Serum neurofilament light chain in behavioral variant frontotemporal dementia

Objective To determine the association of serum neurofilament light chain (NfL) with functional deterioration and brain atrophy during follow-up of patients with behavioral variant frontotemporal dementia (bvFTD). Methods Blood NfL levels from 74 patients with bvFTD, 26 with Alzheimer disease (AD), 17 with mild cognitive impairment (MCI), and 15 healthy controls (Con) at baseline and follow-up were determined and analyzed for the diagnostic potential in relation to functional assessment (Clinical Dementia Rating Scale Sum of Boxes [CDR-SOB], frontotemporal lobar degeneration-related CDR-SOB, Mini-Mental State Examination [MMSE]) and brain volumetry. Results At baseline, serum NfL level correlated with CSFNfL (bvFTD r = 0.706, p < 0.0001;AD/MCI r = 0.666, p = 0.0003). Highest serum levels were observed in bvFTD (p < 0 0.0001 vs Con and MCI, p = 0.0078 vs AD, respectively). Discrimination of bvFTD from Con/MCI/AD was possible with 91%/74%/74% sensitivity and 79%/74%/58% specificity. At follow-up, serum NfL increased in bvFTD and AD (p = 0.0039 and p = 0.0006, respectively). At baseline and follow-up, NfL correlated with functional scores of patients with bvFTD (e.g., CDR-SOB [baseline] r = 0.4157, p = 0.0006;[follow-up] r = 0.5629, p < 0.0001) and with atrophy in the gray and white matter of many brain regions including frontal and subcortical areas (e.g., frontal lobe: r = -0.5857, p < 0.0001;95% confidence interval -0.7415 to -0.3701). For patients with AD/MCI, NfL correlated with the functional performance as well (e.g., CDR-SOB [baseline] r = 0.6624, p < 0.0001;[follow-up] r = 0.5659, p = 0.0003) but not with regional brain volumes. Conclusions As serum NfL correlates with functional impairment and brain atrophy in bvFTD at different disease stages, we propose it as marker of disease severity, paving the way for its future use as outcome measure for clinical trials. Classification of evidence This study provides Class III evidence that for patients with cognitive problems, serum NfL concentration discriminates bvFTD from other forms of dementia

Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease

Importance: An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. Objective: To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. Design, setting, and participants: This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. Exposures: Genetically determined modifiable risk factors. Main outcomes and measures: Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. Results: The EADB-diagnosed cohort included 39 106 participants with clinically diagnosed AD and 401 577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Biobank was excluded from the EADB consortium; odds for AD were similar for HDL cholesterol (OR per 1-SD unit increase, 1.08 [95% CI, 1.02-1.15]) and systolic blood pressure after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.23 [95% CI, 1.01-1.50]). Conclusions and relevance: This genetic association study found novel genetic associations between high HDL cholesterol concentrations and high systolic blood pressure with higher risk of AD. These findings may inspire new drug targeting and improved prevention implementation

Effects of Hypothermia vs Normothermia on Societal Participation and Cognitive Function at 6 Months in Survivors After Out-of-Hospital Cardiac Arrest

ImportanceThe Targeted Hypothermia vs Targeted Normothermia After Out-of-Hospital Cardiac Arrest (TTM2) trial reported no difference in mortality or poor functional outcome at 6 months after out-of-hospital cardiac arrest (OHCA). This predefined exploratory analysis provides more detailed estimation of brain dysfunction for the comparison of the 2 intervention regimens.ObjectivesTo investigate the effects of targeted hypothermia vs targeted normothermia on functional outcome with focus on societal participation and cognitive function in survivors 6 months after OHCA.Design, Setting, and ParticipantsThis study is a predefined analysis of an international multicenter, randomized clinical trial that took place from November 2017 to January 2020 and included participants at 61 hospitals in 14 countries. A structured follow-up for survivors performed at 6 months was by masked outcome assessors. The last follow-up took place in October 2020. Participants included 1861 adult (older than 18 years) patients with OHCA who were comatose at hospital admission. At 6 months, 939 of 1861 were alive and invited to a follow-up, of which 103 of 939 declined or were missing.InterventionsRandomization 1:1 to temperature control with targeted hypothermia at 33 °C or targeted normothermia and early treatment of fever (37.8 °C or higher).Main outcomes and measuresFunctional outcome focusing on societal participation assessed by the Glasgow Outcome Scale Extended ([GOSE] 1 to 8) and cognitive function assessed by the Montreal Cognitive Assessment ([MoCA] 0 to 30) and the Symbol Digit Modalities Test ([SDMT] z scores). Higher scores represent better outcomes.ResultsAt 6 months, 836 of 939 survivors with a mean age of 60 (SD, 13) (range, 18 to 88) years (700 of 836 male [84%]) participated in the follow-up. There were no differences between the 2 intervention groups in functional outcome focusing on societal participation (GOSE score, odds ratio, 0.91; 95% CI, 0.71-1.17; P = .46) or in cognitive function by MoCA (mean difference, 0.36; 95% CI,−0.33 to 1.05; P = .37) and SDMT (mean difference, 0.06; 95% CI,−0.16 to 0.27; P = .62). Limitations in societal participation (GOSE score less than 7) were common regardless of intervention (hypothermia, 178 of 415 [43%]; normothermia, 168 of 419 [40%]). Cognitive impairment was identified in 353 of 599 survivors (59%).ConclusionsIn this predefined analysis of comatose patients after OHCA, hypothermia did not lead to better functional outcome assessed with a focus on societal participation and cognitive function than management with normothermia. At 6 months, many survivors had not regained their pre-arrest activities and roles, and mild cognitive dysfunction was common.Trial RegistrationClinicalTrials.gov Identifier: NCT0290830

Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers

Amyloid-beta 42 (A beta 42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for A beta 42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple A beta 42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.Peer reviewe

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

the complementary use of sphenoidal electrodes and MRI in pre-operative epilepsy diagnostics

Von 1993 bis 2004 unterzogen sich 263 Patienten im Epilepsiezentrum Berlin am Krankenhaus Königin-Elisabeth-Herzberge einem prächirurgischen Monitoring, dem ein entsprechender epilepsiechirurgischer Eingriff folgte. Insgesamt konnten 251 neuropathologische Befunde rekrutiert werden. In 121 Fällen (46,0%) der epilepsichirurgisch versorgten Patienten wurde eine Hippocampussklerose gefunden. Bei 56,2% der Patienten mit einer HS (68 von 121) lag das interiktale Maximum an der Sp1/Sp2-Elektrode - im Gegensatz zu 30,8% der Patienten (40 von 130) mit einem Maximum sphenoidal ohne HS. Weiterhin dominant waren außerdem die Elektroden F7/8 und FT7/8. Bei 43,8% (53 von 121) der Patienten mit HS fand sich kein Maximum sphenoidal, die Patienten ohne HS wiesen in 69,2% (90 von 130) der Fälle kein dortiges Maximum auf. Von 121 Patienten mit HS hatten 75 (61,9%) ein sphenoidales Maximum iktal, von 130 Patienten ohne HS hatten 48 (36,9%) ein sphenoidales Maximum. Bei 38,0% der HS-Patienten (n=46) fand sich kein sphenoidaler Anfallsbeginn, während bei 63,0% der Patienten ohne HS (n=82) kein sphenoidales Maximum iktal vorliegt. Die Einbeziehung des Verteilungsfeldes der ETP (mindestens 80% der Amplitude vom Maximum) konnte keinen statistischen Zugewinn bei der Auswertung erbringen. Die interiktale und iktale Beteiligung der Sp-Elektroden bei Patienten mit einer HS ist signifikant höher als bei Patienten ohne eine HS. Allerdings lässt die geringe Sensitivität die Abgrenzung einer HS von einer extrahippocampalen Pathologie im Einzelfall nicht zu. Die beobachtete Signifikanz legt eine hohe Bedeutsamkeit der Sphenoidalelektroden für die Arbeit in der Klinik nahe, so dass postuliert werden muss, dass die EEG- Untersuchung bei einer Temporallappenepilepsie die genannten Elektroden beinhalten sollte. Dies wird insbesondere auch daher für sehr nützlich gehalten, weil die Anlage wenig invasiv, wenig zeitaufwändig und von hohem Aussagewert ist. Zweihundertundfünfunddreißig MRT-Befunde der 263 Patienten (89,4%) standen zur Verfügung. Nur 226 Befunde konnten verwertet werden, da neun neuropathologische Ergebnisse fehlten. In 76 Fällen der 115 MRT-Befunde der Patienten mit gesicherter HS wurde eine Hippocampussklerose gesehen (richtig positiv). Das entspricht einem Prozentsatz von 66,1%. Neununddreißigmal (33,9%) konnte im MRT bei HS-Patienten keine Hippocampussklerose festgestellt werden (falsch negative Befunde). Bei 111 Patienten ohne HS wurde in elf Fällen radiologisch die Diagnose einer HS gestellt (9,9% falsch positive Befunde). Dass beim Nichtvorliegen einer Hippocampussklerose im cMRT ebenfalls keine HS diagnostiziert wurde, war statistisch hochsignifikant wahrscheinlich (p<0,001). In den Fällen, in denen keine HS identifiziert werden konnte, wurde häufig eine globale kortikale oder diffuse subkortikale oder lokale Atrophie gesehen. Die Sensitivität der MRT betrug 66%, die Spezifität 90,1%. Die MRT-Untersuchung stellte sich als sehr gute Methode zur Diagnosestellung einer HS dar. In dieser Arbeit wurde gezeigt, dass das MRT als die dominante Domäne zur Diagnosestellung der HS anzusehen ist. In Fällen, in denen jedoch eine HS im MRT nicht nachzuweisen ist, fügt komplementär der Nachweis der interiktalen Beteiligung der Sphenoidalelektroden doch in 43% bzw. der iktalen Beteiligung in 40% der Fälle noch Hinweise auf eine mesiale Beteiligung bei den Patienten, bei denen auch eine HS nachzuweisen war, hinzu. Dabei liefern die interiktalen und iktalen Befunde an den Sp-Elektroden allein mit einer Häufigkeit von 62,9% beziehungsweise 60,9% nur schwache Hinweise auf eine mesiale Beteiligung.Between 1993 and 2004, 263 patients at the Berlin Epilepsy Center in the Königin-Elisabeth-Herzberge Hospital underwent pre-operative EEG monitoring followed by epilepsy surgery. It was possible to collect a total of 251 neuropathological findings. Hippocampal sclerosis (HS) was found in 121 cases (46.0%) of the patients who underwent epilepsy surgery. In 56.2% (68 of 121) of the patients with HS, the interictal maximum was in the Sp1/Sp2 electrode – in contrast to 30.8% (40 of 130) of patients without HS with maxima in the sphenoidal electrodes. Furthermore the F7/8 and FT7/8 electrodes were also dominant. In 43.8% (53 of 121) of the patients with HS the maximum was in non- sphenoidal electrodes; 69.2% (90 of 130) of the patients without HS had non- sphenoidal maxima. Of 121 patients with HS, 75 (61.9%) had a sphenoidal ictal maximum while of 130 patients without HS 48 (36.9%) had a sphenoidal ictal maximum. In 38.0% of the HS patients (n=46) the seizure origin was non- sphenoidal while in 63.0% of the patients without HS (n=82) the ictal maximum was non-sphenoidal. The inclusion of distribution fields of epilepsy typical potentials (ETP) (minimum 80% of the amplitude of the maximum) did not provide any additional findings on statistical analysis. In patients with HS, the interictal and ictal involvement of the sphenoidal electrodes is significantly higher than in patients without HS. Admittedly the low sensitivity is not sufficient for differentiation of HS from extra-hippocampal pathology on an individual basis. The observed significance suggests a high level of relevance for sphenoidal electrodes in routine clinical practice, such that it must be postulated that the EEG examination in cases of temporal lobe epilepsy ought to contain these electrodes. This is particularly therefore seen as very useful because the investigation is non-invasive, quick and highly informative. Two hundred and fifty five MRI results from 263 patients (89.4%) were available. Only 226 of the results could be used because 9 neuropathological results were absent. Hippocampal sclerosis was seen in 76 of the 115 MRI findings from HS patients (true positives). That corresponded to 66.1%. In 39 cases (33.9%) of the HS patients, it was not possible to identify hippocampal sclerosis (false negative findings). From 111 patients without HS, the diagnosis of HS was made radiologically in eleven cases (9.9% false positive findings). Where there was no hippocampal sclerosis in cerebral MRI, there was a highly significant statistical probability (p < 0.001) that HS was not diagnosed. In the cases in which HS could not be identified, a global cortical- or diffuse subcortical- or local-atrophy could be frequently seen. The sensitivity of MRI was 66%, the specificity 90.1%. The MRI investigation represented a very good method of diagnosis of HS. In this work it was shown that MRI should be seen as the dominant means of diagnosing HS. In cases where HS cannot be seen in MRI, the finding of involvement of the sphenoidal electrodes provides additional evidence of mesial involvement in 43% (interictal) and 40% (ictal) of patients in whom HS had been shown. In doing so, the interictal and ictal findings from sphenoidal electrodes alone, with frequencies of 62.9% and 60.9% respectively, provide only weak evidence of mesial involvement

Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease

Importance: An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. Objective: To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. Design, Setting, and Participants: This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. Exposures: Genetically determined modifiable risk factors. Main Outcomes and Measures: Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. Results: The EADB-diagnosed cohort included 39 106 participants with clinically diagnosed AD and 401 577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Biobank was excluded from the EADB consortium; odds for AD were similar for HDL cholesterol (OR per 1-SD unit increase, 1.08 [95% CI, 1.02-1.15]) and systolic blood pressure after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.23 [95% CI, 1.01-1.50]). Conclusions and Relevance: This genetic association study found novel genetic associations between high HDL cholesterol concentrations and high systolic blood pressure with higher risk of AD. These findings may inspire new drug targeting and improved prevention implementation.ISSN:2574-380