Giuseppe Tosto

White Matter Hyperintensities and Cerebral Amyloidosis Necessary and Sufficient for Clinical Expression of Alzheimer Disease

IMPORTANCE Current hypothetical models emphasize the importance of β-amyloid in Alzheimer disease (AD) pathogenesis, although amyloid alone is not sufficient to account for the dementia syndrome. The impact of small-vessel cerebrovascular disease, visualized as white matter hyperintensities (WMHs) on magnetic resonance imaging scans, may be a key factor that contributes independently to AD presentation. OBJECTIVE To determine the impact of WMHs and Pittsburgh Compound B (PIB) positron-emission tomography-derived amyloid positivity on the clinical expression of AD. DESIGN Baseline PIB-positron-emission tomography values were downloaded from the Alzheimers Disease Neuroimaging Initiative database. Total WMH volume was derived on accompanying structural magnetic resonance imaging data. We examined whether PIB positivity and total WMHs predicted diagnostic classification of patients with AD (n = 20) and control subjects (n = 21). A second analysis determined whether WMHs discriminated between those with and without the clinical diagnosis of AD among those who were classified as PIB positive (n = 28). A third analysis examined whether WMHs, in addition to PIB status, could be used to predict future risk for AD among subjects with mild cognitive impairment (n = 59). SETTING The Alzheimers Disease Neuroimaging Initiative public database. PARTICIPANTS The study involved data from 21 normal control subjects, 59 subjects with mild cognitive impairment, and 20 participants with clinically defined AD from the Alzheimer Diseases Neuroimaging Initiative database. MAIN OUTCOME MEASURES Clinical AD diagnosis and WMH volume. RESULTS Pittsburgh Compound B positivity and increased total WMH volume independently predicted AD diagnosis. Among PIB-positive subjects, those diagnosed as having AD had greater WMH volume than normal control subjects. Among subjects with mild cognitive impairment, both WMH and PIB status at baseline conferred risk for future diagnosis of AD. CONCLUSIONS AND RELEVANCE White matter hyperintensities contribute to the presentation of AD and, in the context of significant amyloid deposition, may provide a second hit necessary for the clinical manifestation of the disease. As risk factors for the development of WMHs are modifiable, these findings suggest intervention and prevention strategies for the clinical syndrome of AD.

Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease

Recently, several genome-wide association studies (GWASs) have led to the discovery of nine new loci of genetic susceptibility in Alzheimers disease (AD). However, the landscape of the AD genetic susceptibility is far away to be complete and in addition to single-SNP (single-nucleotide polymorphism) analyses as performed in conventional GWAS, complementary strategies need to be applied to overcome limitations inherent to this type of approaches. We performed a genome-wide haplotype association (GWHA) study in the EADI1 study (n=2025 AD cases and 5328 controls) by applying a sliding-windows approach. After exclusion of loci already known to be involved in AD (APOE, BIN1 and CR1), 91 regions with suggestive haplotype effects were identified. In a second step, we attempted to replicate the best suggestive haplotype associations in the GERAD1 consortium (2820 AD cases and 6356 controls) and observed that 9 of them showed nominal association. In a third step, we tested relevant haplotype associations in a combined analysis of five additional case–control studies (5093 AD cases and 4061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analyzed (OR: 1.68; 95% CI: (1.43–1.96); P=1.1 × 10−10). We finally searched for association between SNPs within the FRMD4A locus and Aβ plasma concentrations in three independent non-demented populations (n=2579). We reported that polymorphisms were associated with plasma Aβ42/Aβ40 ratio (best signal, P=5.4 × 10−7). In conclusion, combining both GWHA study and a conservative three-stage replication approach, we characterised FRMD4A as a new genetic risk factor of AD.

Genome-wide Association Studies in Alzheimer’s Disease: A Review

Over the past decade, research aiming to disentangle the genetic underpinnings of late-onset Alzheimer’s disease has mostly focused on the identification of common variants through genome-wide association studies. The identification of several new susceptibility genes through these efforts has reinforced the importance of amyloid precursor protein and tau metabolism in the cause of the disease and has implicated immune response, inflammation, lipid metabolism, endocytosis/intracellular trafficking, and cell migration in the cause of the disease. Ongoing and future large-scale genome-wide association studies, translational studies, and next-generation whole genome or whole exome sequencing efforts, hold the promise to map the specific causative variants in these genes, to identify several additional risk variants, including rare and structural variants, and to identify novel targets for genetic testing, prevention, and treatment.

Genetic variants in the Fat and Obesity Associated (FTO) gene and risk of Alzheimer's disease.

Background Recent studies showed that polymorphisms in the Fat and Obesity-Associated (FTO) gene have robust effects on obesity, obesity-related traits and endophenotypes associated with Alzheimers disease (AD). Methods We used 1,877 Caucasian cases and controls from the NIA-LOAD study and 1,093 Caribbean Hispanics to further explore the association of FTO with AD. Using logistic regression, we assessed 42 SNPs in introns 1 and 2, the region previously reported to be associated with AD endophenotypes, which had been derived by genome-wide screenings. In addition, we performed gene expression analyses of neuropathologically confirmed AD cases and controls of two independent datasets (19 AD cases, 10 controls; 176 AD cases, 188 controls) using within- and between-group factors ANOVA of log10 transformed rank invariant normalized expression data. Results In the NIALOAD study, one SNP was significantly associated with AD and three additional markers were close to significance (rs6499640, rs10852521, rs16945088, rs8044769, FDR p-value: 0.05<p<0.09). Two of the SNPs are in strong LD (D′>0.9) with the previously reported SNPs. In the Caribbean Hispanic dataset, we identified three SNPs (rs17219084, rs11075996, rs11075997, FDR p-value: 0.009<p<0.01) that were associated with AD. These results were confirmed by haplotype analyses and in a metaanalysis in which we included the ADNI dataset. FTO had a significantly lower expresssion in AD cases compared to controls in two independent datasets derived from human cortex and amygdala tissue, respectively (p = 2.18×10−5 and p<0.0001). Conclusions Our data support the notion that genetic variation in Introns 1 and 2 of the FTO gene may contribute to AD risk.

White matter hyperintensities and amyloid are independently associated with entorhinal cortex volume among individuals with mild cognitive impairment

Current hypothetical models of Alzheimers disease (AD) pathogenesis emphasize the role of β‐amyloid (Aβ), tau deposition, and neurodegenerative changes in the mesial temporal lobe, particularly the entorhinal cortex and hippocampus. However, many individuals with clinical AD who come to autopsy also exhibit cerebrovascular disease. The relationship between AD and vascular pathology is unclear, especially whether they represent additive and independent effects on neuronal injury. We used data from the Alzheimers Disease Neuroimaging Initiative (ADNI) to (1) confirm whether entorhinal cortex and hippocampal volume are associated with memory among individuals with amnestic mild cognitive impairment (MCI) who are at risk for AD; and (2) determine whether regional white matter hyperintensity (WMH) volume, a radiological marker of small‐vessel cerebrovascular disease, is associated with entorhinal cortex and hippocampal volume independent of putative AD biomarkers in this group.

Independent and epistatic effects of variants in VPS10-d receptors on Alzheimer disease risk and processing of the amyloid precursor protein (APP)

Genetic variants in the sortilin-related receptor (SORL1) and the sortilin-related vacuolar protein sorting 10 (VPS10) domain-containing receptor 1 (SORCS1) are associated with increased risk of Alzheimer’s disease (AD), declining cognitive function and altered amyloid precursor protein (APP) processing. We explored whether other members of the (VPS10) domain-containing receptor protein family (the sortilin-related VPS10 domain-containing receptors 2 and 3 (SORCS2 and SORCS3) and sortilin (SORT1)) would have similar effects either independently or together. We conducted the analyses in a large Caucasian case control data set (n=11 840 cases, 10 931 controls) to determine the associations between single nucleotide polymorphisms (SNPs) in all the five homologous genes and AD risk. Evidence for interactions between SNPs in the five VPS10 domain receptor family genes was determined in epistatic statistical models. We also compared expression levels of SORCS2, SORCS3 and SORT1 in AD and control brains using microarray gene expression analyses and assessed the effects of these genes on γ-secretase processing of APP. Several SNPs in SORL1, SORCS1, SORCS2 and SORCS3 were associated with AD. In addition, four specific linkage disequilibrium blocks in SORCS1, SORCS2 and SORCS3 showed additive epistatic effects on the risk of AD (P⩽0.0006). SORCS3, but not SORCS2 or SORT1, showed reduced expression in AD compared with control brains, but knockdown of all the three genes using short hairpin RNAs in HEK293 cells caused a significant threefold increase in APP processing (from P<0.001 to P<0.05). These findings indicate that in addition to SORL1 and SORCS1, variants in other members of the VPS10 domain receptor family (that is, SORCS1, SORCS2, SORCS3) are associated with AD risk and alter APP processing. More importantly, the results indicate that variants within these genes have epistatic effects on AD risk.

Predicting Aggressive Decline in Mild Cognitive Impairment: The Importance of White Matter Hyperintensities

IMPORTANCE Although white matter hyperintensities (WMHs) are associated with the risk for Alzheimer disease, it is unknown whether they represent an independent source of impairment or interact with known markers of disease. OBJECTIVE To examine the degree to which WMHs predict aggressive cognitive decline among individuals with mild cognitive impairment, either independently or by modifying the effects of entorhinal cortex volume (ECV), a marker of Alzheimer disease-related neurodegeneration. DESIGN, SETTING, AND PARTICIPANTS The Alzheimers Disease Neuroimaging Initiative is a longitudinal study with 6-month follow-up visits. Three hundred thirty-two participants (mean [SD] age, 74.6 [7.4] years; 118 women) of a total of 374 participants diagnosed as having mild cognitive impairment were included. Participants were excluded if they did not have longitudinal data, apolipoprotein E genotype data, or had evidence of supratentorial infarct. MAIN OUTCOMES AND MEASURES A decline in Mini-Mental State Examination score of 3 points over 6 months or 6 points over 1 year between consecutive visits was defined as aggressive decline. White matter hyperintensity volume and ECV were entered as predictors in Cox proportional hazards models and Wilcoxon-Breslow tests to examine their impact on this outcome, adjusting for sex, age, education, and apolipoprotein E status. RESULTS Greater WMH volume at baseline, apolipoprotein E ε4 status, and smaller ECV at baseline were associated with an increased risk for aggressive decline (hazard ratio [HR], 1.23; 95% CI, 1.05-1.43; P = .01 for WMH volume; HR, 1.49; 95% CI, 1.09-2.05; P = .04 for apolipoprotein E ε4 status; HR, 0.66; 95% CI, 0.55-0.79; P < .001 for ECV). White matter hyperintensity volume modified the effect of ECV on aggressive decline risk: individuals with high ECV and low WMH were at particularly low likelihood of decline (χ2 = 15, P = .001). Participants with Mini-Mental State Examination scores that declined by 3 or more points over 6 months or 6 or more points over 12 months were more likely to have converted to Alzheimer disease by the end of the follow-up period (χ2 = 82, P < .001). CONCLUSIONS AND RELEVANCE White matter hyperintensity burden and ECV predict rapid cognitive decline among individuals with mild cognitive impairment both additively and multiplicatively.

The effect of white matter hyperintensities on neurodegeneration in mild cognitive impairment

It is unclear whether white matter hyperintensities (WMHs), magnetic resonance imaging markers of small‐vessel cerebrovascular disease, promote neurodegeneration and associated clinical decline in Alzheimers disease (AD), or simply co‐occur with recognized pathogenic processes.

Effect of citalopram in treating hypersexuality in an Alzheimer’s Disease case

Hypersexuality in Alzheimer’s disease (AD) has been rarely investigated. Hypersexual behaviours should be classified as a sexual obsession and included in the “obsessive-compulsive disorder-like” spectrum. Hypersexuality has no proven treatment, although reports have described reductions of this behaviour using antiandrogen treatment, H2-receptor antagonists and antipsychotic drugs. Serotonin reuptake blockers seem to be effective in the treatment of sexual obsessions or compulsions and less on paraphilic disturbances. We present the case of a 54-year-old male patient with Alzheimer’s disease with compulsive sexual behaviour as reported by his wife. A 18-FDG PET scan evidenced prevalent hypometabolism of the right hemisphere, congruent with neuropsychological evaluation. Donepezil, 10 mg per day, produced cognitive improvement but no effects on sexual behaviour. Therapy with SSRI was subsequently started (citalopram): after 60 days, the patient showed improvement in both the compulsive pursuit of sex acts and the level of frustration when refused.SommarioPresentiamo il caso clinico di un uomo affetto da demenza di Alzheimer presentante un disturbo della condotta sessuale di tipo ossessivo-compulsivo (ipersessualità) e studiato con strumenti clinico-neuropsicologico e 18-FDG PET. Esistono pochi studi in letteratura su tale disturbo ed in particolare sulle opzioni di trattamento. L’uso di inibitori dell’acetilcolinesterasi non ha prodotto risultati: l’introduzione in terapia di SSRI ha invece notevolmente ridotto il disturbo e portato ad un miglior controllo delle reazioni emotive associate.

The Role of Cardiovascular Risk Factors and Stroke in Familial Alzheimer Disease.

Importance The contribution of cardiovascular disease (CV) and cerebrovascular disease to the risk for late-onset Alzheimer disease (LOAD) has been long debated. Investigations have shown that antecedent CV risk factors increase the risk for LOAD, although other investigations have failed to validate this association. Objective To study the contribution of CV risk factors (type 2 diabetes, hypertension, and heart disease) and the history of stroke to LOAD in a data set of large families multiply affected by LOAD. Design, Setting, and Participants The National Institute on Aging Late-Onset Alzheimer Disease/National Cell Repository for Alzheimer Disease family study (hereinafter referred to as NIA-LOAD study) is a longitudinal study of families with multiple members affected with LOAD. A multiethnic community-based longitudinal study (Washington Heights-Inwood Columbia Aging Project [WHICAP]) was used to replicate findings. The 6553 participants in the NIA-LOAD study were recruited from 23 US Alzheimer disease centers with ongoing data collection since 2003; the 5972 WHICAP participants were recruited at Columbia University with ongoing data collection since 1992. Data analysis was performed from 2003 to 2015. Main Outcomes and Measures Generalized mixed logistic regression models tested the association of CV risk factors (primary association) with LOAD. History of stroke was used for the secondary association. A secondary model adjusted for the presence of an apolipoprotein E (APOE) ε4 allele. A genetic risk score, based on common variants associated with LOAD, was used to account for LOAD genetic risk beyond the APOE ε4 effect. Mediation analyses evaluated stroke as a mediating factor between the primary association and LOAD. Results A total of 6553 NIA-LOAD participants were included in the analyses (4044 women [61.7%]; 2509 men [38.3%]; mean [SD] age, 77.0 [9] years), with 5972 individuals from the WHICAP study included in the replication sample (4072 women [68.2%]; 1900 men [31.8%]; mean [SD] age, 76.5 [7.0] years). Hypertension was associated with decreased LOAD risk (odds ratio [OR], 0.63; 95% CI, 0.55-0.72); type 2 diabetes and heart disease were not. History of stroke conferred greater than 2-fold increased risk for LOAD (OR, 2.23; 95% CI, 1.75-2.83). Adjustment for APOE ε4 did not alter results. The genetic risk score was associated with LOAD (OR, 2.85; 95% CI, 2.05-3.97) but did not change the independent association of LOAD with hypertension or stroke. In the WHICAP sample, hypertension was not associated with LOAD (OR, 0.99; 95% CI, 0.88-1.11), whereas history of stroke increased the risk for LOAD (OR, 1.96; 95% CI, 1.56-2.46). The effect of hypertension on LOAD risk was also mediated by stroke in the NIA-LOAD and the WHICAP samples. Conclusions and Relevance In familial and sporadic LOAD, a history of stroke was significantly associated with increased disease risk and mediated the association between selected CV risk factors and LOAD, which appears to be independent of the LOAD-related genetic background.