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INTRODUCTION: The risk reduction for Alzheimer's disease (rrAD) trial was a multisite clinical trial to assess exercise and intensive vascular pharmacological treatment on cognitive function in community‐dwelling older adults at increased risk for Alzheimer's disease. METHODS: Eligibility, consent, and randomization rates across different referral sources were compared. Informal interviews conducted with each site's project team were conducted upon study completion. RESULTS: Initially, 3290 individuals were screened, of whom 28% were eligible to consent, 805 consented to participate (87.2% of those eligible), and 513 (36.3% of those consented) were randomized. Emails sent from study site listservs/databases yielded the highest amount (20.9%) of screened individuals. Professional referrals from physicians yielded the greatest percentage of consented individuals (57.1%). Referrals from non‐professional contacts (ie, friends, family; 75%) and mail/phone contact from a site (73.8%) had the highest yield of randomization. DISCUSSION: Professional referrals or email from listservs/registries were most effective for enrolling participants. The greatest yield of eligible/randomized participants came from non‐professional and mail/phone contacts. Future trials should consider special efforts targeting these recruitment approaches. Highlights: Clinical trial recruitment is commonly cited as a significant barrier to advancing our understanding of cognitive health interventions.The most cited referral source was email, followed by interviews/editorials on the radio, television, local newspapers, newsletters, or magazine articles.The referral method that brought in the largest number of contacts was email but did not result in the greatest yield of consents or eligible participants.The sources that yielded the greatest likelihood of consent were professional referrals (ie, physician), social media, and mail/phone contact from study site.The greatest yield of eligible/randomized participants came from non‐professional contacts and mail/phone contact from a site.Findings suggest that sites may need to focus on more selective referral sources, such as using contact mailing and phone lists, rather than more widely viewed recruitment sources, such as social media or TV/radio advertisements. [ABSTRACT FROM AUTHOR]

Objective. Neuropsychological measures of processing speed have long been used as sensitive indices of cognitive functioning. Most of these commonly used tests are proprietary, and there is a need for brief, freely available tools that can be used in diverse clinical and research settings. The Southwestern Assessment of Processing Speed (SWAPS) is a 60-second digit-symbol transcription task developed as a brief alternative to commercially available coding tests. Demographically-corrected normative data are presented along with reliability and sensitivity/specificity values in older adults with and without cognitive impairment. Method. SWAPS data from 915 healthy aging individuals (NC) and 858 subjects with clinical diagnoses of mild cognitive impairment (MCI; n = 430) and Alzheimer's disease clinical syndrome (ADCS; n = 428) were obtained from the Texas Alzheimer's Research and Care Consortium (TARCC). TARCC participants represent ethnically and educationally diverse community-dwelling individuals age 50+. Results. SWAPS scores showed the expected associations with age, sex, and education, and the interaction between age and education were significant predictors of SWAPS scores. Test-retest reliability in NC was good, and the SWAPS distinguished impaired and non-impaired groups with adequate to excellent sensitivity and specificity for the primary analyses, with optimal cut-off points provided. Raw score- to uncorrected normalized T-scores and demographically-corrected SWAPS T-scores using regression-based norms are presented along with scoring programs for the calculation of each. Conclusions. The SWAPS is a brief, free, easily administered test with demographically-corrected regression-based norms and promising utility for detection of cognitive impairment and efficient assessment of processing speed. [ABSTRACT FROM AUTHOR]

Background: Life expectancy (LE) following Alzheimer's disease (AD) is highly variable. The literature to date is limited by smaller sample sizes and clinical diagnoses.Objective: No study to date has evaluated predictors of AD LE in a retrospective large autopsy-confirmed sample, which was the primary objective of this study.Methods: Participants (≥50 years old) clinically and neuropathologically diagnosed with AD were evaluated using National Alzheimer's Coordinating Center (N = 1,401) data. Analyses focused on 21 demographic, medical, neuropsychiatric, neurological, functional, and global cognitive predictors of LE at AD dementia diagnosis. These 21 predictors were evaluated in univariate analyses. Variables found to be significant were then entered into a forward multiple regression. LE was defined as months between AD diagnosis and death.Results: Fourteen predictors were significant in univariate analyses and entered into the regression. Seven predictors explained 27% of LE variance in 764 total participants. Mini-Mental State Examination (MMSE) score was the strongest predictor of LE, followed by sex, age, race/ethnicity, neuropsychiatric symptoms, abnormal neurological exam results, and functional impairment ratings. Post-hoc analyses revealed correlations of LE were strongest with MMSE ≤12.Conclusion: Global cognitive functioning was the strongest predictor of LE following diagnosis, and AD patients with severe impairment had the shortest LE. AD patients who are older, male, white, and have more motor symptoms, functional impairment, and neuropsychiatric symptoms were also more likely have shorter LE. While this model cannot provide individual prognoses, additional studies may focus on these variables to enhance predictions of LE in patients with AD. [ABSTRACT FROM AUTHOR]

Background: Little is known about the prevalence of polypharmacy, the taking of five or more medications a day, in older adults with specific dementia risk factors.Objective: To examine the prevalence of polypharmacy in participants at baseline in a vascular risk reduction focused Alzheimer's disease (rrAD) trial targeting older patients with hypertension and elevated dementia risk.Methods: We conducted a detailed review of medications in a cross-sectional study of community-dwelling older adults with hypertension and elevated dementia risk. Medications were identified in a structured interview process with an onsite pharmacist or qualified designee. Polypharmacy was defined as use of five or more medications on a regular basis. Descriptive analyses were conducted on the sample as well as direct comparisons of subgroups of individuals with hypertension, diabetes, and hyperlipidemia.Results: The 514 rrAD participants, mean age 68.8 (standard deviation [sd] 6), reported taking different combinations of 472 unique medications at their baseline visit. The median number of medications taken by participants was eight [Range 0-21], with 79.2% exhibiting polypharmacy (n = 407). Sites differed in their prevalence of polypharmacy, χ2(3) = 56.0, p < 0.001. A nearly identical percentage of the 2,077 prescribed (51.8%) and over the counter (48.2%) medications were present in the overall medication profile. The presence of diabetes (87.5%), hyperlipidemia (88.2%), or both (97.7%) was associated with a higher prevalence of polypharmacy than participants who exhibited hypertension in the absence of either of these conditions (63.2%), χ2(3) = 35.8, p < 0.001.Conclusion: Participants in a dementia risk study had high levels of polypharmacy, with the co-existence of diabetes or hyperlipidemia associated with a greater prevalence of polypharmacy as compared to having hypertension alone. [ABSTRACT FROM AUTHOR]

Objective: Medical history information regarding prior traumatic brain injury (TBI) usually relies on self-report, although little is known about the reliability of this information with regard to injuries sustained years or decades earlier. Even less is known about the reliability of self-reported medical history information in older individuals with cognitive impairment. To this end, we assessed the test-retest reliability of self-reported TBI history in a large, national sample. Methods: Participants (n = 4309) were older adults with intact cognition, mild cognitive impairment (MCI) and Alzheimer's disease (AD) from the National Alzheimer's Coordinating Center. Subjects provided TBI history information at baseline and one annual followup visit. Consistency of self-reported history of TBI with <5 minutes loss of consciousness (mLOC) and TBI with =5 mLOC reported at time 1 and 2 was analyzed across diagnostic groups. Results: Overall, subjects provided reports of TBI history at follow-up that were highly consistent with baseline reports (97.8-99.6% agreement), and Cohen's kappa coefficients were all larger than .80 and statistically significant, maximum p < .001. Furthermore, level of cognitive impairment was not a significant predictor of consistency in reporting. Conclusions: These data are some of the first to suggest that self-report may be a consistent method of obtaining remote TBI history in the absence of medical records for older individuals, regardless of cognitive impairment. [ABSTRACT FROM AUTHOR]

[Journal of Alzheimer's Disease, 86 (2022) 271-281, DOI 10.3233/JAD-215200] https://content.iospress.com/articles/journal-of-alzheimers-disease/jad215200 On page 275, there is an error in paragraph 2, section "Additional MMSE I post-hoc i analyses", line 9. In the original, it reads: I "Tukey's post-hoc test revealed significant differences (ps<0.001) in LE between mild (M = 35.8, SD = 26.6), moderate (M = 54.53, SD = 27.23), and severe (M = 67.14, SD = 27.49) cognitive impairment." i The correct line is: I "Tukey's post-hoc test revealed significant differences (p's<0.001) in LE between severe (M = 35.8, SD = 26.6), moderate (M = 54.53, SD = 27.23), and mild (M = 67.14,SD = 27.49) cognitive impairment.". [Extracted from the article]

Objective: The Montreal Cognitive Assessment (MoCA) is a cognitive screening instrument growing in popularity, but few studies have conducted psychometric item analyses or attempted to develop abbreviated forms. We sought to derive and validate a short-form MoCA (SF-MoCA) and compare its classification accuracy to the standard MoCA and Mini-Mental State Examination (MMSE) in mild cognitive impairment (MCI), Alzheimer disease (AD), and normal aging.Methods: 408 subjects (MCIn = 169, ADn = 87, and normaln = 152) were randomly divided into derivation and validation samples. Item analysis in the derivation sample identified most sensitive MoCA items. Receiver Operating Characteristic (ROC) analyses were used to develop cut-off scores and evaluate the classification accuracy of the SF-MoCA, standard MoCA, and MMSE. Net Reclassification Improvement (NRI) analyses and comparison of ROC curves were used to compare classification accuracy of the three measures.Results: Serial subtraction (Cramer’sV = .408), delayed recall (Cramer’sV = .702), and orientation items (Cramer’sV = .832) were included in the SF-MoCA based on largest effect sizes in item analyses. Results revealed 72.6% classification accuracy of the SF-MoCA, compared with 71.9% for the standard MoCA and 67.4% for the MMSE. Results of NRI analyses and ROC curve comparisons revealed that classification accuracy of the SF-MoCA was comparable to the standard version and generally superior to the MMSE.Conclusions: Findings suggest the SF-MoCA could be an effective brief tool in detecting cognitive impairment. [ABSTRACT FROM PUBLISHER]

Alzheimer disease (AD) characteristically begins with episodic memory impairment followed by other cognitive deficits; however, the course of illness varies, with substantial differences in therateof cognitive decline. For research and clinical purposes it would be useful to distinguish between persons who will progress slowly from persons who will progress at an average or faster rate. Our objective was to use neurocognitive performance features and disease-specific and health information to determine a predictive model for the rate of cognitive decline in participants with mild AD. We reviewed the records of a series of 96 consecutive participants with mild AD from 1995 to 2011 who had been administered selected neurocognitive tests and clinical measures. Based on Clinical Dementia Rating (CDR) of functional and cognitive decline over 2 years, participants were classified as Faster (n= 45) or Slower (n= 51) Progressors. Stepwise logistic regression analyses using neurocognitive performance features, disease-specific, health, and demographic variables were performed. Neuropsychological scores that distinguished Faster from Slower Progressors included Trail Making Test - A, Digit Symbol, and California Verbal Learning Test (CVLT) Total Learned and Primacy Recall. No disease-specific, health, or demographic variable predicted rate of progression; however, history of heart disease showed a trend. Among the neuropsychological variables, Trail Making Test - A best distinguished Faster from Slower Progressors, with an overall accuracy of 68%. In an omnibus model including neuropsychological, disease-specific, health, and demographic variables, only Trail Making Test - A distinguished between groups. Several neuropsychological performance features were associated with the rate of cognitive decline in mild AD, with baseline Trail Making Test - A performance best separating those who declined at an average or faster rate from those who showed slower progression. [ABSTRACT FROM AUTHOR]

We used functional connectivity magnetic resonance imaging (fcMRI) to investigate changes in interhemispheric brain connectivity in 11 patients with mild Alzheimer's disease (AD) following eight weeks of treatment with the cholinesterase inhibitor donepezil. We examined functional connectivity between four homologous temporal, frontal, and occipital regions. These regions were selected to represent sites of AD neuropathology, sites of donepezil-related brain activation change in prior studies, and sites that are minimally affected by the pathologic changes of AD. Based on previous findings of selective, localized frontal responses to donepezil, we predicted that frontal connectivity would be most strongly impacted by treatment. Of the areas examined, we found that treatment had a significant effect only on functional connectivity between right and left dorsolateral prefrontal cortices. Implications for understanding the impact of donepezil treatment on brain functioning and behavior in patients with AD are discussed. This preliminary report suggests that fcMRI may provide a useful index of treatment outcome in diseases affecting brain connectivity. Future research should investigate these treatment-related changes in larger samples of patients and age-matched controls. [ABSTRACT FROM AUTHOR]

Background: Leptin has been reported to have positive effects on cognition but has not been studied in a population-based sample or stratified by race or gender. Methods Leptin and fat mass were measured in 2,731 subjects, including 50% African Americans. Eight years later, subjects were administered the Montreal Cognitive Assessment (MoCA). Demographic factors and baseline measures, including a deficiency in leptin or levels in excess of what was predicted by fat, were investigated to see which predicted cognitive performance. Results:There was a statistical trend for lower leptin levels to be associated with higher cognitive scores. Once stratified by race and gender, excessive leptin was associated with lower MoCA total scores and delayed recall domain score for black men, but white men demonstrated a reverse relationship. Conclusion: Excess leptin appears to have differential effects on delayed recall in black and white men. [ABSTRACT FROM AUTHOR]

To determine if measures of adipokines and other blood lipids differentiate between normal controls and persons with Alzheimer's disease (AD), we examined levels of leptin, adiponectin, total cholesterol, high density lipoproteins (HDL), calculated low density lipoproteins (LDL), triglycerides and apolipoprotein E allele status in 148 early AD subjects and 198 normal controls. We were unable to demonstrate a significant difference between leptin and adiponectin levels between normal controls and AD subjects. We were able to confirm observations of lower HDL and higher total and LDL cholesterol concentration in AD subjects than in controls. As expected, the presence of the apolipoprotein E4 allele distinguished between the two groups. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study is to determine if the three-step Luria test is useful for differentiating between cognitive disorders.Methods: A retrospective record review of performance on the three-step Luria test was conducted on 383 participants from a university-based dementia clinic. The participants ranged in their diagnosis from frontotemporal dementia (FTD; n = 43), Alzheimer disease (AD; n = 153), mild cognitive impairment (MCI; n = 56), and normal controls (NC; n = 131). Performance of the Luria test was graded as normal or abnormal.Results: An abnormal test occurred in 2.3% of NC, 21.4% of MCI, 69.8% of FTD, and 54.9% of AD subjects. The frequency of abnormal tests in all diagnostic groups increased with functional impairment as assessed by the Clinical Dementia Rating scale (CDR). When CDR = 3 (severe), 100% of the FTD and 72.2% of the AD subjects had abnormal Luria tests.Conclusions: The three-step Luria test distinguished NC and persons with MCI from FTD and AD, but did not distinguish FTD from AD subjects. [ABSTRACT FROM AUTHOR]

Objective: To establish the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychologic battery as a valid measure of cognitive progression in Alzheimer disease (AD) by deriving annualized CERAD Total Change Scores and correspond- ing confidence intervals in AD and controls from which to define clinically meaningful change. Method: Subjects included 383 normal control (NC) and 655 AD subjects with serial data from the CERAD registry database. Annualized CERAD Total Change Scores were derived and Reliable Change Indexes (RCIs) calculated to establish statistically reliable change values. CERAD Change Scores were compared with annualized change scores from the Mini-Mental State Examination (MMSE), Clinical Dementia Rating Scale (CDR) Sum of Boxes, and Blessed Dementia Rating Scale (BDRS). Results: For the CERAD Total Score, the AD sample showed significantly greater decline than the NC sample over the 4-year interval, with AD subjects declining an average of 22.2 points compared with the NCs' improving an average 2.8 points from baseline to last visit [Group × Time interaction [F(4,1031) = 246.08, P <0.001)]. By Visit 3, the majority of AD subjects (65.2%) showed a degree of cognitive decline that fell outside the RD. CERAD Change Scores significantly correlated (P < 0.001) with MMSE (r = -0.66), CDR (r = -0.42). and BDRS (r = -0.38) change scores. Conclusion: Results support the utility of the CERAD Total Score as a measure of AD progression and provide comparative data for annualized change in CERAD Total Score and other summary measures. [ABSTRACT FROM AUTHOR]

Abstract: Background: The recent development of a national Alzheimer’s disease database makes it possible to compare the course of illness in various ethnic groups. Methods: The National Alzheimer’s Coordinating Center database was used to compare the clinical presentation and course of Alzheimer’s disease (AD) in American Indians with whites and African-Americans, and to compare findings in American Indians seen in Oklahoma with those seen elsewhere. We ascertained the diagnosis of probable and possible AD, gender, education, history of affected first-degree relative, depression, history of stroke, Parkinson symptoms, age at onset of dementia, initial visit, and death. We also ascertained years from symptom onset and initial evaluation to death, initial Mini-Mental State Exam (MMSE) score adjusted for education, and years from onset of symptoms. Results: Data from 30,993 subjects were analyzed. There were statistically significant but only small differences between groups. American Indians had the lowest proportion of affected first-degree relatives, depression, and extrapyramidal symptoms. Whites had the highest proportion of subjects with affected first-degree relatives and depression, but the lowest history of stroke. African Americans had the most frequent history of stroke and extrapyramidal symptoms. Indians seen in Oklahoma had a lower proportion of affected first-degree relatives than did those seen elsewhere. Conclusions: Although there were no clinically significant differences in course of illness between these self-identified ethnic groups, this finding with regard to American Indians must be interpreted with caution, because the subjects for whom we had information regarding ancestry reported a smaller proportion of American Indian (25%) than white (75%) heritage. [Copyright &y& Elsevier]

The clinical diagnostic criteria for frontotemporal degeneration (FTD) include relative preservation of memory and visuospatial function, in contradistinction to characteristics of Alzheimer’s disease (AD). The Mini-Mental State Examination (MMSE) contains items to assess these areas of cognition. In a retrospective case-control study of participants at two institutionally-based AD centers, we determined whether total MMSE and MMSE subscores would reflect the disease progression projected by the clinical criteria of FTD vs. AD. Participants were 44 subjects with FTD (7 pathologically confirmed) and 45 with pathologically confirmed AD. Each subject had at least two MMSEs with minimum inter-test intervals of 9 months. We compared annualized rates of change for total MMSE scores and cognitive domain subscores over time and between groups by two independent samples t-tests and proportion tests. The total MMSE score (p = 0.03) and language subscore (p = 0.02) showed a greater rate of decline for the FTD group than the AD group, although the constructional praxis item declined less rapidly in the FTD group (p = 0.018). Changes in MMSE subscores paralleled the clinical diagnostic criteria for FTD. The more rapid progression on the language subscore was observed in both language and behavioral variants of FTD. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Two hundred forty-seven patients with early Alzheimer's disease were studied for the association of demographic, functional, and cognitive status and vascular comorbidities and risk factors present at index visit to rate of clinical disease progression over 3 years and to survival time. Patients who progressed to the moderate stage were designated fast progressors; those who remained in the early stage were designated slow progressors. At index visit, Mini- Mental State Exam score was significantly lower for the fast than the slow group; global impairment was significantly higher for the fast group. Cognitive scores showed greater annual decline in the fast group, and the fast group also had a greater annualized global change. The fast group had a shorter median survival time from onset, but age at onset, age at initial visit, history of heart problems, myocardial infarct, stroke, hypertension, diabetes, or past or current smoking did not differ between groups. [ABSTRACT FROM AUTHOR]

Abstract: The amyloid precursor protein (APP) in brain is processed either by an amyloidogenic pathway by β-secretase and γ-secretase to yield Aβ (β-amyloid 4 kDa) peptide or by α-secretase within the β-amyloid domain to yield non-amyloidogenic products. We have studied blood platelet levels of a 22-kDa fragment containing the Aβ (β-amyloid 4 kDa) peptide, β-secretase (BACE1), α-secretase (ADAM10), and APP isoform ratios of the 120–130 kDa to 110 kDa peptides from 31 Alzheimer''s disease (AD) patients and 10 age-matched healthy control subjects. We found increased levels of Aβ4, increased activation of β-secretase (BACE1), decreased activation of α-secretase (ADAM10) and decreased APP ratios in AD patients compared to normal control subjects. These observations indicate that the blood platelet APP is processed by the same amyloidogenic and non-amyloidogenic pathways as utilized in brain and that APP processing in AD patients is altered compared to control subjects and may be a useful bio-marker for the diagnosis of AD, the progression of disease and for monitoring drug responses in clinical trials. [Copyright &y& Elsevier]

This randomized study evaluated the combined effect of a cognitive-communication program plus an acetylcholinesterase inhibitor (donepezil; donepezil-plusstimulation group; n = 26), as compared with donepezil alone (donepezil-only group; n = 28) in 54 patients with mild to moderate Alzheimer's disease (AD; Mini-Mental Status Examination score of 12-- 28) ranging in age from 54 to 91 years. It was hypothesized that cognitive-communication stimulation in combination with donepezil would positively affect the following: (a) relevance of discourse, (b) performance of functional abilities, (c) emotional symptoms, (d) quality of life, and (e) overall global function, as measured by caregiver and participant report and standardized measures. Cognitive-communication, neuropsychiatric, functional performance, and quality of life evaluations were conducted at baseline and Month 4, the month after the 2-month active stimulation period. Follow-up evaluations were performed at Months 8 and 12. The stimulation program consisted of 12 hr of intervention over an 8-week period and involved participantled discussions requiring homework, interactive sessions about AD, and discussions using salient life stories. Additive effects of active stimulation with donepezil were examined in 2 ways: (1) comparing mean group performance over time and (2) evaluating change scores from baseline. A Group x Time interaction was found for the donepezil-plus-stimulation group in the emotional symptoms of apathy and irritability as compared with the donepezil-only group. Evaluation of change scores from baseline to 12 months revealed a positive effect for the donepezilplus- stimulation group on discourse and functional abilities with a trend on apathy, irritability, and patient-reported quality of life. In sum, the research revealed benefits to the donepezil-plus-stimulation group in the areas of discourse abilities, functional abilities, emotional symptoms, and overall global performance. This stu... [ABSTRACT FROM AUTHOR]

Lateralization on neuroimaging was compared in cases of frontotemporal lobar degeneration (FTLD; n = 10) and cases of definite Alzheimer's disease (AD; n = 17). All of the cases were pathologically confirmed and semi-quantitative and statistical parametric mapping methods were employed. Seven of the 10 FTLD cases had lateralization on at least one neuroimaging modality: single photon emission computerized tomography (SPECT), MRI, or CT. All 6/6 FTLD cases with SPECT showed lateralization. MRI results generally agreed with SPECT findings. Three of 4 FTLD cases had lateralized atrophy on CT. For the AD cases, 10/17 SPECTs, 2/7 MRIs, and 1/9 CTs showed lateralized findings. Of the neuroimaging modalities utilized, SPECT was the most sensitive in detecting lateralization. [ABSTRACT FROM AUTHOR]

To determine if Alzheimer's disease (AD), its Lewy body (LB) variant (LBV), and diffuse LB disease (DLBD) are distinguishable at initial clinical evaluation, data from autopsy-confirmed AD, LBV, and DLBD were examined. No significant differences were found in age at onset, age at death, total duration of illness, duration of illness before initial visit, duration of illness from initial visit to death, or severity of illness at initial evaluation. Hallucinations and delusions were significantly more frequent for LBV and DLBD, respectively, than for AD, and falls were more frequent for DLBD than for AD. Extrapyramidal symptoms (EPS) were less frequent in neuroleptic-free AD subjects than in LB subjects; the percentage of AD patients with EPS after neuroleptic exposure was less than that among LB patients. Seizures were significantly more common for DLBD than for AD or LBV. LB dementias differed from AD at initial evaluation, with more frequent hallucinations and delusions, EPSs, and seizures, and longitudinally in neuroleptic sensitivity, but the data did not distinguish LBV from DLBD. [ABSTRACT FROM AUTHOR]

Background: Synapse loss has been found to be the major correlate of cognitive decline in Alzheimer disease (AD), and prefrontal synapse loss has been found in patients with frontotemporal dementia (FTD). Objective: To see if our hypothesis that within each FTD case, regional synapse loss would correlate with lateralizing neuropsychologic and neurobehavioral deficits would be correct. Design: We analyzed synaptophysin as a marker for synapse loss in snap-frozen brain samples, using an enzyme-linked immunosorbent assay technique. Quantitative results were obtained by comparing patient data with a standard curve made by analyzing serial dilutions of a recombinant synaptophysin protein fragment. A board-certified neuropsychologist and a board-certified neurologist, both unaware of the synaptophysin results, determined areas of primary neuropsychologic and neurobehavioral dysfunction. Relationships between areas of primary dysfunction and synapse loss were analyzed using the binomial test. Patients: Six cases of FTD, 28 cases of AD, and 16 nondemented control subjects. Results: Five of 6 FTD cases had regional synaptophysins correlating with lateralizing frontal or temporal deficits. Three of 6 correlated in 2 or more regions. Although our results were higher than that expected based on a pure-chance mechanism (50% vs 34%), statistical significance was not attained. Conclusions: We found a trend for an association between synapse loss and lateralizing neuropsychologic and neurobehavioral deficits in FTD. Studies in larger numbers of FTD cases are planned with the goal of attaining statistically significant conclusions. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) has been associated with accumulation of amyloid beta (Aβ) peptides in brain, and immunotherapy targeting Aβ provides potential for AD prevention. We have used a DNA Aβ42 trimer construct for immunization of 3xTg-AD mice and found previously significant reduction of amyloid and tau pathology due to the immunotherapy. We show here that DNA Aβ42 immunized 3xTg-AD mice showed better performance in nest building activities and had a higher 24 months survival rate compared to the non-treated AD controls. The analysis of differently expressed genes in brains from 24 months old mice showed significant increases transcript levels between non-immunized AD mice and wild-type controls for genes involved in microglia and astrocyte function, cytokine and inflammatory signaling, apoptosis, the innate and adaptive immune response and are consistent with an inflammatory phenotype in AD. Most of these upregulated genes were downregulated in the DNA Aβ42 immunized 3xTg-AD mice due to the vaccine. Transcript numbers for the immediate early genes, Arc, Bdnf, Homer1, Egr1 and cfos , involved in neuronal and neurotransmission pathways which were much lower in the non-immunized 3xTg-AD mice, were restored to wild-type mouse brain levels in DNA Aβ42 immunized 3xTg-AD mice indicating positive effects of DNA Aβ42 immunotherapy on synapse stability and plasticity. The immune response after immunization is complex, but the multitude of changes after DNA Aβ42 immunization shows that this response moves beyond the amyloid hypothesis and into direction of disease prevention. Image 1 • DNA Aβ42 immunization increases life span in 3xTg-AD mouse model • DNA Aβ42 immunization downregulates transcripts of inflammatory genes in brain of 3xTg-AD mouse model • DNA Aβ42 immunization restores expression of immediate early genes in brain of 3xTg-AD mouse model to wild-type levels • This is a first report showing effects of DNA Aβ42 immunotherapy on reducing the expression of genes upregulated in AD brain. [ABSTRACT FROM AUTHOR]

Abstract Alzheimer's Disease (AD) is an age-related disease with modifiable risk factors such as hypertension, hypercholesterolemia, obesity, and physical inactivity influencing the onset and progression. There is however, no direct evidence that reducing these risk factors prevents or slows AD. The Risk Reduction for Alzheimer's Disease (rrAD) trial is designed to study the independent and combined effects of intensive pharmacological control of blood pressure and cholesterol and exercise training on neurocognitive function. Six hundred and forty cognitively normal older adults age 60 to 85 years with hypertension and increased risk for dementia will be enrolled. Participants are randomized into one of four intervention group for two years: usual care, Intensive Reduction of Vascular Risk factors (IRVR) with blood pressure and cholesterol reduction, exercise training (EX), and IRVR+EX. Neurocognitive function is measured at baseline, 6, 12, 18, and 24 months; brain MRIs are obtained at baseline and 24 months. We hypothesize that both IRVR and EX will improve global cognitive function, while IRVR+EX will provide a greater benefit than either IRVR or EX alone. We also hypothesize that IRVR and EX will slow brain atrophy, improve brain structural and functional connectivity, and improve brain perfusion. Finally, we will explore the mechanisms by which study interventions impact neurocognition and brain. If rrAD interventions are shown to be safe, practical, and successful, our study will have a significant impact on reducing the risks of AD in older adults. NCT Registration: NCT02913664 [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common form of dementia found in the elderly and disease progression is associated with accumulation of Amyloid beta 1–42 (Aβ42) in brain. An immune-mediated approach as a preventive intervention to reduce amyloid plaques without causing brain inflammation is highly desirable for future clinical use. Genetic immunization, in which the immunizing agent is DNA encoding Aβ42, has great potential because the immune response to DNA delivered into the skin is generally non-inflammatory, and thus differs quantitatively and qualitatively from immune responses elicited by peptides, which are inflammatory with production of IFNγ and IL-17 cytokines by activated T cells. DNA immunization has historically been proven difficult to apply to larger mammals. A potential barrier to use DNA immunization in large mammals is the method for delivery of the DNA antigen. We tested jet injection in mice and rabbits and found good antibody production and safe immune responses (no inflammatory cytokines). We found significant reduction of amyloid plaques and Aβ peptides in brains of the DNA Aβ42 immunized 3xTg-AD mouse model. This study was designed to optimize DNA delivery for possible testing of the DNA Aβ42 vaccine for AD prevention in a clinical trial. • DNA Aβ42 immunization via Jet injection into the skin induced high antibody responses in mice and rabbits. • DNA Aβ42 immunization via Jet injection into the skin did not lead to inflammatory cellular responses. • DNA Aβ42 immunization via Jet injection into the skin resulted in amyloid removal from brain in the 3xTg-AD mouse model. • DNA Aβ42 immunization via Jet injection into the skin improved nesting behavior in the 3xTg-AD mouse model. [ABSTRACT FROM AUTHOR]

Objective: To determine how attributions caregivers make about the source of problem behavior of frail, older care recipients may contribute to caregiver resentment of care recipients and obligations associated with providing care. Design: Cross-sectional interview data, screened according to primary cause of need for care. Participants: 103 caregiver-care recipient dyads in which care recipient was cognitively impaired (CI; n = 72) or physically disabled without cognitive impairment (n = 31). Outcome Measure: 17-item Caregiver Resentment Scale. Results: Caregivers of CI elders reported providing more care in response to CI-related care recipient disturbing behavior. However, beyond the source of impairment, disturbing (externally attributable) behavior typical of CI, and amount of care provided, resentment was predicted by controlling and manipulative (internally attributable) care recipient behavior. Conclusions: Caregivers are more resentful when care recipients are difficult in ways that they can attribute to the person rather than to the illness. [ABSTRACT FROM AUTHOR]

Abstract: Women are at a 2-fold risk of developing late-onset Alzheimer''s disease (AD) (onset at 65 years of age or older) compared with men. During perimenopausal years, women undergo hormonal changes that are accompanied by metabolic, cardiovascular, and inflammatory changes. These all together have been suggested as risk factors for late-onset AD. However, not all perimenopausal women develop AD; we hypothesize that certain genetic factors might underlie the increased susceptibility for developing AD in postmenopausal women. We investigated the Androgen Receptor gene (AR) in a clinical cohort of male and female AD patients and normal control subjects by sequencing all coding exons and evaluating the length and distribution of the CAG repeat in exon 1. We could not establish a correlation between the repeat length, sex, and the disease status, nor did we identify possible pathogenic variants. AR is located on the X chromosome; to assess its role in AD, X-inactivation patterns will need to be studied to directly correlate the actual expressed repeat length to a possible sex-specific phenotypic effect. [Copyright &y& Elsevier]