Association of acquired and heritable factors with intergenerational differences in age at symptomatic onset of Alzheimer disease between offspring and parents with dementia

Importance: Acquired and heritable traits are associated with dementia risk; however, how these traits are associated with age at symptomatic onset (AAO) of Alzheimer disease (AD) is unknown. Identifying the associations of acquired and heritable factors with variability in intergenerational AAO of AD could facilitate diagnosis, assessment, and counseling of the offspring of parents with AD. Objective: To quantify the associations of acquired and heritable factors with intergenerational differences in AAO of AD. Design, Setting, and Participants: This nested cohort study used data from the Knight Alzheimer Disease Research Center that included community-dwelling participants with symptomatic AD, parental history of dementia, and available DNA data who were enrolled in prospective studies of memory and aging from September 1, 2005, to August 31, 2016. Clinical, biomarker, and genetic data were extracted on January 17, 2017, and data analyses were conducted from July 1, 2017, to August 20, 2019. Main Outcomes and Measures: The associations of acquired (ie, years of education; body mass index; history of cardiovascular disease, hypertension, hypercholesterolemia, diabetes, active depression within 2 years, traumatic brain injury, tobacco use, and unhealthy alcohol use; and retrospective determination of AAO) and heritable factors (ie, ethnicity/race, paternal or maternal inheritance, parental history of early-onset dementia, APOE ε4 allele status, and AD polygenic risk scores) to intergenerational difference in AAO of AD were quantified using stepwise forward multivariable regression. Missense or frameshift variants within genes associated with AD pathogenesis were screened using whole-exome sequencing. Results: There were 164 participants with symptomatic AD, known parental history of dementia, and available DNA data (mean [SD] age, 70.9 [8.3] years; 90 [54.9%] women) included in this study. Offspring were diagnosed with symptomatic AD a mean (SD) 6.1 (10.7) years earlier than their parents (P \u3c .001). The adjusted R2 for measured acquired and heritable factors for intergenerational difference in AAO of AD was 0.29 (F8,155 = 9.13; P \u3c .001). Paternal (β = -9.52 [95% CI, -13.79 to -5.25]) and maternal (β = -6.68 [95% CI, -11.61 to -1.75]) history of dementia, more years of education (β = -0.58 [95% CI -1.08 to -0.09]), and retrospective determination of AAO (β = -3.46 [95% CI, -6.40 to -0.52]) were associated with earlier-than-expected intergenerational difference in AAO of AD. Parental history of early-onset dementia (β = 21.30 [95% CI, 15.01 to 27.59]), presence of 1 APOE ε4 allele (β = 5.00 [95% CI, 2.11 to 7.88]), and history of hypertension (β = 3.81 [95% CI, 0.88 to 6.74]) were associated with later-than-expected intergenerational difference in AAO of AD. Missense or frameshift variants within genes associated with AD pathogenesis were more common in participants with the greatest unexplained variability in intergenerational AAO of AD (19 of 48 participants [39.6%] vs 26 of 116 participants [22.4%]; P = .03). Conclusions and Relevance: Acquired and heritable factors were associated with a substantial proportion of variability in intergenerational AAO of AD. Variants in genes associated with AD pathogenesis may contribute to unexplained variability, justifying further study

The impact of secondary cytoreductive surgery on survival in first recurrence of platinum sensitive epithelial ovarian cancer

Objective: Analyze the effect on survival of secondary cytoreduction surgery (SCS) in treatment of first recurrence platinumsensitive epithelial ovarian cancer (REOC). Methods: Retrospective analysis of patients with first REOC who had platinum timefree interval (TFIp) > 6 months and were treated either with SCS followed by chemotherapy or chemotherapy only (CT). Clinical data such as patient’s performance status and number of sites with metastases were specifically assessed. The primary endpoint was overall survival (OS). Results: Seventyone patients were treated either by SCS (n = 37) or CT (n = 34). Complete resection after SCS was achieved in 89% of patients. After a median followup of 51.2 months, median OS, and progressionfree survival (PFS) were 68.2 and 21.6 months, respectively, for the whole series of the SCS patients had better survival and disease progression survival than the CT only patients (HR: 0.33, 95%CI: 0.170.6; p= 0.001) and (HR: 0.28, 95%CI: 0.150.5; p= 0.001), respectively. TFIp < 12 months and multiple metastases were most important prognostic factors for risk of death (HR: 7.7 and 6.2, respectively) and recurrence (HR: 5.8 and 3.8, respectively). Probability to undergo successful SCS is related to oligometastatic disease and no residual disease after first surgery (OR: 30.0 and 5.9, respectively). Conclusions: In women with REOC oligometastatic disease and no residual disease at first surgery are associated with successful SCS. In these patients oligometastatic disease and long platinum TFI are associated with improved probability of survival

Quantification of white matter cellularity and damage in preclinical and early symptomatic Alzheimer\u27s disease

Interest in understanding the roles of white matter (WM) inflammation and damage in the pathophysiology of Alzheimer disease (AD) has been growing significantly in recent years. However, in vivo magnetic resonance imaging (MRI) techniques for imaging inflammation are still lacking. An advanced diffusion-based MRI method, neuro-inflammation imaging (NII), has been developed to clinically image and quantify WM inflammation and damage in AD. Here, we employed NII measures in conjunction with cerebrospinal fluid (CSF) biomarker classification (for β-amyloid (Aβ) and neurodegeneration) to evaluate 200 participants in an ongoing study of memory and aging. Elevated NII-derived cellular diffusivity was observed in both preclinical and early symptomatic phases of AD, while disruption of WM integrity, as detected by decreased fractional anisotropy (FA) and increased radial diffusivity (RD), was only observed in the symptomatic phase of AD. This may suggest that WM inflammation occurs earlier than WM damage following abnormal Aβ accumulation in AD. The negative correlation between NII-derived cellular diffusivity and CSF Aβ42 level (a marker of amyloidosis) may indicate that WM inflammation is associated with increasing Aβ burden. NII-derived FA also negatively correlated with CSF t-tau level (a marker of neurodegeneration), suggesting that disruption of WM integrity is associated with increasing neurodegeneration. Our findings demonstrated the capability of NII to simultaneously image and quantify WM cellularity changes and damage in preclinical and early symptomatic AD. NII may serve as a clinically feasible imaging tool to study the individual and composite roles of WM inflammation and damage in AD. Keywords: Inflammation, White matter damage, Diffusion basis spectrum imaging, Neuro-inflammation imaging, Cerebrospinal fluid, Preclinical Alzheimer disease, Early symptomatic Alzheimer disease, Magnetic resonance imagin

Clinically early-stage CSPα mutation carrier exhibits remarkable terminal stage neuronal pathology with minimal evidence of synaptic loss

Autosomal dominant adult-onset neuronal ceroid lipofuscinosis (AD-ANCL) is a multisystem disease caused by mutations in the DNAJC5 gene. DNAJC5 encodes Cysteine String Protein-alpha (CSPα), a putative synaptic protein. AD-ANCL has been traditionally considered a lysosomal storage disease based on the intracellular accumulation of ceroid material. Here, we report for the first time the pathological findings of a patient in a clinically early stage of disease, which exhibits the typical neuronal intracellular ceroid accumulation and incipient neuroinflammation but no signs of brain atrophy, neurodegeneration or massive synaptic loss. Interestingly, we found minimal or no apparent reductions in CSPα or synaptophysin in the neuropil. In contrast, brain homogenates from terminal AD-ANCL patients exhibit significant reductions in SNARE-complex forming presynaptic protein levels, including a significant reduction in CSPα and SNAP-25. Frozen samples for the biochemical analyses of synaptic proteins were not available for the early stage AD-ANLC patient. These results suggest that the degeneration seen in the patients with AD-ANCL reported here might be a consequence of both the early effects of CSPα mutations at the cellular soma, most likely lysosome function, and subsequent neuronal loss and synaptic dysfunction

Alzheimer\u27s disease alters oligodendrocytic glycolytic and ketolytic gene expression

INTRODUCTION: Sporadic Alzheimer\u27s disease (AD) is strongly correlated with impaired brain glucose metabolism, which may affect AD onset and progression. Ketolysis has been suggested as an alternative pathway to fuel the brain. METHODS: RNA-seq profiles of post mortem AD brains were used to determine whether dysfunctional AD brain metabolism can be determined by impairments in glycolytic and ketolytic gene expression. Data were obtained from the Knight Alzheimer\u27s Disease Research Center (62 cases; 13 controls), Mount Sinai Brain Bank (110 cases; 44 controls), and the Mayo Clinic Brain Bank (80 cases; 76 controls), and were normalized to cell type: astrocytes, microglia, neurons, oligodendrocytes. RESULTS: In oligodendrocytes, both glycolytic and ketolytic pathways were significantly impaired in AD brains. Ketolytic gene expression was not significantly altered in neurons, astrocytes, and microglia. DISCUSSION: Oligodendrocytes may contribute to brain hypometabolism observed in AD. These results are suggestive of a potential link between hypometabolism and dysmyelination in disease physiology. Additionally, ketones may be therapeutic in AD due to their ability to fuel neurons despite impaired glycolytic metabolism

CSF Protein Changes Associated with Hippocampal Sclerosis Risk Gene Variants Highlight Impact of \u3cem\u3eGRN\u3c/em\u3e/PGRN

Objective—Hippocampal sclerosis of aging (HS-Aging) is a common cause of dementia in older adults. We tested the variability in cerebrospinal fluid (CSF) proteins associated with previously identified HS-Aging risk single nucleotide polymorphisms (SNPs). Methods—Alzheimer’s Disease Neuroimaging Initiative cohort (ADNI; n=237) data, combining both multiplexed proteomics CSF and genotype data, were used to assess the association between CSF analytes and risk SNPs in four genes (SNPs): GRN (rs5848), TMEM106B (rs1990622), ABCC9 (rs704180), and KCNMB2 (rs9637454). For controls, non-HS-Aging SNPs in APOE (rs429358/rs7412) and MAPT (rs8070723) were also analyzed against Aβ1-42 and total tau CSF analytes. Results—The GRN risk SNP (rs5848) status correlated with variation in CSF proteins, with the risk allele (T) associated with increased levels of AXL Receptor Tyrosine Kinase (AXL), TNF-Related Apoptosis-Inducing Ligand Receptor 3 (TRAIL-R3), Vascular Cell Adhesion Molecule-1 (VCAM-1) and clusterin (CLU) (all p \u3c 0.05 after Bonferroni correction). The TRAIL-R3 correlation was significant in meta-analysis with an additional dataset (p=5.05×10−5). Further, the rs5848 SNP status was associated with increased CSF tau protein – a marker of neurodegeneration (p=0.015). These data are remarkable since this GRN SNP has been found to be a risk factor for multiple types of dementia-related brain pathologies

Exome-Sequencing Confirms DNAJC5 Mutations as Cause of Adult Neuronal Ceroid-Lipofuscinosis

We performed whole-exome sequencing in two autopsy-confirmed cases and an elderly unaffected control from a multigenerational family with autosomal dominant neuronal ceroid lipofuscinosis (ANCL). A novel single-nucleotide variation (c.344T>G) in the DNAJC5 gene was identified. Mutational screening in an independent family with autosomal dominant ANCL found an in-frame single codon deletion (c.346_348 delCTC) resulting in a deletion of p.Leu116del. These variants fulfill all genetic criteria for disease-causing mutations: they are found in unrelated families with the same disease, exhibit complete segregation between the mutation and the disease, and are absent in healthy controls. In addition, the associated amino acid substitutions are located in evolutionarily highly conserved residues and are predicted to functionally affect the encoded protein (CSPα). The mutations are located in a cysteine-string domain, which is required for membrane targeting/binding, palmitoylation, and oligomerization of CSPα. We performed a comprehensive in silico analysis of the functional and structural impact of both mutations on CSPα. We found that these mutations dramatically decrease the affinity of CSPα for the membrane. We did not identify any significant effect on palmitoylation status of CSPα. However, a reduction of CSPα membrane affinity may change its palmitoylation and affect proper intracellular sorting. We confirm that CSPα has a strong intrinsic aggregation propensity; however, it is not modified by the mutations. A complementary disease-network analysis suggests a potential interaction with other NCLs genes/pathways. This is the first replication study of the identification of DNAJC5 as the disease-causing gene for autosomal dominant ANCL. The identification of the novel gene in ANCL will allow us to gain a better understanding of the pathological mechanism of ANCLs and constitutes a great advance toward the development of new molecular diagnostic tests and may lead to the development of potential therapies

Resequencing analysis of five Mendelian genes and the top genes from genome-wide association studies in Parkinson’s Disease

BACKGROUND: Most sequencing studies in Parkinson’s disease (PD) have focused on either a particular gene, primarily in familial and early onset PD samples, or on screening single variants in sporadic PD cases. To date, there is no systematic study that sequences the most common PD causing genes with Mendelian inheritance [α-synuclein (SNCA), leucine-rich repeat kinase 2 (LRRK2), PARKIN, PTEN-induced putative kinase 1 (PINK1) and DJ-1 (Daisuke-Junko-1)] and susceptibility genes [glucocerebrosidase beta acid (GBA) and microtubule-associated protein tau (MAPT)] identified through genome-wide association studies (GWAS) in a European-American case-control sample (n=815). RESULTS: Disease-causing variants in the SNCA,LRRK2 and PARK2 genes were found in 2 % of PD patients. The LRRK2, p.G2019S mutation was found in 0.6 % of sporadic PD and 4.8 % of familial PD cases. Gene-based analysis suggests that additional variants in the LRRK2 gene also contribute to PD risk. The SNCA duplication was found in 0.8 % of familial PD patients. Novel variants were found in 0.8 % of PD cases and 0.6 % of controls. Heterozygous Gaucher disease-causing mutations in the GBA gene were found in 7.1 % of PD patients. Here, we established that the GBA variant (p.T408M) is associated with PD risk and age at onset. Additionally, gene-based and single-variant analyses demostrated that GBA gene variants (p.L483P, p.R83C, p.N409S, p.H294Q and p.E365K) increase PD risk. CONCLUSIONS: Our data suggest that the impact of additional untested coding variants in the GBA and LRRK2 genes is higher than previously estimated. Our data also provide compelling evidence of the existence of additional untested variants in the primary Mendelian and PD GWAS genes that contribute to the genetic etiology of sporadic PD