Jennifer S. Yokoyama

A genomewide association study of citalopram response in major depressive disorder.

BACKGROUND Antidepressant response is likely influenced by genetic constitution, but the actual genes involved have yet to be determined. We have carried out a genomewide association study to determine whether common DNA variation influences antidepressant response. METHODS Our sample is derived from Level 1 participants in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, all treated with citalopram. Association for the response phenotype included 883 responders and 608 nonresponders. For the remission phenotype, 743 subjects that achieved remission were compared with 608 nonresponders. We used a subset of single nucleotide polymorphisms (SNPs; n = 430,198) from the Affymetrix 500K and 5.0 Human SNP Arrays, and association analysis was carried out after correcting for population stratification. RESULTS We identified three SNPs associated with response with p values less than 1 x 10(-5) near the UBE3C gene (rs6966038, p = 4.65 x 10(-7)), another 100 kb away from BMP7 (rs6127921, p = 3.45 x 10(-6)), and a third that is intronic in the RORA gene (rs809736, p = 8.19 x 10(-6)). These same SNPs were also associated with remission. Thirty-nine additional SNPs are of interest with p values < or = .0001 for the response and remission phenotypes. CONCLUSIONS Although the findings reported here do not meet a genomewide threshold for significance, the regions identified from this study provide targets for independent replication and novel pathways to investigate mechanisms of antidepressant response. This study was not placebo controlled, making it possible that we are also observing associations to nonspecific aspects of drug treatment of depression.

Frontotemporal dementia due to C9ORF72 mutations: Clinical and imaging features

Objective: To describe the phenotype of patients with C9FTD/ALS (C9ORF72) hexanucleotide repeat expansion. Methods: A total of 648 patients with frontotemporal dementia (FTD)–related clinical diagnoses and Alzheimer disease (AD) dementia were tested for C9ORF72 expansion and 31 carried expanded repeats (C9+). Clinical and neuroimaging data were compared between C9+ (15 behavioral variant FTD [bvFTD], 11 FTD–motor neuron disease [MND], 5 amyotrophic lateral sclerosis [ALS]) and sporadic noncarriers (48 bvFTD, 19 FTD-MND, 6 ALS). Results: All C9+ patients displayed clinical syndromes of bvFTD, ALS, or FTD-MND. At first evaluation, C9+ bvFTD patients had more delusions and greater impairment of working memory, but milder eating dysregulation compared to bvFTD noncarriers. C9+FTD-MND patients had a trend for longer survival and had an earlier age at onset than FTD-MND noncarriers. Voxel-based morphometry demonstrated more thalamic atrophy in FTD and FTD-MND carriers than in noncarriers. Conclusions: Patients with the C9ORF72 hexanucleotide repeat expansion develop bvFTD, ALS, or FTD-MND with similar clinical and imaging features to sporadic cases. Other FTD spectrum diagnoses and AD dementia appear rare or absent among C9+ individuals. Longer survival in C9+ FTD-MND suggests slower disease progression and thalamic atrophy represents a novel and unexpected feature.

Atypical, slowly progressive behavioural variant frontotemporal dementia associated with C9ORF72 hexanucleotide expansion

Background Some patients meeting behavioural variant frontotemporal dementia (bvFTD) diagnostic criteria progress slowly and plateau at mild symptom severity. Such patients have mild neuropsychological and functional impairments, lack characteristic bvFTD brain atrophy and have thus been referred to as bvFTD ‘phenocopies’ or slowly progressive (bvFTD-SP). The few patients with bvFTD-SP that have been studied at autopsy have demonstrated no evidence of FTD pathology, suggesting that bvFTD-SP is neuropathologically distinct from other forms of FTD. Here, two patients with bvFTD-SP with chromosome 9 open reading frame 72 (C9ORF72) hexanucleotide expansions are described. Methods 384 patients with an FTD clinical spectrum and Alzheimers disease diagnoses were screened for C9ORF72 expansion. Two bvFTD-SP mutation carriers were identified. Neuropsychological and functional data, as well as brain atrophy patterns, assessed using voxel based morphometry (VBM), were compared with 44 patients with sporadic bvFTD and 85 healthy controls. Results Both patients were aged 48 years at baseline and met possible bvFTD criteria. In the first patient, VBM revealed thalamic and posterior insula atrophy. Over 7 years, his neuropsychological performance and brain atrophy remained stable. In the second patient, VBM revealed cortical atrophy with subtle frontal and insular volume loss. Over 2 years, her neuropsychological and functional scores as well as brain atrophy remained stable. Conclusions C9ORF72 mutations can present with a bvFTD-SP phenotype. Some bvFTD-SP patients may have neurodegenerative pathology, and C9ORF72 mutations should be considered in patients with bvFTD-SP and a family history of dementia or motor neuron disease.

Life Extension Factor Klotho Enhances Cognition

Aging is the primary risk factor for cognitive decline, an emerging health threat to aging societies worldwide. Whether anti-aging factors such as klotho can counteract cognitive decline is unknown. We show that a lifespan-extending variant of the human KLOTHO gene, KL-VS, is associated with enhanced cognition in heterozygous carriers. Because this allele increased klotho levels in serum, we analyzed transgenic mice with systemic overexpression of klotho. They performed better than controls in multiple tests of learning and memory. Elevating klotho in mice also enhanced long-term potentiation, a form of synaptic plasticity, and enriched synaptic GluN2B, an N-methyl-D-aspartate receptor (NMDAR) subunit with key functions in learning and memory. Blockade of GluN2B abolished klotho-mediated effects. Surprisingly, klotho effects were evident also in young mice and did not correlate with age in humans, suggesting independence from the aging process. Augmenting klotho or its effects may enhance cognition and counteract cognitive deficits at different life stages.

Activation of cerebellar parallel fibers monitored in transgenic mice expressing a fluorescent Ca2+ indicator protein

Genetically encoded fluorescent Ca2+ indicator proteins (FCIPs) are promising tools to study Ca2+ signaling in large assemblies of nerve cells. Currently, there are few examples of stable transgenic mouse lines that functionally express such sensors in well‐defined neuronal cell populations. Here we report the generation and characterization of transgenic mice expressing an FCIP under the 5′ regulatory sequences of the Kv3.1 potassium channel promoter. In the cerebellar cortex, expression was restricted to granule cells. We first demonstrated reliable measurements of Ca2+ transients from beams of parallel fibers and compared the FCIP signals with intrinsic autofluorescence signals. We demonstrate that, in a transgenic line that exhibits a high expression level of the FCIP, autofluorescence signals are negligible and stimulation‐induced fluorescence transients represent FCIP signals. Using frontal cerebellar slices we imaged antidromic activation of granule cells following electrical stimulation of parallel fibers and orthodromic activation of beams of parallel fibers following electrical stimulation of granule cells. We found that paired pulse‐induced presynaptic Ca2+ transients of parallel fibers are not affected by blockade of N‐methyl‐d‐aspartate receptors.

Heightened emotional contagion in mild cognitive impairment and Alzheimer’s disease is associated with temporal lobe degeneration

Emotional changes are common in mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Intrinsic connectivity imaging studies suggest that default mode network degradation in AD is accompanied by the release of an emotion-relevant salience network. We investigated whether emotional contagion, an evolutionarily conserved affect-sharing mechanism, is higher in MCI and AD secondary to biological alterations in neural networks that support emotion. We measured emotional contagion in 237 participants (111 healthy controls, 62 patients with MCI, and 64 patients with AD) with the Interpersonal Reactivity Index Personal Distress subscale. Depressive symptoms were evaluated with the Geriatric Depression Scale. Participants underwent structural MRI, and voxel-based morphometry was used to relate whole-brain maps to emotional contagion. Analyses of covariance found significantly higher emotional contagion at each stage of disease progression [controls < MCI (P < 0.01) and MCI < AD (P < 0.001)]. Depressive symptoms were also higher in patients compared with controls [controls < MCI (P < 0.01) and controls < AD (P < 0.0001)]. Higher emotional contagion (but not depressive symptoms) was associated with smaller volume in right inferior, middle, and superior temporal gyri (PFWE < 0.05); right temporal pole, anterior hippocampus, parahippocampal gyrus; and left middle temporal gyrus (all P < 0.001, uncorrected). These findings suggest that in MCI and AD, neurodegeneration of temporal lobe structures important for affective signal detection and emotion inhibition are associated with up-regulation of emotion-generating mechanisms. Emotional contagion, a quantifiable index of empathic reactivity that is present in other species, may be a useful tool with which to study emotional alterations in animal models of AD.

Progranulin Mutations as Risk Factors for Alzheimer Disease

IMPORTANCE Mutations in the progranulin gene are known to cause diverse clinical syndromes, all attributed to frontotemporal lobar degeneration. We describe 2 patients with progranulin gene mutations and evidence of Alzheimer disease (AD) pathology. We also conducted a literature review. OBSERVATIONS This study focused on case reports of 2 unrelated patients with progranulin mutations at the University of California, San Francisco, Memory and Aging Center. One patient presented at age 65 years with a clinical syndrome suggestive of AD and showed evidence of amyloid aggregation on positron emission tomography. Another patient presented at age 54 years with logopenic progressive aphasia and, at autopsy, showed both frontotemporal lobar degeneration with TDP-43 inclusions and AD. CONCLUSIONS AND RELEVANCE In addition to autosomal-dominant frontotemporal lobar degeneration, mutations in the progranulin gene may be a risk factor for AD clinical phenotypes and neuropathology.

Altered network connectivity in frontotemporal dementia with C9orf72 hexanucleotide repeat expansion.

Hexanucleotide repeat expansion in C9orf72 represents the most common genetic cause of familial and sporadic behavioural variant frontotemporal dementia. Previous studies show that some C9orf72 carriers with behavioural variant frontotemporal dementia exhibit distinctive atrophy patterns whereas others show mild or undetectable atrophy despite severe behavioural impairment. To explore this observation, we examined intrinsic connectivity network integrity in patients with or without the C9orf72 expansion. We studied 28 patients with behavioural variant frontotemporal dementia, including 14 C9orf72 mutation carriers (age 58.3 ± 7.7 years, four females) and 14 non-carriers (age 60.8 ± 6.9 years, four females), and 14 age- and sex-matched healthy controls. Both patient groups included five patients with comorbid motor neuron disease. Neuropsychological data, structural brain magnetic resonance imaging, and task-free functional magnetic resonance imaging were obtained. Voxel-based morphometry delineated atrophy patterns, and seed-based intrinsic connectivity analyses enabled group comparisons of the salience, sensorimotor, and default mode networks. Single-patient analyses were used to explore network imaging as a potential biomarker. Despite contrasting atrophy patterns in C9orf72 carriers versus non-carriers, patient groups showed topographically similar connectivity reductions in the salience and sensorimotor networks. Patients without C9orf72 expansions exhibited increases in default mode network connectivity compared to controls and mutation carriers. Across all patients, behavioural symptom severity correlated with diminished salience network connectivity and heightened default mode network connectivity. In C9orf72 carriers, salience network connectivity reduction correlated with atrophy in the left medial pulvinar thalamic nucleus, and this region further showed diminished connectivity with key salience network hubs. Single-patient analyses revealed salience network disruption and default mode network connectivity enhancement in C9orf72 carriers with early-stage or slowly progressive symptoms. The findings suggest that patients with behavioural variant frontotemporal dementia with or without the C9orf72 expansion show convergent large-scale network breakdowns despite distinctive atrophy patterns. Medial pulvinar degeneration may contribute to the behavioural variant frontotemporal dementia syndrome in C9orf72 carriers by disrupting salience network connectivity. Task-free functional magnetic resonance imaging shows promise in detecting early-stage disease in C9orf72 carriers and may provide a unifying biomarker across diverse anatomical variants.

Association Between Genetic Traits for Immune-Mediated Diseases and Alzheimer Disease

IMPORTANCE Late-onset Alzheimer disease (AD), the most common form of dementia, places a large burden on families and society. Although epidemiological and clinical evidence suggests a relationship between inflammation and AD, their relationship is not well understood and could have implications for treatment and prevention strategies. OBJECTIVE To determine whether a subset of genes involved with increased risk of inflammation are also associated with increased risk for AD. DESIGN, SETTING, AND PARTICIPANTS In a genetic epidemiology study conducted in July 2015, we systematically investigated genetic overlap between AD (International Genomics of Alzheimers Project stage 1) and Crohn disease, ulcerative colitis, rheumatoid arthritis, type 1 diabetes, celiac disease, and psoriasis using summary data from genome-wide association studies at multiple academic clinical research centers. P values and odds ratios from genome-wide association studies of more than 100 000 individuals were from previous comparisons of patients vs respective control cohorts. Diagnosis for each disorder was previously established for the parent study using consensus criteria. MAIN OUTCOMES AND MEASURES The primary outcome was the pleiotropic (conjunction) false discovery rate P value. Follow-up for candidate variants included neuritic plaque and neurofibrillary tangle pathology; longitudinal Alzheimers Disease Assessment Scale cognitive subscale scores as a measure of cognitive dysfunction (Alzheimers Disease Neuroimaging Initiative); and gene expression in AD vs control brains (Gene Expression Omnibus data). RESULTS Eight single-nucleotide polymorphisms (false discovery rate P < .05) were associated with both AD and immune-mediated diseases. Of these, rs2516049 (closest gene HLA-DRB5; conjunction false discovery rate P = .04 for AD and psoriasis, 5.37 × 10-5 for AD, and 6.03 × 10-15 for psoriasis) and rs12570088 (closest gene IPMK; conjunction false discovery rate P = .009 for AD and Crohn disease, P = 5.73 × 10-6 for AD, and 6.57 × 10-5 for Crohn disease) demonstrated the same direction of allelic effect between AD and the immune-mediated diseases. Both rs2516049 and rs12570088 were significantly associated with neurofibrillary tangle pathology (P = .01352 and .03151, respectively); rs2516049 additionally correlated with longitudinal decline on Alzheimers Disease Assessment Scale cognitive subscale scores (β [SE], 0.405 [0.190]; P = .03). Regarding gene expression, HLA-DRA and IPMK transcript expression was significantly altered in AD brains compared with control brains (HLA-DRA: β [SE], 0.155 [0.024]; P = 1.97 × 10-10; IPMK: β [SE], -0.096 [0.013]; P = 7.57 × 10-13). CONCLUSIONS AND RELEVANCE Our findings demonstrate genetic overlap between AD and immune-mediated diseases and suggest that immune system processes influence AD pathogenesis and progression.

Genetic assessment of age-associated Alzheimer disease risk: Development and validation of a polygenic hazard score

Background Identifying individuals at risk for developing Alzheimer disease (AD) is of utmost importance. Although genetic studies have identified AD-associated SNPs in APOE and other genes, genetic information has not been integrated into an epidemiological framework for risk prediction. Methods and findings Using genotype data from 17,008 AD cases and 37,154 controls from the International Genomics of Alzheimer’s Project (IGAP Stage 1), we identified AD-associated SNPs (at p < 10−5). We then integrated these AD-associated SNPs into a Cox proportional hazard model using genotype data from a subset of 6,409 AD patients and 9,386 older controls from Phase 1 of the Alzheimer’s Disease Genetics Consortium (ADGC), providing a polygenic hazard score (PHS) for each participant. By combining population-based incidence rates and the genotype-derived PHS for each individual, we derived estimates of instantaneous risk for developing AD, based on genotype and age, and tested replication in multiple independent cohorts (ADGC Phase 2, National Institute on Aging Alzheimer’s Disease Center [NIA ADC], and Alzheimer’s Disease Neuroimaging Initiative [ADNI], total n = 20,680). Within the ADGC Phase 1 cohort, individuals in the highest PHS quartile developed AD at a considerably lower age and had the highest yearly AD incidence rate. Among APOE ε3/3 individuals, the PHS modified expected age of AD onset by more than 10 y between the lowest and highest deciles (hazard ratio 3.34, 95% CI 2.62–4.24, p = 1.0 × 10−22). In independent cohorts, the PHS strongly predicted empirical age of AD onset (ADGC Phase 2, r = 0.90, p = 1.1 × 10−26) and longitudinal progression from normal aging to AD (NIA ADC, Cochran–Armitage trend test, p = 1.5 × 10−10), and was associated with neuropathology (NIA ADC, Braak stage of neurofibrillary tangles, p = 3.9 × 10−6, and Consortium to Establish a Registry for Alzheimer’s Disease score for neuritic plaques, p = 6.8 × 10−6) and in vivo markers of AD neurodegeneration (ADNI, volume loss within the entorhinal cortex, p = 6.3 × 10−6, and hippocampus, p = 7.9 × 10−5). Additional prospective validation of these results in non-US, non-white, and prospective community-based cohorts is necessary before clinical use. Conclusions We have developed a PHS for quantifying individual differences in age-specific genetic risk for AD. Within the cohorts studied here, polygenic architecture plays an important role in modifying AD risk beyond APOE. With thorough validation, quantification of inherited genetic variation may prove useful for stratifying AD risk and as an enrichment strategy in therapeutic trials.