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Therapeutic modulation of TREM2-dependent microglial function might provide an additional strategy to slow the progression of Alzheimer's disease. Although studies in animal models suggest that TREM2 is protective against Alzheimer's pathology, its effect on tau pathology and its potential beneficial role in people with Alzheimer's disease is still unclear. Our aim was to study associations between the dynamics of soluble TREM2, as a biomarker of TREM2 signalling, and amyloid β (Aβ) deposition, tau-related pathology, neuroimaging markers, and cognitive decline, during the progression of autosomal dominant Alzheimer's disease.We did a longitudinal analysis of data from the Dominantly Inherited Alzheimer Network (DIAN) observational study, which includes families with a history of autosomal dominant Alzheimer's disease. Participants aged over 18 years who were enrolled in DIAN between Jan 1, 2009, and July 31, 2019, were categorised as either carriers of pathogenic variants in PSEN1, PSEN2, and APP genes (n=155) or non-carriers (n=93). We measured amounts of cleaved soluble TREM2 using a novel immunoassay in CSF samples obtained every 2 years from participants who were asymptomatic (Clinical Dementia Rating [CDR]=0) and annually for those who were symptomatic (CDR>0). CSF concentrations of Aβ40, Aβ42, total tau (t-tau), and tau phosphorylated on threonine 181 (p-tau) were measured by validated immunoassays. Predefined neuroimaging measurements were total cortical uptake of Pittsburgh compound B PET (PiB-PET), cortical thickness in the precuneus ascertained by MRI, and hippocampal volume determined by MRI. Cognition was measured using a validated cognitive composite (including DIAN word list test, logical memory delayed recall, digit symbol coding test [total score], and minimental status examination). We based our statistical analysis on univariate and bivariate linear mixed effects models.In carriers of pathogenic variants, a high amyloid burden at baseline, represented by low CSF Aβ42 (β=-4·28 × 10-2 [SE 0·013], p=0·0012), but not high cortical uptake in PiB-PET (β=-5·51 × 10-3 [0·011], p=0·63), was the only predictor of an augmented annual rate of subsequent increase in soluble TREM2. Augmented annual rates of increase in soluble TREM2 were associated with a diminished rate of decrease in amyloid deposition, as measured by Aβ42 in CSF (r=0·56 [0·22], p=0·011), in presymptomatic carriers of pathogenic variants, and with diminished annual rate of increase in PiB-PET (r=-0·67 [0·25], p=0·0060) in symptomatic carriers of pathogenic variants. Presymptomatic carriers of pathogenic variants with annual rates of increase in soluble TREM2 lower than the median showed a correlation between enhanced annual rates of increase in p-tau in CSF and augmented annual rates of increase in PiB-PET signal (r=0·45 [0·21], p=0·035), that was not observed in those with rates of increase in soluble TREM2 higher than the median. Furthermore, presymptomatic carriers of pathogenic variants with rates of increase in soluble TREM2 above or below the median had opposite associations between Aβ42 in CSF and PiB-PET uptake when assessed longitudinally. Augmented annual rates of increase in soluble TREM2 in presymptomatic carriers of pathogenic variants correlated with decreased cortical shrinkage in the precuneus (r=0·46 [0·22]), p=0·040) and diminished cognitive decline (r=0·67 [0·22], p=0·0020).Our findings in autosomal dominant Alzheimer's disease position the TREM2 response within the amyloid cascade immediately after the first pathological changes in Aβ aggregation and further support the role of TREM2 on Aβ plaque deposition and compaction. Furthermore, these findings underpin a beneficial effect of TREM2 on Aβ deposition, Aβ-dependent tau pathology, cortical shrinkage, and cognitive decline. Soluble TREM2 could, therefore, be a key marker for clinical trial design and interpretation. Efforts to develop TREM2-boosting therapies are ongoing.German Research Foundation, US National Institutes of Health.

Altres ajuts: "Marató TV3" grant (20141210, 044412, 20143710). Cerebrospinal fluid (CSF) biomarkers are useful in the diagnosis and the prediction of progression of several neurodegenerative diseases. Among them, CSF neurofilament light (NfL) protein has particular interest, as its levels reflect neuroaxonal degeneration, a common feature in various neurodegenerative diseases. In the present study, we analyzed NfL levels in the CSF of 535 participants of the SPIN (Sant Pau Initiative on Neurodegeneration) cohort including cognitively normal participants, patients with Alzheimer disease (AD), Down syndrome (DS), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). We evaluated the differences in CSF NfL accross groups and its association with other CSF biomarkers and with cognitive scales. All neurogenerative diseases showed increased levels of CSF NfL, with the highest levels in patients with ALS, FTD, CBS and PSP. Furthermore, we found an association of CSF NfL levels with cognitive impairment in patients within the AD and FTD spectrum and with AD pathology in DLB and DS patients. These results have implications for the use of NfL as a marker in neurodegenerative diseases.

Desconocemos los mecanismos fisiopatológicos subyacentes a la aparición de alucinaciones/alucinosis visual en pacientes con ictus, su incidencia, características y valor predictivo topográfico o pronóstico. En este trabajo estudiamos prospectivamente 78 pacientes con ictus isquémico/hemorrágico agudo y ausencia de enfermedad neurodegenerativa/psiquiátrica basal o clínica alucinatoria previa, administrándoles cuestionario estandarizado sobre alucinaciones/alucinosis visual y realizándoles prueba de neuroimagen. Un subgrupo de pacientes también cuenta con EEG y evaluación neuropsicológica. La incidencia de alucinaciones/alucinosis fue del 16,7%, siendo la mayoría imágenes complejas, con presentación precoz y curso autolimitado. Se asoció con lesiones occipitales, defecto campimétrico inicial, y alteraciones del sueño entre otras variables. Desconeixem els mecanismes fisiopatològics subjacents a la aparició d'al·lucinacions/al·lucinosi visual a pacients amb ictus, la seva incidència, característiques i valor predictiu topogràfic o pronòstic. En aquest treball estudiem prospectivament 78 pacients amb ictus isquèmic/hemorràgic agut i absència de malaltia neurodegenerativa/psiquiàtrica basal o clínica al·lucinatòria prèvia. Es va realitzar neuroimatge i es va administrar qüestionari sobre al·lucinacions/al·lucinosi. En un subgrup es va realitzar EEG i avaluació neuropsicològica. La incidència de al·lucinacions/al·lucinosis va ser 16,7%, la majoria van ser imatges complexes, d'aparició precoç i autolimitadas. La seva aparició es relaciona amb lesions occipitals, defecte campimetric inicial y alteracions del son entre altres.

The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once.

La demència amb cossos de Lewy (DCLw) es caracteritza per la seva heterogeneïtat. En aquesta tesi, el meu objectiu és investigar aquesta heterogeneïtat a través de l'anàlisi dels diferents subtipus clínics basats tant en les característiques de presentació predominants en la fase prodròmica de la malaltia com en la diversitat dels trastorns de la son presents, centrant-me en el trastorn del comportament de la son REM (TCSR). En aquesta tesi, també investigo el paper de l'activitat glial en DLB mesurant els nivells en el líquid cefaloraquidi (LCR) de les proteïnes glials YKL-40, TREM2 soluble (sTREM2) i progranulina i la seva relació amb els biomarcadors de la malaltia d'Alzheimer (EA). Els pacients amb un diagnòstic clínic de DCLw probable van ser reclutats consecutivament durant el període d'aquesta tesi. Per capturar l'inici clínic predominant, vaig calcular la durada relativa de cada símptoma central en relació amb la durada total de la malaltia des de l'inici fins a complir els criteris de DCLw probable. Es va utilitzar una anàlisi de clústers tipus K-means basat en la presentació clínica inicial. Un subconjunt de pacients també es va sotmetre a una avaluació específica del son, incloent-hi escales de son i vídeo-polisomnografia (V-PSG). Per a l'estudi dels marcadors glials, també incloem pacients amb DCLw prodròmic (prodDCLw), demència tipus EA, EA prodròmica (prodEA) i voluntaris cognitivament normals (CN). En aquesta tesi descric tres subtipus clínics en DCLw com a resultat de l'anàlisi de clústers realitzat. El subtipus predominantment cognitiu va ser el subgrup obtingut principal i es va caracteritzar per un inici clínic cognitiu i una fase prodròmica més llarga en comparació amb la resta. Els pacients del subtipus predominantment neuropsiquiàtric van presentar un inici tardà i es van caracteritzar pel predomini d'al·lucinacions durant l'etapa primerenca. Els pacients del subtipus predominantment parkinsonians van mostrar una evolució més ràpida cap a la demència i un temps més curt des de l'inici de la malaltia fins a la presència de parkinsonisme. Pel que fa als trastorns de la son, es va trobar una àmplia gamma d'alteracions en el subconjunt de pacients avaluats. Les alteracions en l'arquitectura de la son-vigília van ser especialment freqüents. El TCSR va ser diagnosticat en el 50% dels pacients estudiats, sent en la majoria anterior a l'inici de la deterioració cognitiva. Altres patologies com al·lucinacions, apnea obstructiva severa de la son i moviments periòdics de les cames simulaven la clínica del TCSR en alguns pacients. La freqüència d'EEG occipital en vigília es va correlacionar negativament amb la taxa d'activitat electromiogràfica en el somni REM. Pel que fa als marcadors glials, els nivells de YKL-40, sTREM2 i progranulina no van diferir entre els grups DCLw i CN. No obstant això, els nivells de YKL-40, però no de sTREM2 o PGRN, van ser més alts en pacients amb DCLw i perfil de LCR suggestiu de copatologia EA. En DCLw i prodDCLw, només YKL-40 es va correlacionar amb t-tau i p-tau. En resum, aquesta tesi investiga l'heterogeneïtat en la DCLw i descriu tres subtipus clínics amb diferents perfils i patrons de progressió definits per les característiques predominants durant la seva fase prodròmica, així com la varietat i complexitat dels trastorns de la son en DCLw, destacant la necessitat de V-PSG per identificar-los adequadament. Aquesta tesi també emfatitza que els marcadors glials en LCR sTREM2 i PGRN no augmenten en DCLw i que YKL-40 només augmenta en pacients amb DCLw amb un perfil de biomarcadors EA, el que suggereix que aquest augment és impulsat per la copatologia Alzheimer. Una de las características principales de la demencia con cuerpos de Lewy (DCLw) es su heterogeneidad. En esta tesis, mi objetivo es investigar esta heterogeneidad a través del análisis de los diferentes subtipos clínicos basados tanto en las características predominantes durante la fase prodrómica de la enfermedad como en la diversidad de los trastornos del sueño presentes en la enfermedad, centrándome en el trastorno del comportamiento del sueño REM (TCSR). En esta tesis, también investigo el papel de la actividad glial en la DCLw mediante el estudio de los niveles en líquido cefalorraquídeo (LCR) de las proteínas YKL-40, TREM2 soluble (sTREM2) y progranulina y su relación con biomarcadores carácterísticos de la enfermedad de Alzheimer (EA). Para ello, pacientes con un diagnóstico clínico de DCLw probable fueron reclutados consecutivamente durante el transcurso de esta tesis. Para capturar la clínica predominante al inicio, calculé la duración relativa de cada síntoma central en relación a la duración total de la enfermedad desde el inicio hasta cumplir criterios diagnósticos de DCLw probable. Los subtipos clínicos fueron hallados mediante un análisis de clusters basado en la presentación clínica. Un subconjunto de pacientes también se sometió a una evaluación específica de sueño, incluyendo escalas de sueño y video-polisomnografía (V-PSG). Para el estudio de los marcadores gliales, se incluyeron también pacientes con DCLw prodrómica (prodDCLw), demencia tipo EA, EA prodrómica (prodEA) y voluntarios cognitivamente normales (CN). En esta tesis describo tres subtipos clínicos en DCLw como resultado del análisis de clusters realizado. El subtipo predominantemente cognitivo fue el subgrupo mayoritario y se caracterizó por un inicio clínico cognitivo y una fase prodrómica más larga en comparación con el resto de subtipos. Los pacientes dentro del subtipo predominantemente neuropsiquiátrico presentaron un inicio tardío de la enfermedad y se caracterizaron por el predominio de alucinaciones durante el mismo. Los pacientes en el subtipo predominantemente parkinsoniano mostraron una evolución más rápida a demencia y un tiempo más corto desde el inicio de la enfermedad hasta la presencia de parkinsonismo. Con respecto a los trastornos del sueño, se encontró una amplia gama de alteraciones en el subconjunto de pacientes evaluados. Las alteraciones en la arquitectura del sueño-vigilia fueron especialmente frecuentes. El TCSR fue diagnosticado en el 50% de los pacientes estudiados, siendo en la mayoría anterior al inicio del deterioro cognitivo. Otras patologías como alucinaciones, apnea obstructiva severa del sueño y movimientos periódicos de las piernas simularon la clínica de TCSR en algunos pacientes. La frecuencia occipital en el EEG en vigilia se correlacionó negativamente con la tasa de actividad electromiográfica durante el sueño REM. Con respecto a los marcadores gliales, los niveles de YKL-40, sTREM2 y progranulina no difirieron entre los grupos DCLw y CN. Sin embargo, los niveles de YKL-40, pero no sTREM2 o PGRN, fueron más altos en pacientes con DCLw y perfil de LCR sugestivo de copatología EA. En DCLw y prodDCLw, sólo YKL-40 se correlacionó con t-tau y p-tau. En resumen, esta tesis investiga la heterogeneidad de la DCLw y describe tres subtipos clínicos con diferentes perfiles y patrones de progresión definidos por las características predominantes durante su fase prodrómica, así como la variedad y complejidad de los trastornos del sueño en DCLw, destacando la necesidad de V- PSG para identificarlos adecuadamente. Esta tesis también enfatiza que los marcadores gliales en LCR sTREM2 y PGRN no aumentan en DCLw y que YKL-40 solo aumenta en pacientes con DCLw que además presentan biomarcadores compatibles con copatología Alzheimer en LCR, lo que sugiere que este aumento es impulsado dicha copatología. Dementia with Lewy bodies (DLB) is characterized by its heterogeneity. In this thesis, I aim to investigate this clinical heterogeneity through the analysis of the different clinical subtypes based both on the predominant presentation features at the prodromal phase of the disease and by the assessment of sleep disorders, focusing on REM sleep behaviour disorder (RBD). I also investigate the role of glial activity in DLB by measuring the levels in cerebrospinal fluid (CSF) of glial proteins YKL-40, soluble TREM2 (sTREM2) and progranulin and its relationship with Alzheimer's disease (AD) biomarkers. Patients with a clinical diagnosis of probable DLB were consecutively recruited during the period of this thesis. To capture the predominant clinical onset, I calculated the relative duration of each core symptom respective to the total disease duration from onset to fulfilment of probable DLB criteria. A K-means clustering method based on the initial clinical presentation was applied. A subset of patients also underwent a specific assessment of sleep including sleep scales and video-polysomnography (V-PSG). For the study of glial markers, we also included patients with prodromal DLB (prodDLB), AD dementia, prodromal AD (prodAD), and cognitively normal volunteers (CN). In this thesis I report three different clinical subtypes in DLB resulted from the cluster analysis performed. The cognitive-predominant subtype was the main subgroup obtained and was featured by a cognitive onset and a longer prodromal phase. Patients in the neuropsychiatric-predominant subtype were older at disease onset and were characterised by the predominance of hallucinations during the early stage. Patients in the parkinsonism-predominant subtype showed a faster decline until a dementia stage and a shorter time from onset to presence of parkinsonism. Regarding the sleep disturbances, a wide range of alterations were found in the subset of patients specifically evaluated. Abnormalities in sleep-wake architecture were especially frequent. RBD was diagnosed in 50% of the studied patients, in most cases preceding the onset of cognitive impairment. Mimics of RBD were hallucinatory-like behaviours, severe obstructive sleep apnea and prominent periodic limb movements in sleep. Occipital EEG frequency while awake negatively correlated with the rate of electromyographic activity in REM sleep. Concerning glial markers, YKL-40, sTREM2 and progranulin levels did not differ between DLB groups and CN. However, YKL-40 levels, but not sTREM2 or PGRN, were higher in DLB patients who had a CSF profile suggestive of AD copathology than those without. In DLB and prodDLB, only YKL-40 correlated with t-tau and p-tau. To conclude, this thesis investigates the heterogeneity in DLB and reports three clinical subtypes with different clinical profiles and progression patterns defined by the predominant features during its prodromal phase as well as the variety and complexity of sleep disorders in DLB, highlighting the need of V-PSG to properly identify them. This thesis also emphasises that CSF glial markers sTREM2 and PGRN are not increased in DLB and that YKL-40 is only increased in DLB patients with an AD biomarker profile, suggesting that this increase is driven by AD copathology.

“The authors would like to thank the Norwegian Dementia Genetics Network (DemGene), the European DLB Consortium (E-DLB), Dementia Genetics Spanish Consortium (DEGESCO) and Genomic Research at Fundació ACE (GR@ACE) Consortium. Fundació ACE would like to thank patients and controls who participated in this project. We are indebted to private donors for their support of Fundació ACE research programs. Fundació ACE collaborates with the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, Spain) and is one of the participating centers of the Dementia Genetics Spanish Consortium (DEGESCO). The study was founded by the Research Council of Norway, Norwegian Regional Health Authorities and Norwegian Health Association and 237250/EU/JPND (APGeM). The Cohort 2 results were generated with the assistance of financial support of grants PI13/02434 and PI16/01861. Acción Estratégica en Salud, integrated in the Spanish National R + D + I Plan and financed by ISCIII (Instituto de Salud Carlos III)-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER- “Una manera de Hacer Europa”). GR@ACE project has been funded by Fundación bancaria “La Caixa”, Grifols SA, Fundació ACE. The funding sources did not in any way affect the results or presentation of the results.” should read: “The authors would like to thank the Norwegian Dementia Genetics Network (DemGene), the European DLB Consortium (E-DLB), Dementia Genetics Spanish Consortium (DEGESCO) and Genomic Research at Fundació ACE (GR@ACE) Consortium. Fundació ACE would like to thank patients and controls who participated in this project. We are indebted to private donors for their support of Fundació ACE research programs. Fundació ACE collaborates with the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, Spain) and is one of the participating centers of the Dementia Genetics Spanish Consortium (DEGESCO). The study was founded by the Research Council of Norway, Norwegian Regional Health Authorities and Norwegian Health Association and 237250/EU/JPND (APGeM). The Cohort 2 results were generated with the assistance of financial support of grants PI13/02434 and PI16/01861. Acción Estratégica en Salud, integrated in the Spanish National R + D + I Plan and financed by ISCIII (Instituto de Salud Carlos III)-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER- “Una manera de Hacer Europa”). GR@ACE project has been funded by Fundación bancaria “La Caixa”, Grifols SA, Fundació ACE. The funding sources did not in any way affect the results or presentation of the results. This paper represents independent research partly funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the author and not necessarily those of the NIHR or the Department of Health and Social Care”.

The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target. The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target.

Background: In progressive multiple sclerosis (MS), glial activation is thought to be a relevant mechanism of disability progression. Therefore, in vivo assessment of the glial cell activity is, in the emerging treatment era of primary progressive MS (PPMS), more important than ever. Objectives: To test the association of cerebrospinal fluid (CSF) and serum markers of glial activation in PPMS patients; including glial fibrillary acidic protein (GFAP), chitinase-3-like protein 1 (CHI3L1), soluble variant of triggering receptor expressed on myeloid cells 2 (sTREM2), and marker of neuroaxonal damage (Neurofilament light chain, NfL) as well as clinical severity. Methods: CSF and serum samples from PPMS patients were collected in the MS-centers at Universities of Freiburg (n = 49), Ulm (n = 27), Muenster (n = 11), and Rostock (n = 6). sTREM2 and CHI3L1 levels were measured using the previously reported ELISA assays, while NfL and GFAP were measured using SIMOA assays. Clinical data included age, gender, disease duration, treatment status, and Expanded Disability Status Scale (EDSS). Results: 93 CSF samples and 71 matching serum samples were analyzed. The median age of patients was 49 years and disease duration 4.5 years. GFAPserum correlated with EDSS after correction for age (β = 0.3, p = 0.001). Furthermore, EDSS was higher in patients with a GFAPserum level ≥ 151.7 pg/ml compared to patients with GFAPserum below this cut-off (5.5 vs. 4.0, p = 0.009). Other markers did not correlate with the clinical severity. Moreover, we found a correlation between NfLCSF and GFAPCSF, sTREM2 and CHI3L1 (ρ = 0.4 for GFAPCSF and sTREM2, ρ = 0.3 for CHI3L1, p < 0.01 for sTREM2 and CHI3L1 and