of the TYROBP deletion is not a major risk factor of cognitive impairment. Highlights: 3-5 bullet points • Loss-of-function mutations in TYROBP and TREM2 cause early-onset frontotemporal dementia with bone lesions (PLOSL) • TREM2 and TYROBP are part of the same receptor-signaling complex • Heterozygous variants in TREM2 are risk factors for neurodegenerative diseases • The PLOSLFIN deletion of TYROBP is not a strong risk factor for cognitive impairment when heterozygous
Archives of Gerontology and Geriatrics, Jul 1, 2009
We investigated the association between histologically defined atherosclerotic lesions in the car... more We investigated the association between histologically defined atherosclerotic lesions in the carotid arteries and the genetic variants of APOE and LPL in a population-based sample of Finns aged 85 or over. Post-mortem analysis of carotid arteries was performed in 240 subjects. Atherosclerotic lesions were categorized according to the modified American Heart Association criteria, and classified into four different categories: pathological intimal thickening (PIT), fibrous cap atheromas (FCA), calcified lesions (CL), and atherosclerotic burden (AB) (a combination of the other three categories). APOE e4 genetic variant was associated with PIT (p = 0.018) and AB (p = 0.006) in the carotid arteries, and its effect was independent of the serum lipid levels. The genetic variant LPL Ser447Ter was protective against FCA (p = 0.031) and AB (p = 0.012), while APOE e2 was protective against FCA (p = 0.035). Our results suggest that the APOE e4, e2 and LPL Ser447Ter variants may have different roles in the atherosclerotic process and their effects are seen even in the oldest old population.
Amyloid, Jan 25, 2011
Cerebral amyloid angiopathy (CAA) is a frequent finding in the brains of patients with Alzheimer&... more Cerebral amyloid angiopathy (CAA) is a frequent finding in the brains of patients with Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (AD). CAA may be complicated with CAA-associated intracerebral haemorrhage (CAAH). Previous studies have revealed matrix metalloproteinase (MMP) expression in a mouse model of CAA and in human intracerebral haemorrhage. Here we studied the involvement of MMPs in human CAA and CAAH. To investigate the putative expression of MMPs in human CAA and CAAH (Step 1), immunohistochemistry (IHC) against MMPs-1, -2, -7, -9, -19 and -26 was applied on tissue microarray (TMA) constructed of cerebral samples from 29 individuals with AD, 15 with CAAH and 2 controls. The findings in TMA were confirmed (Step 2) in tissue samples from 64 individuals, 45 presenting with CAA (including 36 with CAAH) and 19 without CAA (including 11 with hypertensive cerebral haemorrhage). In Step 1, immunoreactivity against MMPs-19 and -26 was detected in cerebral blood vessels in CAA. The results were confirmed in Step 2, where CAA (p&amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001) and intracerebral haemorrhage (p=0.045) were associated with vascular immunoreactivity against MMP-19. Multivariate analysis showed that the association between vascular MMP-19 and intracerebral haemorrhage was dependent from CAA. MMP-26 associated with CAA (p=0.021) but not with intracerebral haemorrhage. This is the first human study showing local MMP-19 immunoreactivity in the Aβ-amyloid-laden blood vessels in CAA, suggesting that MMPs may be involved in CAA.
Current Alzheimer Research, Dec 31, 2013
Previous reports suggest that brain white matter changes, a surrogate for small vessel disease, a... more Previous reports suggest that brain white matter changes, a surrogate for small vessel disease, are related to cerebral amyloid angiopathy (CAA). However, this relationship has not been explored in population-based studies or in the oldest old (&amp;amp;amp;amp;gt;85 years of age). We studied the relationships between white matter hyperintensities (WMH) determined by post-mortem magnetic resonance imaging (MRI) and neuropathologically assessed CAA in demented and nondemented subjects enrolled in the prospective community-based Finnish Vantaa 85+ Study. In this analysis, we evaluated scans and brain samples from 123 subjects (86% women) with a mean age of 90.6 years. We found CAA to be present in 63 % of the 123 subjects, whereas WMH was present in 74%, and dementia in 59 %. The presence of WMH of any severity did not relate to the presence or the degree of CAA severity, irrespective of the dementia status of the subjects. Furthermore, multivariate regression analysis showed a clear association between CAA and dementia but WMH was not related to dementia in this very old sample. We conclude that severe WMH may not be determined by CAA in this very elderly population.
Neurobiology of Disease, Dec 1, 2009
Neuronal ceroid lipofuscinoses (NCLs) are pediatric, neurodegenerative, lysosomal storage disorde... more Neuronal ceroid lipofuscinoses (NCLs) are pediatric, neurodegenerative, lysosomal storage disorders. Mutations in cathepsin D result in the most severe, congenital form of NCLs. We have previously generated a cathepsin D deficient Drosophila model, which exhibits the key features of NCLs: progressive intracellular accumulation of autofluorescent storage material and modest neurodegeneration in the brain areas related to visual functions. Here we extend the phenotypic characterization of cathepsin D deficient Drosophila and report that modest degenerative changes are also present in their retinae. Furthermore, by utilizing this phenotype, we examined the possible effect of 17 candidate modifiers, selected based on the results from other cathepsin D deficiency models. We found enhancers of this phenotype that support the involvement of endocytosis-, lipid metabolism- and oxidation-related factors in the cathepsin D deficiency induced degeneration. Our results warrant further investigation of these mechanisms in the pathogenesis of cathepsin D deficiency.
Acta Neuropathologica
An international consensus report in 2019 recommended a classification system for limbic-predomin... more 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 with unusual features that do not fit with current diagnostic categories. The goal of this report is to update the neuropathologic criteria for the diagnosis and staging of LATE-NC, based primarily on published data. We provide practical suggestions about how to integrate available genetic information and comorbid pathologies [e.g., Alzheimer’s disease neuropathologic changes (ADNC) and Lewy body disease]. We also describe recent research findings that have enabled more precise guidance on how to differentiate LATE-NC from other subtypes of TDP-43 pathology [e.g., frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (A...
npj Parkinson's Disease
The dual-hit hypothesis of Parkinson’s disease (PD) originally postulated that a neurotropic path... more The dual-hit hypothesis of Parkinson’s disease (PD) originally postulated that a neurotropic pathogen leads to formation of α-synuclein pathology in the olfactory bulb (OB) and dorsal motor nucleus of the vagus (DMV) and then invades the brain from these two entry points. Little work has been conducted to validate an important underlying premise for the dual-hit hypothesis, namely that the initial Lewy pathology does arise simultaneously in the OB and the enteric nervous system (ENS) plexuses and DMV at the earliest disease stage. We conducted a focused re-analysis of two postmortem datasets, which included large numbers of mild Lewy body disease (LBD) cases. We found that cases with α-synuclein pathology restricted to the peripheral autonomic nervous system and/or lower brainstem (early body-first LBD cases) very rarely had any OB pathology, suggesting that Lewy pathology commonly arises in the ENS without concomitant involvement of the OB. In contrast, cases with mild amygdala-pre...
Acta Neurologica Scandinavica
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial ... more This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
Acta Neuropathologica
Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) and Alzheim... more 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, genetic, and clinical data were compiled from 13 high-quality community-and population-based longitudinal studies. Participants were recruited from United States (8 cohorts, including one focusing on Japanese-American men), United Kingdom (2 cohorts), Brazil, Austria, and Finland. The total number of participants included was 6196, and the average age of death was 88.1 years. Not all data were available on each individual and there were differences between the cohorts in study designs and the amount of missing data. Among those with known cognitive status before death (n = 5665), 43.0% were cognitively normal, 14.9% had MCI, and 42.4% had dementiabroadly consistent with epidemiologic data in this age group. Approximately 99% of participants (n = 6125) had available CERAD neuritic amyloid plaque score data. In this subsample, 39.4% had autopsy-confirmed LATE-NC of any stage. Among brains with "frequent" neuritic amyloid plaques, 54.9% had comorbid LATE-NC, whereas in brains with no detected neuritic amyloid plaques, 27.0% had LATE-NC. Data on LATE-NC stages were available for 3803 participants, of which 25% had LATE-NC stage > 1 (associated with cognitive impairment). In the subset of individuals with Thal Aβ phase = 0 (lacking detectable Aβ plaques), the brains with LATE-NC had relatively more severe primary age-related tauopathy (PART). A total of 3267 participants had available clinical data relevant to frontotemporal dementia (FTD), and none were given the clinical diagnosis of definite FTD nor the pathological diagnosis of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). In the 10 cohorts with detailed neurocognitive assessments proximal to death, cognition tended to be worse with LATE-NC across the full spectrum of ADNC severity. This study provided a credible estimate of the current prevalence of LATE-NC Nelson et al.
Acta Neurologica Scandinavica, 2022
Objectives: The genetic background of vascular cognitive impairment (VCI) is poorly understood co... more Objectives: The genetic background of vascular cognitive impairment (VCI) is poorly understood compared to other dementia disorders. The aim of the study was to investigate the genetic background of VCI in a well-characterized Finnish cohort. Materials & Methods: Whole-exome sequencing (WES) was applied in 45 Finnish VCI patients. Copy-number variant (CNV) analysis using a SNP array was performed in 80 VCI patients. This study also examined the prevalence of variants at the miR-29 binding site of COL4A1 in 73 Finnish VCI patients. Results: In 40% (18/45) of the cases, WES detected possibly causative variants in genes associated with cerebral small vessel disease (CSVD) or other neurological or stroke-related disorders. These variants included HTRA1:c.847G>A p.(Gly283Arg),
Scientific Reports, 2021
Recently, several genome-wide association studies identified PHACTR1 as key locus for five divers... more Recently, several genome-wide association studies identified PHACTR1 as key locus for five diverse vascular disorders: coronary artery disease, migraine, fibromuscular dysplasia, cervical artery dissection and hypertension. Although these represent significant risk factors or comorbidities for ischemic stroke, PHACTR1 role in brain small vessel ischemic disease and ischemic stroke most important survival mechanism, such as the recruitment of brain collateral arteries like posterior communicating arteries (PcomAs), remains unknown. Therefore, we applied exome and genome sequencing in a multi-ethnic cohort of 180 early-onset independent familial and apparently sporadic brain small vessel ischemic disease and CADASIL-like Caucasian patients from US, Portugal, Finland, Serbia and Turkey and in 2 C57BL/6J stroke mouse models (bilateral common carotid artery stenosis [BCCAS] and middle cerebral artery occlusion [MCAO]), characterized by different degrees of PcomAs patency. We report 3 ver...
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Papers by Liisa Myllykangas