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1.
Nutr Rev ; 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31504836

RESUMO

CONTEXT: The results of preclinical and observational studies support the beneficial effect of soy isoflavones on cognition. OBJECTIVE: This review aimed to evaluate the effects of soy isoflavones on cognition in adults. DATA SOURCES: The PUBMED, EMBASE, Ovid Medline, Cochrane Library, and clinicaltrials.gov databases were searched. STUDY SELECTION: Two researchers independently screened 1955 records, using the PICOS criteria: participants were adults; intervention was dietary sources with soy isoflavones or isolated soy isoflavones; comparator was any comparator; outcome was cognitive function; study type was randomized controlled trials (RCTs). A third researcher was consulted to resolve any discrepancies. Sixteen RCTs were included and their quality assessed. DATA EXTRACTION: Information on study design, characteristics of participants, and outcomes was extracted. PRISMA guidelines were followed. DATA ANALYSIS: A random-effects meta-analysis was used to pool estimates across studies. In the 16 RCTs (1386 participants, mean age = 60 y), soy isoflavones were found to improve overall cognitive function (standardized mean difference [SMD], 0.19; 95% confidence interval [CI], 0.07-0.32) and memory (SMD, 0.15; 95%CI, 0.03-0.26). CONCLUSION: The results showed that soy isoflavones may improve cognitive function in adults. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42018082070.

2.
Alzheimers Dement ; 15(8): 1029-1038, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31255494

RESUMO

INTRODUCTION: Both high or low plasma amyloid levels have been associated with risk of dementia in nondemented subjects. METHODS: We examined baseline plasma ß-amyloid (Aß) levels in relationship to incident dementia during a period of 8.5 years in 2840 subjects age >75 years; 2381 were cognitively normal (CN) and 450 mild cognitive impairment. RESULTS: Increased plasma Aß1-40 and Aß1-42 levels were associated with gender (women), age, low education, creatinine levels, history of stroke, and hypertension. CN participants who developed dementia had lower levels of Aß1-42 and Aß1-42/Aß1-40 ratio compared with those who did not. Aß levels did not predict dementia in mild cognitive impairment participants. DISCUSSION: There was an inverse association between Aß1-42 and Aß1-42/Aß1-40 ratio to risk of dementia in CN participants. Cerebral and cardiovascular disease and renal function are important determinants of increased Aß levels and must be considered in evaluations of relationship of plasma Aß and subsequent risk of dementia.

3.
Am J Geriatr Psychiatry ; 27(9): 908-917, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31126722

RESUMO

OBJECTIVE: To identify medications that may prevent psychosis in patients with Alzheimer disease (AD). METHODS: The authors compared the frequency of medication usage among patients with AD with or without psychosis symptoms (AD + P versus AD - P). The authors also conducted survival analysis on time to psychosis for patients with AD to identify drugs with beneficial effects. The authors further explored the potential molecular mechanisms of identified drugs by gene-signature analysis. Specifically, the gene expression profiles induced by the identified drug(s) were collected to derive a list of most perturbed genes. These genes were further analyzed by the associations of their genetic variations with AD or psychosis-related phenotypes. RESULTS: Vitamin D was used more often in AD - P patients than in AD + P patients. Vitamin D was also significantly associated with delayed time to psychosis. AD and/or psychosis-related genes were enriched in the list of genes most perturbed by vitamin D, specifically genes involved in the regulation of calcium signaling downstream of the vitamin D receptor. CONCLUSION: Vitamin D was associated with delayed onset of psychotic symptoms in patients with AD. Its mechanisms of action provide a novel direction for development of drugs to prevent or treat psychosis in AD. In addition, genetic variations in vitamin D-regulated genes may provide a biomarker signature to identify a subpopulation of patients who can benefit from vitamin D treatment.

4.
J Neurovirol ; 2019 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-31028692

RESUMO

The age of the HIV-infected population is increasing. Although many studies document gray matter volume (GMV) changes following HIV infection, GMV also declines with age. Findings have been inconsistent concerning interactions between HIV infection and age on brain structure. Effects of age, substance use, and inadequate viral suppression may confound identification of GMV serostatus effects using quantitative structural measures. In a cross-sectional study of HIV infection, including 97 seropositive and 84 seronegative, demographically matched participants, ages 30-70, we examined serostatus and age effects on GMV and neuropsychological measures. Ninety-eight percent of seropositive participants were currently treated with anti-retroviral therapies and all were virally suppressed. Gray, white, and CSF volumes were estimated using high-resolution T1-weighted MRI. Linear regression modeled effects of serostatus, age, education, comorbidities, and magnetic field strength on brain structure, using both a priori regions and voxel-based morphometry. Although seropositive participants exhibited significant bilateral decreases in striatal GMV, no serostatus effects were detected in the thalamus, hippocampus, or cerebellum. Age was associated with cortical, striatal, thalamic, hippocampal, and cerebellar GMV reductions. Effects of age and serostatus on striatal GMV were additive. Although no main effects of serostatus on neuropsychological performance were observed, serostatus moderated the relationship between pegboard performance and striatal volume. Both HIV infection and age were associated with reduced striatal volume. The lack of interaction of these two predictors suggests that HIV infection is associated with premature, but not accelerated, brain age. In serostatus groups matched on demographic and clinical variables, there were no observed differences in neuropsychological performance. Striatal GMV measures may be promising biomarker for use in studies of treated HIV infection.

5.
Int J Geriatr Psychiatry ; 34(7): 957-965, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30868641

RESUMO

OBJECTIVES: Interventions addressing burden have limited impact among long-term family caregivers. We examined whether problem-solving therapy (PST) would reduce burden levels of caregivers of individuals diagnosed with mild cognitive impairment (MCI) or early-stage dementia (AD). METHODS: Caregivers (N = 73) randomly received PST or nutritional training (NT). Burden measures were assessed over 1-year post-intervention. RESULTS: Relative to NT, caregivers receiving PST endorsed improved perceived burden levels over time, regardless of the type of caregiver. Distress over the care recipient's dementia-related behaviors remained low over time among MCI caregivers receiving PST, while these burden levels among MCI caregivers receiving NT rose over time. AD caregivers receiving PST endorsed reductions in these burden levels over time, while AD caregivers in the NT group endorsed higher burden levels over time. CONCLUSION: PST, taught early in the caregiving trajectory, improves subjective burden levels among caregivers of family members with relatively mild cognitive deficits.

6.
JAMA Netw Open ; 2(3): e191350, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30924900

RESUMO

Importance: Some of the unexplained heritability of Alzheimer disease (AD) may be due to rare variants whose effects are not captured in genome-wide association studies because very large samples are needed to observe statistically significant associations. Objective: To identify genetic variants associated with AD risk using a nonstatistical approach. Design, Setting, and Participants: Genetic association study in which rare variants were identified by whole-exome sequencing in unrelated individuals of European ancestry from the Alzheimer's Disease Sequencing Project (ADSP). Data were analyzed between March 2017 and September 2018. Main Outcomes and Measures: Minor alleles genome-wide and in 95 genes previously associated with AD, AD-related traits, or other dementias were tabulated and filtered for predicted functional impact and occurrence in participants with AD but not controls. Support for several findings was sought in a whole-exome sequencing data set comprising 19 affected relative pairs from Utah high-risk pedigrees and whole-genome sequencing data sets from the ADSP and Alzheimer's Disease Neuroimaging Initiative. Results: Among 5617 participants with AD (3202 [57.0%] women; mean [SD] age, 76.4 [9.3] years) and 4594 controls (2719 [59.0%] women; mean [SD] age, 86.5 [4.5] years), a total of 24 variants with moderate or high functional impact from 19 genes were observed in 10 or more participants with AD but not in controls. These variants included a missense mutation (rs149307620 [p.A284T], n = 10) in NOTCH3, a gene in which coding mutations are associated with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), that was also identified in 1 participant with AD and 1 participant with mild cognitive impairment in the whole genome sequencing data sets. Four participants with AD carried the TREM2 rs104894002 (p.Q33X) high-impact mutation that, in homozygous form, causes Nasu-Hakola disease, a rare disorder characterized by early-onset dementia and multifocal bone cysts, suggesting an intermediate inheritance model for the mutation. Compared with controls, participants with AD had a significantly higher burden of deleterious rare coding variants in dementia-associated genes (2314 vs 3354 cumulative variants, respectively; P = .006). Conclusions and Relevance: Different mutations in the same gene or variable dose of a mutation may be associated with result in distinct dementias. These findings suggest that minor differences in the structure or amount of protein may be associated with in different clinical outcomes. Understanding these genotype-phenotype associations may provide further insight into the pathogenic nature of the mutations, as well as offer clues for developing new therapeutic targets.

7.
Stat Med ; 38(12): 2184-2205, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-30701586

RESUMO

We study regularized estimation in high-dimensional longitudinal classification problems, using the lasso and fused lasso regularizers. The constructed coefficient estimates are piecewise constant across the time dimension in the longitudinal problem, with adaptively selected change points (break points). We present an efficient algorithm for computing such estimates, based on proximal gradient descent. We apply our proposed technique to a longitudinal data set on Alzheimer's disease from the Cardiovascular Health Study Cognition Study. Using data analysis and a simulation study, we motivate and demonstrate several practical considerations such as the selection of tuning parameters and the assessment of model stability. While race, gender, vascular and heart disease, lack of caregivers, and deterioration of learning and memory are all important predictors of dementia, we also find that these risk factors become more relevant in the later stages of life.

8.
Neurology ; 2019 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-30651383

RESUMO

OBJECTIVE: To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. METHODS: We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI. RESULTS: The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 × 10-8; and LINC00539/ZDHHC20, p = 5.82 × 10-9. Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p [BI] = 9.38 × 10-25; p [SSBI] = 5.23 × 10-14 for hypertension), smoking (p [BI] = 4.4 × 10-10; p [SSBI] = 1.2 × 10-4), diabetes (p [BI] = 1.7 × 10-8; p [SSBI] = 2.8 × 10-3), previous cardiovascular disease (p [BI] = 1.0 × 10-18; p [SSBI] = 2.3 × 10-7), stroke (p [BI] = 3.9 × 10-69; p [SSBI] = 3.2 × 10-24), and MRI-defined white matter hyperintensity burden (p [BI] = 1.43 × 10-157; p [SSBI] = 3.16 × 10-106), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p ≤ 0.0022), without indication of directional pleiotropy. CONCLUSION: In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI.

10.
Lab Invest ; 99(7): 1068-1077, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30573872

RESUMO

Huntington's disease (HD) is an autosomal dominant disorder caused by a trinucleotide expansion in the huntingtin gene. Recently, a new role for tau has been implicated in the pathogenesis of HD, whereas others have argued that postmortem tau pathology findings are attributable to concurrent Alzheimer's disease pathology. The frequency of other well-defined common age-related tau pathologies in HD has not been examined in detail. In this single center, retrospective analysis, we screened seven cases of Huntington's disease (5 females, 2 males, age at death: 47-73 years) for neuronal and glial tau pathology using phospho-tau immunohistochemistry. All seven cases showed presence of neuronal tau pathology. Five cases met diagnostic criteria for primary age-related tauopathy (PART), with three cases classified as definite PART and two cases as possible PART, all with a Braak stage of I. One case was diagnosed with low level of Alzheimer's disease neuropathologic change. In the youngest case, rare perivascular aggregates of tau-positive neurons, astrocytes and processes were identified at sulcal depths, meeting current neuropathological criteria for stage 1 chronic traumatic encephalopathy (CTE). Although the patient had no history of playing contact sports, he experienced several falls, but no definitive concussions during his disease course. Three of the PART cases and the CTE-like case showed additional evidence of aging-related tau astrogliopathy. None of the cases showed significant tau pathology in the striatum. In conclusion, while we found evidence for tau hyperphosphorylation and aggregation in all seven of our HD cases, the tau pathology was readily classifiable into known diagnostic entities and most likely represents non-specific age- or perhaps trauma-related changes. As the tau pathology was very mild in all cases and not unexpected for a population of this age range, it does not appear that the underlying HD may have promoted or accelerated tau accumulation.

11.
Mol Psychiatry ; 2018 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-30514930

RESUMO

Categorizing people with late-onset Alzheimer's disease into biologically coherent subgroups is important for personalized medicine. We evaluated data from five studies (total n = 4050, of whom 2431 had genome-wide single-nucleotide polymorphism (SNP) data). We assigned people to cognitively defined subgroups on the basis of relative performance in memory, executive functioning, visuospatial functioning, and language at the time of Alzheimer's disease diagnosis. We compared genotype frequencies for each subgroup to those from cognitively normal elderly controls. We focused on APOE and on SNPs with p < 10-5 and odds ratios more extreme than those previously reported for Alzheimer's disease (<0.77 or >1.30). There was substantial variation across studies in the proportions of people in each subgroup. In each study, higher proportions of people with isolated substantial relative memory impairment had ≥1 APOE ε4 allele than any other subgroup (overall p = 1.5 × 10-27). Across subgroups, there were 33 novel suggestive loci across the genome with p < 10-5 and an extreme OR compared to controls, of which none had statistical evidence of heterogeneity and 30 had ORs in the same direction across all datasets. These data support the biological coherence of cognitively defined subgroups and nominate novel genetic loci.

12.
Alzheimers Dement (N Y) ; 4: 542-555, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30386819

RESUMO

Introduction: We investigated the effect of antihypertensive (aHTN) medications and cholinesterase inhibitors (ChEIs) on the cognitive decline in patients with Alzheimer's disease (AD) and analyzed synergism by chemogenomics systems pharmacology mapping. Methods: We compared the effect of aHTN drugs on Mini-Mental State Examination scores in 617 AD patients with hypertension, and studied the synergistic effects. Results: The combination of diuretics, calcium channel blockers, and renin-angiotensin-aldosterone system blockers showed slower cognitive decline compared with other aHTN groups (Δß = +1.46, P < .0001). aHTN medications slow down cognitive decline in ChEI users (Δß = +0.56, P = .006), but not in non-ChEI users (Δß = -0.31, P = .53). Discussion: aHTN and ChEI drugs showed synergistic effects. A combination of diuretics, renin-angiotensin-aldosterone system blockers, and calcium channel blockers had the slowest cognitive decline. The chemogenomics systems pharmacology-identified molecular targets provide system pharmacology interpretation of the synergism of the drugs in clinics. The results suggest that improving vascular health is essential for AD treatment and provide a novel direction for AD drug development.

13.
Mol Psychiatry ; 2018 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-30361487

RESUMO

Deposition of amyloid plaques in the brain is one of the two main pathological hallmarks of Alzheimer's disease (AD). Amyloid positron emission tomography (PET) is a neuroimaging tool that selectively detects in vivo amyloid deposition in the brain and is a reliable endophenotype for AD that complements cerebrospinal fluid biomarkers with regional information. We measured in vivo amyloid deposition in the brains of ~1000 subjects from three collaborative AD centers and ADNI using 11C-labeled Pittsburgh Compound-B (PiB)-PET imaging followed by meta-analysis of genome-wide association studies, first to our knowledge for PiB-PET, to identify novel genetic loci for this endophenotype. The APOE region showed the most significant association where several SNPs surpassed the genome-wide significant threshold, with APOE*4 being most significant (P-meta = 9.09E-30; ß = 0.18). Interestingly, after conditioning on APOE*4, 14 SNPs remained significant at P < 0.05 in the APOE region that were not in linkage disequilibrium with APOE*4. Outside the APOE region, the meta-analysis revealed 15 non-APOE loci with P < 1E-05 on nine chromosomes, with two most significant SNPs on chromosomes 8 (P-meta = 4.87E-07) and 3 (P-meta = 9.69E-07). Functional analyses of these SNPs indicate their potential relevance with AD pathogenesis. Top 15 non-APOE SNPs along with APOE*4 explained 25-35% of the amyloid variance in different datasets, of which 14-17% was explained by APOE*4 alone. In conclusion, we have identified novel signals in APOE and non-APOE regions that affect amyloid deposition in the brain. Our data also highlights the presence of yet to be discovered variants that may be responsible for the unexplained genetic variance of amyloid deposition.

14.
J Alzheimers Dis ; 66(1): 297-306, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30282361

RESUMO

Cardiovascular disease risk factors, including age, hypertension, and diabetes, contribute to aortic stiffness and subclinical cardiovascular and brain disease, increasing dementia risk. Aortic stiffness, measured by carotid-femoral pulse wave velocity (cfPWV), reduces the buffering of pulsatile blood flow, exposing cerebral small arteries to microvascular damage. High cfPWV is related to white matter hyperintensities and brain amyloid deposition, and to cognitive decline, but it is unclear whether cfPWV independently predicts incident dementia. Therefore, we tested the hypothesis that cfPWV predicts incident dementia in older adults, independent of potential confounders. The Cardiovascular Health Study Cognition Study followed 532 non-demented older adults with annual cognitive exams from 1998-99 through 2013. CfPWV was measured on 356 (mean age = 78, 59% women) between 1996-2000. Over 15 years, 212 (59.6%) developed dementia (median time from cfPWV measurement = 4 years). In age and sex-adjusted Cox models, cfPWV was significantly associated with increased risk of dementia, but systolic blood pressure, mean arterial pressure and pulse pressure were not. CfPWV (transformed as - 1/cfPWV) remained significantly associated with dementia risk when further adjusted for education, race, APOEɛ4, diabetes, body mass index, mean arterial pressure, and anti-hypertensive medication (hazard ratio = 1.60, 95% CI = 1.02, 2.51). Results were similar when further adjusted for baseline global cognition, subclinical brain measures, and coronary artery calcification. Finally, higher cfPWV was related to lower physical activity intensity and higher systolic blood pressure, heart rate, and waist circumference measured 5 years prior. An important unanswered question is whether interventions to slow arterial stiffening can reduce the risk of dementia.

15.
Alzheimers Dement (Amst) ; 10: 545-553, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30370330

RESUMO

Introduction: Apolipoproteins of demonstrated importance to brain cholesterol and ß-amyloid metabolism may serve as novel risk markers for Alzheimer's pathology. Methods: We measured apolipoproteins (apoE, apoJ, apoA-I, and apoC-III and their uniquely defined subspecies) by enzyme-linked immunosorbent assay in plasma collected in 2000 and 2008 from 176 dementia-free participants of the Ginkgo Evaluation of Memory Study and related these to ß-amyloid on positron emission tomography scans, hippocampal volume, and white matter lesion volume in 2009. Results: Higher apoE was associated with lower ß-amyloid deposition. Despite apoA-I being unrelated to hippocampal volume, subspecies of apoA-I containing or lacking apoJ or apoC-III showed opposite associations with hippocampal volume. Higher apoJ and apoE lacking apoJ were associated with higher hippocampal volume and higher white matter lesion volume, respectively. Associations were similar in participants without cognitive impairment or APOE ε4 noncarrier and when analyzing apolipoproteins in 2000-2002. Discussion: Apolipoproteins may be important minimally invasive biomarkers indicative of Alzheimer's pathology.

17.
Nat Commun ; 9(1): 3945, 2018 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-30258056

RESUMO

The volume of the lateral ventricles (LV) increases with age and their abnormal enlargement is a key feature of several neurological and psychiatric diseases. Although lateral ventricular volume is heritable, a comprehensive investigation of its genetic determinants is lacking. In this meta-analysis of genome-wide association studies of 23,533 healthy middle-aged to elderly individuals from 26 population-based cohorts, we identify 7 genetic loci associated with LV volume. These loci map to chromosomes 3q28, 7p22.3, 10p12.31, 11q23.1, 12q23.3, 16q24.2, and 22q13.1 and implicate pathways related to tau pathology, S1P signaling, and cytoskeleton organization. We also report a significant genetic overlap between the thalamus and LV volumes (ρgenetic = -0.59, p-value = 3.14 × 10-6), suggesting that these brain structures may share a common biology. These genetic associations of LV volume provide insights into brain morphology.

18.
Neurobiol Aging ; 71: 142-148, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30138767

RESUMO

Amyloid-ß (Aß) accumulation is a hallmark of Alzheimer's disease, although Aß alone may be insufficient to cause impairments. Modifiable health factors, including sleep, may mitigate functional symptoms of neurodegeneration. We assessed whether sleep moderated the relationship between Aß and cognitive performance in 41 older adults, mean age 83 years. Sleep measures included actigraphy-assessed wake after sleep onset and total sleep time. Cognitive performance was assessed with memory recall, cognitive flexibility, and verbal fluency. Memory recall was assessed with the Rey-Osterrieth Complex Figure task, cognitive flexibility with the Trail Making test, and verbal fluency with FAS word generation. Aß was assessed with a global measure of Pittsburgh Compound B. Wake after sleep onset moderated the relationship between Aß and memory, with a stronger positive association for Aß and forgetting in those with poorer sleep. These results suggest a possible protective role of sleep in preclinical Alzheimer's disease.

19.
Alzheimers Dement (Amst) ; 10: 413-420, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30094328

RESUMO

Introduction: Given mounting calls to disclose biomarker test results to research participants, we explored factors underlying decisions by patients with mild cognitive impairment to receive amyloid imaging results. Methods: Prospective, qualitative interviews were conducted with 59 participants (30 = mild cognitive impairment patients, 29 = care partners) from the scan arm of a randomized controlled trial on the effects of amyloid PET results disclosure in an Alzheimer Disease Research Center setting. Results: Sixty-three percent of the participants were female, with an average age of 72.9 years, and most had greater than a high school level of education (80%). Primary motivations included: (1) better understanding one's mild cognitive impairment etiology and prognosis to plan ahead, and (2) learning one's brain amyloid status for knowledge's sake, regardless of whether the information is actionable. Most participants demonstrated an adequate understanding of the scan's limitations, yet instances of characterizing amyloid PET as a definitive test for Alzheimer's disease occurred. Mention of potential drawbacks, such as negative psychological outcomes, was minimal, even among care partners. Discussion: Findings demonstrate a risk of disproportionate focus on possible benefits of testing among amyloid scan candidates and suggest a need to clearly emphasize the limitations of amyloid PET when counseling cognitively impaired patients and their families before testing. Future research should examine whether minimizing drawbacks at the pre-imaging stage has adverse consequences on results disclosure.

20.
Am J Psychiatry ; 175(10): 999-1009, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30021459

RESUMO

OBJECTIVE:: The presence of psychosis in Alzheimer's disease denotes a phenotype with more rapid cognitive deterioration than in Alzheimer's disease without psychosis. Discovery of novel pharmacotherapies that engage therapeutic targets for prevention or treatment of Alzheimer's disease with psychosis would benefit from identifying the neurobiology of resilience to psychosis in Alzheimer's disease. The primary objective of this study was to determine whether alterations in the synaptic proteome were associated with resilience to psychotic symptoms in Alzheimer's disease and, if present, were independent of neuropathologic burden. METHOD:: Quantitative immunohistochemistry was used to measure multiple neuropathologies in dorsolateral prefrontal cortex from subjects with early and middle-stage Alzheimer's disease who differed in psychosis status. Synaptic proteins were quantified by liquid chromatography-mass spectrometry in gray matter homogenates from these subjects and from neuropathologically unaffected subjects. The synaptic proteome was similarly evaluated in cortical gray matter homogenate and in postsynaptic density fractions from an APPswe/PSEN1dE9 mouse model of amyloidosis with germline reduction in Kalrn, which has been shown to confer resilience to progression of psychosis-associated behaviors relative to APPswe/PSEN1dE9 alone. RESULTS:: Subjects resilient to psychotic symptoms in Alzheimer's disease had higher levels of synaptic proteins compared with those with psychosis and unaffected control subjects. Neuropathologic burden predicted less than 20% of the variance in psychosis status and did not account for the synaptic protein level differences between groups. Reduction of Kalrn in APPswe/PSEN1dE9 mice resulted in higher levels of synaptic proteins in cortical homogenate and normalized protein levels in the postsynaptic density. CONCLUSIONS:: Accumulation of synaptic proteins, particularly those that are enriched in the postsynaptic density, is associated with resilience to psychosis in Alzheimer's disease. One candidate mechanism for this synaptic proteome compensation is alteration in levels of proteins that facilitate the transport of synaptic proteins to and from the postsynaptic density.

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