Cancer and Vascular Comorbidity Effects on Dementia Risk and Neuropathology in the Oldest-Old.

BACKGROUND: Dementia, vascular disease, and cancer increase with age, enabling complex comorbid interactions. Understanding vascular and cancer contributions to dementia risk and neuropathology in oldest-old may improve risk modification and outcomes. OBJECTIVE: Investigate the contributions of vascular factors and cancer to dementia and neuropathology. METHODS: Longitudinal clinicopathologic study of prospectively followed Mayo Clinic participants dying≥95 years-old who underwent autopsy. Participants were stratified by dementia status and compared according to demographics, vascular risk factors, cancer, and neuropathology. RESULTS: Participants (n = 161; 83% female; 99% non-Hispanic whites)≥95 years (95-106 years-old) with/without dementia did not differ based on demographics. APOE ɛ2 frequency was higher in no dementia (20/72 [28%]) versus dementia (11/88 [12%]; p = 0.03), but APOE ɛ4 frequency did not differ. Coronary artery disease was more frequent in no dementia (31/72 [43%]) versus dementia (23/89 [26%]; p = 0.03) associated with 56% lower dementia odds (odds ratio [OR] = 0.44 [confidence interval (CI) = 0.19-0.98]; p = 0.04) and fewer neuritic/diffuse plaques. Diabetes had an 8-fold increase in dementia odds (OR = 8.42 [CI = 1.39-163]; p = 0.02). Diabetes associated with higher cerebrovascular disease (Dickson score; p = 0.05). Cancer associated with 63% lower dementia odds (OR = 0.37 [CI = 0.17-0.78]; p < 0.01) and lower Braak stage (p = 0.01). CONCLUSION: Cancer exposure in the oldest-old was associated with lower odds of dementia and tangle pathology, whereas history of coronary artery disease was associated with lower odds of dementia and amyloid-ß plaque pathology. History of diabetes mellitus was associated with increased odds of dementia and cerebrovascular disease pathology. Cancer-related mechanisms and vascular risk factor reduction strategies may alter dementia risk and neuropathology in oldest-old.

Plasma Biomarkers of Alzheimer's Disease in African Americans.

BACKGROUND/OBJECTIVE: The aim of this study was to determine if plasma concentrations of 5 surrogate markers of Alzheimer's disease (AD) pathology and neuroinflammation are associated with disease status in African Americans. METHODS: We evaluated 321 African Americans (159 AD, 162 controls) from the Florida Consortium for African-American Alzheimer's Disease Studies (FCA3DS). Five plasma proteins reflecting AD neuropathology or inflammation (Aß42, tau, IL6, IL10, TNFα) were tested for associations with AD, age, sex, APOE and MAPT genotypes, and for pairwise correlations. RESULTS: Plasma tau levels were higher in AD when adjusted for biological and technical covariates. APOEɛ4 was associated with lower plasma Aß42 and tau levels. Older age was associated with higher plasma Aß42, tau, and TNFα. Females had lower IL10 levels. Inflammatory proteins had strong pairwise correlations amongst themselves and with Aß42. CONCLUSION: We identified effects of demographic and genetic variants on five potential plasma biomarkers in African Americans. Plasma inflammatory biomarkers and Aß42 may reflect correlated pathologies and elevated plasma tau may be a biomarker of AD in this population.

The impact of stereotactic laser ablation at a typical epilepsy center.

PURPOSE: Stereotactic laser ablation (SLA) is a novel form of epilepsy surgery for patients with drug-resistant focal epilepsy. We evaluated one hundred consecutive surgeries performed for patients with epilepsy to address the impact of SLA on our therapeutic approach, as well as patient outcomes. METHODS: A retrospective, single center analysis of the last one hundred neurosurgeries for epilepsy was performed from 2013 to 2015. Demographics, surgical procedures, and postoperative measures were assessed up to 5years to compare the effect of SLA on outcome. Confidence intervals (CI) and comparative tests of proportions compared outcomes for SLA and resective surgery. Procedural categorical comparison used Chi-square and Kaplan-Meier curves. Student t-test was utilized for single variables such as age at procedure and seizure onset. RESULTS: One hundred surgeries for epilepsy yielded thirty-three SLAs and twenty-one resections with a mean of 21.7-month and 21.3-month follow-up, respectively. The temporal lobe was the most common target for SLA (92.6%) and resection (75%). A discrete lesion was present on brain magnetic resonance imaging (MRI) in 27/32 (84.4%) of SLA patients compared with 7/20 (35%) of resection patients with a normal MRI. Overall, 55-60% of patients became seizure-free (SF). Four of five patients with initial failure to SLA became SF with subsequent resection surgery. Complications were more frequent with resection although SF outcomes did not differ (Chi square; p=0.79). Stereotactic laser ablation patients were older than those with resections (47.0years vs. 35.4years, p=0.001). The mean length of hospitalization prior to discharge was shorter for SLA (1.18days) compared with open resection (3.43days; SD: 3.16 days) (p=0.0002). CONCLUSION: We now use SLA as a first line therapy at our center in patients with lesional temporal lobe epilepsy (TLE) before resection. Seizure-free outcome with SLA and resection was similar but with a shorter length of stay. Long-term follow-up is recommended to determine sustained SF status from SLA.

Neuropsychological outcomes following stereotactic laser amygdalohippocampectomy.

OBJECTIVE: The objective was to analyze neuropsychological testing data from 15 patients before and after stereotactic laser ablation surgery for temporal lobe epilepsy and to describe the seizure outcomes after stereotactic laser ablation surgery. METHODS: A retrospective review of 15 patients who underwent stereotactic laser ablation and who also underwent neuropsychological testing before and after surgery was performed. Verbal and visual memory was assessed in all 15 patients using California Verbal Learning Test and Wechsler Memory Scale IV. Naming was assessed in 9 of 15 patients using the Boston Naming Test. Statistical analysis was performed to determine clinically significant changes using previously validated reliable change indices and proprietary Advanced Clinical Solutions software. Seizure outcome data were evaluated using Engel classification. RESULTS: Postsurgery neuropsychological evaluation demonstrated that all 15 patients experienced at least 1 clinically significant decline in either verbal or visual memory. Ten patients in this series, including five with dominant-hemisphere surgery, demonstrated decline in delayed memory for narrative information (Logical Memory II). By contrast, the Boston Naming Test demonstrated more favorable results after surgery. Two of nine patients demonstrated a clinically significant increase in naming ability, and only one of nine patients demonstrated a clinically significant decline in naming ability. With at least 6months of follow-up after surgery, 33% reported seizure freedom. CONCLUSION: Stereotactic laser ablation can result in clinically significant and meaningful decline in verbal and visual memory when comparing patients to their own presurgical baseline. Naming ability, conversely, is much less likely to be impacted by stereotactic laser ablation and may improve after the procedure.

Neurocognitive outcome following stereotactic laser ablation in two patients with MRI-/PET+ mTLE.

The most effective treatment for drug-resistant seizures associated with mesial temporal lobe epilepsy (mTLE) is surgical resection. Neurocognitive sequelae may occur and are especially likely to occur after left temporal lobectomy. Smaller resections observed with selective amygdalohippocampectomy have resulted in a more favorable neurocognitive outcome in some cases when compared to standard anterior temporal lobectomy. Specifically, MRI-guided interstitial laser thermal ablation (MRgLITT) uses a superselective stereotactic amygdalohippocampotomy that has been reported to preserve object recognition and naming abilities compared with standard temporal lobe resection. We report two patients with drug-resistant mTLE and a normal high-resolution 3-T brain MRI who underwent neuropsychological assessment pre- and postleft temporal MRgLITT. Both patients demonstrated preserved visual naming ability following surgery. Semantic verbal fluency declined after surgery, but the magnitude of decline did not reach the statistical threshold for reliable change. Both patients demonstrated statistically significant and clinically meaningful declines in memory, but abilities across other nonmemory neurocognitive domains (i.e., visuospatial ability, attention) were preserved.

Dietary fish oil supplementation inhibits formation of endometriosis-associated adhesions in a chimeric mouse model.

OBJECTIVE: To examine whether dietary fish oil supplementation reduces development of spontaneous endometriosis-associated adhesions using an established model. DESIGN: Laboratory-based study. SETTING: Medical center research laboratory. PATIENT(S)/ANIMAL(S): Disease-free women of reproductive age and nude mice. INTERVENTION(S): Women were not provided any intervention. Mice were randomized to receive fish oil supplementation or control diet. MAIN OUTCOME MEASURE(S): Experimental endometriosis was established in mice via injection of human endometrial tissue within 16 hours of ovariectomy. Mice were provided standard or menhaden fish oil-supplemented diets for ≥ 2 weeks before initiation of experimental endometriosis and until killing them 1 week later. At necropsy, mice were examined for the presence and extent of adhesions and endometriotic-like lesions. Tissues were excised and morphologically characterized. RESULT(S): Adhesions/lesions were reduced in mice provided with dietary fish oil compared with control animals. Leukocytes were more numerous within the adhesions/lesions of the mice maintained on the standard diet compared with animals provided with fish oil. As indicated by staining intensity, collagen deposition was greater at adhesion sites within control mice compared with fish oil-supplemented animals. CONCLUSION(S): Wound-healing associated with surgery created an inflammatory peritoneal microenvironment that promoted the development of both experimental endometriosis and adhesions in a murine model. Targeting excessive inflammation with fish oil may be an effective adjuvant therapy to reduce the development of postsurgical adhesions related to endometriosis.

Immune interactions in endometriosis.

Endometriosis is a common, complex gynecologic disorder characterized by the presence of endometrial glands and stroma at extrauterine (ectopic) sites. In women who develop this disease, alterations in specific biological processes involving both the endocrine and immune systems have been observed, which may explain the survival and growth of displaced endometrial tissue in affected women. In the past decade, a considerable amount of research has implicated a role for alterations in progesterone action at both eutopic and ectopic sites of endometrial growth which may contribute to the excessive inflammation associated with progression of endometriosis; however, it remains unclear whether these anomalies induce the condition or are simply a consequence of the disease process. In this article, we summarize current knowledge of alterations within the immune system of endometriosis patients and discuss how endometrial cells from women with this disease not only have the capacity to escape immunosurveillance, but also use inflammatory mechanisms to promote their growth within the peritoneal cavity. Finally, we discuss evidence that exposure to an environmental endocrine disruptor, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin, can mediate the development of an endometrial phenotype that exhibits both reduced progesterone responsiveness and hypersensitivity to proinflammatory stimuli mimicking the endometriosis phenotype. Future studies in women with endometriosis should consider whether a heightened inflammatory response within the peritoneal microenvironment contributes to the development and persistence of this disease.

Validation of the Mayo Sleep Questionnaire to screen for REM sleep behavior disorder in an aging and dementia cohort.

OBJECTIVE: To validate a questionnaire focused on rapid eye movement sleep (REM) sleep behavior disorder (RBD) among participants in an aging and dementia cohort. BACKGROUND: RBD is a parasomnia that can develop in otherwise neurologically-normal adults as well as in those with a neurodegenerative disease. Confirmation of RBD requires polysomnography (PSG). A simple screening measure for RBD is desirable for clinical and research purposes. METHODS: We had previously developed the Mayo Sleep Questionnaire (MSQ), a 16 item measure, to screen for the presence of RBD and other sleep disorders. We assessed the validity of the MSQ by comparing the responses of patients' bed partners with the findings on PSG. All subjects recruited in the Mayo Alzheimer's Disease Research Center at Mayo Clinic Rochester and Mayo Clinic Jacksonville from 1/00 to 7/08 who had also undergone a PSG were the focus of this analysis. RESULTS: The study sample was comprised of 176 subjects (150 male; median age 71 years (range 39-90)), with the following clinical diagnoses: normal (n = 8), mild cognitive impairment (n = 44), Alzheimer's disease (n = 23), dementia with Lewy bodies (n = 74), as well as other dementia and/or parkinsonian syndromes (n = 27). The core question on recurrent dream enactment behavior yielded a sensitivity (SN) of 98% and specificity (SP) of 74% for the diagnosis of RBD. The profile of responses on four additional subquestions on RBD and one on obstructive sleep apnea improved specificity. CONCLUSIONS: These data suggest that among aged subjects with cognitive impairment and/or parkinsonism, the MSQ has adequate SN and SP for the diagnosis of RBD. The utility of this scale in other patient populations will require further study.

ST6Gal-I expression in ovarian cancer cells promotes an invasive phenotype by altering integrin glycosylation and function.

BACKGROUND: Ovarian adenocarcinoma is not generally discovered in patients until there has been widespread intraperitoneal dissemination, which is why ovarian cancer is the deadliest gynecologic malignancy. Though incompletely understood, the mechanism of peritoneal metastasis relies on primary tumor cells being able to detach themselves from the tumor, escape normal apoptotic pathways while free floating, and adhere to, and eventually invade through, the peritoneal surface. Our laboratory has previously shown that the Golgi glycosyltransferase, ST6Gal-I, mediates the hypersialylation of beta1 integrins in colon adenocarcinoma, which leads to a more metastatic tumor cell phenotype. Interestingly, ST6Gal-I mRNA is known to be upregulated in metastatic ovarian cancer, therefore the goal of the present study was to determine whether ST6Gal-I confers a similarly aggressive phenotype to ovarian tumor cells. METHODS: Three ovarian carcinoma cell lines were screened for ST6Gal-I expression, and two of these, PA-1 and SKOV3, were found to produce ST6Gal-I protein. The third cell line, OV4, lacked endogenous ST6Gal-I. In order to understand the effects of ST6Gal-I on cell behavior, OV4 cells were stably-transduced with ST6Gal-I using a lentiviral vector, and integrin-mediated responses were compared in parental and ST6Gal-I-expressing cells. RESULTS: Forced expression of ST6Gal-I in OV4 cells, resulting in sialylation of beta1 integrins, induced greater cell adhesion to, and migration toward, collagen I. Similarly, ST6Gal-I expressing cells were more invasive through Matrigel. CONCLUSION: ST6Gal-I mediated sialylation of beta1 integrins in ovarian cancer cells may contribute to peritoneal metastasis by altering tumor cell adhesion and migration through extracellular matrix.

A cost effective method of identifying and recruiting persons over 80 free of dementia or mild cognitive impairment.

For observational or prevention studies, accurately identifying by mail and telephone cognitively normal elderly volunteers would be cost effective. We describe how to recruit cognitively normal sib-pairs over age 80 using commercially available lists by age and ZIP code. We mailed an Institutional Review Board-approved letter to 24,366 persons over 85 around Jacksonville, FL, and received approximately 3,000 postcard replies with approximately 500 answering 3 screening statements affirmatively. Of these, we recruited 128 persons who underwent both in-person and telephone evaluations, the latter using the Telephone Interview of Cognitive Status-modified (TICS-m) and Clinical Dementia Rating scale (CDR). Blinded to the TICS-m and CDR data, clinicians made a consensus diagnosis for each participant, 120 were normal and 8 had mild cognitive impairment. With CDR, 119 patients (93%) screened as normal, and of these 115 (97%) were confirmed as normal with the consensus diagnosis. A TICS-m score cut-off of <29 resulted in a similar proportion of normals in the screened sample (97% or 103/106); however, 13 normal volunteers would have been excluded because they scored <29 on the TICS-m. Supplementing the sample, we recruited 12 age-matched cases having consensus diagnosis of dementia (n=2) or mild cognitive impairment (n=10). A CDR>0 correctly identified 12/12, whereas the TICS-m <29 correctly identified 7/12. Hearing loss present in 50% did not influence TICS-m or CDR performance. Using stringent entry criteria and the telephone CDR, this method accurately identified normal elderly persons.