Biomarkers are needed to improve the sensitivity and accuracy of diagnosis as well as prognosis in individuals with early Alzheimer disease (AD). Measures of brain structure and disease-related proteins in the cerebrospinal fluid (CSF) have been proposed as biomarkers, yet relatively little is known about the relationships between such measures. The present study was conducted to assess the relationship between CSF Aβ and tau protein levels and longitudinal measures of hippocampal structure in individuals with and without very mild dementia of the Alzheimer type.
A single CSF sample and longitudinal MR scans were collected. The CSF samples were assayed for tau, p-tau181, Aβ1–42 and Aβ1–40 by ELISA. Large-deformation diffeomorphic metric mapping was used to generate hippocampal surfaces, and a composite hippocampal surface (previously constructed from 86 healthy participants) was used as a structural reference.
Patients or Other Participants
13 participants with very mild AD (Clinical Dementia Rating, CDR 0.5) and 11 cognitively normal participants (CDR 0).
Main Outcome Measures
Initial and rate-of-change measures of total hippocampal volume and displacement of the hippocampal surface within zones overlying the CA1, subiculum and CA2-4+DG cellular subfields. Their correlations with initial CSF measures.
Lower CSF Aβ1–42 levels and higher tau/Aβ1–42 and p-tau181/Aβ1–42 ratios were strongly correlated with decreases in hippocampal volume and measure of progressive inward deformations of the CA1 subfield in participants with early AD, but not cognitively normal participants.
Despite small sample size, we found that Aβ1–42 and tau-related CSF measures were related to hippocampal degeneration in individuals with clinically diagnosed early AD, and may reflect an association with a common underlying disease mechanism.
Magnetic Resonance Imaging (MRI); Hippocampal subfields; β-Amyloid; Tau; P-Tau; biomarkers
If smoking is a risk factor for Alzheimer’s disease (AD) but a smoker dies of another cause before developing or manifesting AD, smoking-related mortality may mask the relationship between smoking and AD. This phenomenon, referred to as competing risk, complicates efforts to model the effect of smoking on AD. Typical survival regression models assume that censorship from analysis is unrelated to an individual’s probability of developing AD (i.e., that censoring is noninformative). However, if individuals who die before developing AD are younger than those who survive long enough to develop AD, and if they include a higher percentage of smokers than nonsmokers, the incidence of AD will appear to be higher in older individuals and in nonsmokers. Further, age-specific mortality rates are higher in smokers because they die earlier than nonsmokers. Therefore, if we fail to take into account the competing risk of death when we estimate the effect of smoking on AD, we bias the results and are really only comparing the incidence of AD in nonsmokers with that in the healthiest smokers. In this study, we demonstrate that the effect of smoking on AD differs in models that are and are not adjusted for competing risks.
Alzheimer disease; competing risks; elderly; mortality; smoking
Subjective cognitive complaints (SCCs) are increasingly a focus in studies of prodromal Alzheimer disease (AD) and risk for dementia. Little is known about the optimal approach to measure SCCs. We used item response theory (IRT) to examine characteristics of 24 SCC items in a sample of 3,495 older adults pooled from four community-based studies. We investigated the potential advantages of IRT scoring over conventional scoring, based on participants' item response patterns. Items most likely endorsed by individuals low in SCC severity relate to word retrieval and general subjective memory decline. Items likely endorsed only by individuals high in SCC severity relate to non-episodic memory changes, such as decline in comprehension, judgment and executive functions, praxis and procedural memory, and social behavior changes. IRT scoring of SCCs was associated with performance on objective cognitive test performance above and beyond total SCC scores, and was associated with objective cognitive test performance among participants endorsing only one SCC item. Thus, IRT scoring captures additional information beyond a simple sum of SCC symptoms. Modern psychometric approaches including IRT may be useful in developing 1) brief community screening questionnaires, and 2) more sensitive measures of very subtle subjective decline for use in prodromal AD research.
Subjective memory; item response theory; dementia; neuropsychological tests; subjective cognitive impairment
Some propose maternal Alzheimer disease (1) inheritance. We compared dementia family histories in AD cases and cognitively normal controls. We expected more mothers to have AD in both groups. If maternal risk was not only due to female longevity more AD cases’ than controls’ mothers should be demented. We matched 196 AD cases to 200 controls by gender and age. We obtained parent dementia status and age of death for 348 AD and 319 control parents. 24 (12%) controls’ fathers, 26 (13%) AD patient fathers, 58 (29%) controls’ mothers and 55 (28%) AD mothers had memory difficulty. More mothers than fathers had memory problems in both groups and the statistical significance persisted after adjusting for parent age at death and APOE for controls (OR=2.40, p=0.004) but not cases (OR=1.63, p=0.14), although results are qualitatively similar. There was no evidence of a real difference between the two groups in interaction analysis (p=0.41). Mothers of both cases and controls were more often affected than fathers, even after adjusting for age. Cases’ mothers were no more often demented than controls’ mothers, which does not support the maternal AD transmission. Rather, the increased number of affected mothers relates, at least in part, to female longevity.
Alzheimer disease; Inheritance; Genetics; Maternal
The paucity of valid and reliable instruments designed to measure end-of-life experiences limits advanced dementia and palliative care research. Two end-of-life in dementia (EOLD) scales that evaluate the experiences of severely cognitively impaired persons and their health care proxies (HCP) have been developed: 1) symptom management (SM) and 2) satisfaction with care (SWC). The study objective was to examine the sensitivity of the EOLD scales to detect significant differences in clinically relevant outcomes in nursing home residents with advanced dementia. The SM-EOLD scale was sensitive to detecting changes in comfort among residents with pneumonia, pain, dyspnea, and receiving burdensome interventions. The SWC-EOLD scale was sensitive to detecting changes in HCP satisfaction with the care of residents when addressing whether the health care provider spent > 15 minutes discussing the resident’s advanced care planning, whether the physician counseled about the resident’s live expectancy, whether resident resided in a special care unit and whether the physician counseled possible resident health problems. This study extends the psychometric properties of the EOLD scales by showing the sensitivity to clinically meaningful change in these scales to specific outcomes related to end-of-life care and quality of life among residents with end-stage advanced dementia and their HCPs.
Dementia; Nursing homes; End-of-life; Health care proxy; Sensitivity to change; Responsiveness
The safety, tolerability, and pharmacokinetics (PKs) of bapineuzumab (AAB–001), a humanized monoclonal antibody to amyloid β, were evaluated in patients with mild-to-moderate Alzheimer disease in a phase 1, randomized, third-party unblinded, placebo-controlled, single ascending dose trial. Thirty patients received bapineuzumab infusion of 0.5, 1.5, or 5mg/kg or placebo (6 active, 2 placebo for 0.5 and 1.5-mg/kg cohorts; 10 active, 4 placebo for 5.0-mg/kg cohort). Three patients in the highest dose cohort (5.0mg/kg) developed magnetic resonance imaging abnormalities consistent with vasogenic edema, predominantly high signal abnormalities on fluid-attenuated inversion recovery sequences, all of which resolved over time. Plasma amyloid β was elevated from baseline, peaking approximately 24 hours after infusion. PK analysis demonstrated a half-life of 21 to 26 days, supporting a 13-week dosing interval for bapineuzumab. This small, single-dose study demonstrated the safety profile and PK characteristics of bapineuzumab and was used to design later safety and efficacy trials.
bapineuzumab; Alzheimer disease; humans; pharmacokinetics; monoclonal antibody
Frontotemporal lobar degeneration (FTLD) with ubiquitin-positive, tau-negative inclusions, and linkage to chromosome 17 was recently found to be caused by mutations in the progranulin (PGRN) gene. In this study, we screened a group of 51 FTLD patients for PGRN mutations and identified a novel exon 6 splice donor site deletion (IVS6+5_8delGTGA) in 2 unrelated patients. This mutation displayed an altered splicing pattern generating 2 aberrant transcripts and causing frameshifts of the coding sequence, premature termination codons, and a near absence of PGRN mRNA from the mutated alleles most likely through nonsense-mediated decay. The subsequent PGRN haploinsufficiency is consistent with previously described PGRN mutations. We present a molecular characterization of the IVS6+5_8delGTGA mutation and also describe clinical and neuropathologic features from the 2 patients carrying this PGRN mutation. From the screening of these 51 FTLD patients, we could also identify the earlier reported mutation Gln130fs, and several coding sequence variants that are most likely nonpathogenic.
frontotemporal lobar degeneration; frontotemporal dementia; progranulin; ubiquitin; TDP-43
Actigraphic measures of physical activity do not rely on participant self-report and may be of particular importance for efforts to examine the health benefits of physical activity across the full spectrum of older individuals especially those with dementia, a group in which loss of motor function is particularly salient. We tested whether actigraphy could be employed to examine the relationship between total daily physical activity and motor function in community-dwelling older persons both with (n=70) and without clinical dementia (n=624). Total daily activity was measured with actigraphy for a median of 9 (range 2–16) days. All participants also underwent a structured examination including 9 muscle strength and 9 motor performance measures summarized as a composite measure. In linear regression models controlling for age, sex, and education, total daily activity was associated with global motor scores (β=0.13, SD=0.01, p<0.001). This association remained significant after adjusting for body composition, cognition, depressive symptoms, disability, vascular risk factors and diseases (β=0.07, SD=0.01, p < 0.001). The association did not vary by dementia status (interaction p=0.53). In persons without dementia, the association was independent of self-reported physical activity. Total daily activity was associated with both muscle strength (β=0.10, SD=0.02, p<0.001) and motor performance (β=0.16, SD=0.02, p<0.001). Actigraphy can be employed in the community-setting to provide objective measures of total daily activity that are associated with a broad range of motor performances and these associations did not vary by dementia status. Actigraphy may provide a means to more fully explicate the nature and course of motor impairment in old age.
actigraphy; physical activity; motor function
We previously established reliability and cross-sectional validity of the SIST-M (Structured Interview and Scoring Tool–Massachusetts Alzheimer's Disease Research Center), a shortened version of an instrument shown to predict progression to Alzheimer disease (AD), even among persons with very mild cognitive impairment (vMCI).
To test predictive validity of the SIST-M.
Participants were 342 community-dwelling, non-demented older adults in a longitudinal study. Baseline Clinical Dementia Rating (CDR) ratings were determined by either: 1) clinician interviews or 2) a previously developed computer algorithm based on 60 questions (of a possible 131) extracted from clinician interviews. We developed age+gender+education-adjusted Cox proportional hazards models using CDR-sum-of-boxes (CDR-SB) as the predictor, where CDR-SB was determined by either clinician interview or algorithm; models were run for the full sample (n=342) and among those jointly classified as vMCI using clinician- and algorithm-based CDR ratings (n=156). We directly compared predictive accuracy using time-dependent Receiver Operating Characteristic (ROC) curves.
AD hazard ratios (HRs) were similar for clinician-based and algorithm-based CDR-SB: for a 1-point increment in CDR-SB, respective HRs (95% CI)=3.1 (2.5,3.9) and 2.8 (2.2,3.5); among those with vMCI, respective HRs (95% CI) were 2.2 (1.6,3.2) and 2.1 (1.5,3.0). Similarly high predictive accuracy was achieved: the concordance probability (weighted average of the area-under-the-ROC curves) over follow-up was 0.78 vs. 0.76 using clinician-based vs. algorithm-based CDR-SB.
CDR scores based on items from this shortened interview had high predictive ability for AD – comparable to that using a lengthy clinical interview.
Alzheimer disease; mild cognitive impairment; dementia; CDR; instrument; questionnaire; validity; prediction; psychometric
A dementia diagnosis is challenging to deliver and to hear, yet agreement about a diagnosis is essential for effective dementia care. We examined consensus about the results of a dementia evaluation in 90 patients assessed at an Alzheimer’s Disease Research Center. Diagnostic impressions were obtained from five sources: 1) the physician’s chart diagnosis, 2) the patient who was evaluated, 3) a companion present at the evaluation, 4) a diagnostic summary written by a nurse present during the evaluation, and 5) raters who watched a video of the diagnostic disclosure conversation. Overall, diagnostic consensus was only moderate. Patients and companions exhibited just fair agreement with one another. Agreement was better between physicians and companions compared to physicians and patients, though imperfect between the physician and video raters and the written summary. Agreement among sources varied by dementia severity, with lowest agreement occurring in instances of very mild dementia. This study documents discrepancies that can arise in diagnostic communication, which could influence adjustment to a dementia diagnosis and decisions regarding future planning and care.
Alzheimer’s disease; dementia; diagnostic disclosure; doctor-patient communication; patient education
The sources of stress for families of nursing home (NH) residents with advanced dementia have not been well described. Semi--structured interviews were conducted with 16 family members previously enrolled in the Choices, Attitudes and Strategies for Care of Advanced Dementia at the End-of-Life (CASCADE) study, a prospective cohort of 323 NH residents with advanced dementia and their family members. Questions inquired about the experience of having a family member in the NH, communication with health care professionals, surrogate decision-making, emotional distress and recommendations for improvement in care. Transcripts were analyzed using the constant comparative method. The majority of participants were female (63%), children of the resident (94%) and white (94%). The average age was 62 years. Four themes emerged: 1) inadequate resident personal care, resulting in family member vigilance and participation in care; 2) stress at the time of NH admission; 3) lack of communication with NH physicians; and 4) challenges of surrogate decision making, including the need for education to support advance care planning and end-of-life decisions. Our results support the provision of emotional support to families upon resident admission, education regarding prognosis to guide decision making, improved resident care and greater communication with health care professionals.
caregivers; long-term care; Alzheimer’s disease
Increased susceptibility of the aging brain to both chronic stress and incipient dementia-related neuropathology may accelerate cognitive decline. We investigated associations between chronic stress and diagnostic change in 62 individuals (mean age=78.7) participating in an Alzheimer’s disease research center longitudinal study. Subjects, diagnosed at baseline as cognitively normal (CN) or Mild Cognitive Impairment (MCI) were followed an average of 2.5 years. Senior neurologists, blind to detailed measures of stress and cognition, assigned diagnoses annually. Logistic regression analyses assessed accuracy with which measures of stress (event-based ratings, cortisol levels) predicted conversion to MCI and dementia. Eleven individuals with MCI at baseline received a dementia diagnosis during follow-up. Sixteen converted from CN to MCI. Prolonged, highly stressful experiences were associated with conversion from MCI to dementia. The cortisol awakening response, with age and education, was associated with diagnostic change to MCI. Cortisol measures were not associated with progression from MCI to dementia, and there was no association between stressful experiences and change to MCI. Mechanisms associated with the transition from normal cognition to MCI may differ from those associated with diagnostic change to dementia. These findings could facilitate identification of interventional strategies to reduce risk of decline at different stages of susceptibility.
chronic stress; aging; Alzheimer’s disease; mild cognitive impairment; dementia; diurnal rhythm; cortisol awakening response
Preclinical and epidemiologic studies suggest a protective effect of statins on Alzheimer disease (AD). Experimental evidence indicates that some statins can cross the blood-brain barrier, alter brain cholesterol metabolism, and may ultimately decrease the production of amyloid-β (Aβ) peptide. Despite these promising leads, clinical trials have yielded inconsistent results regarding the benefits of statin treatment in AD. Seeking to detect a biological signal of statins effect on AD, we conducted a 12-week open-label trial with simvastatin 40 mg/d and then 80 mg/d in 12 patients with AD or amnestic mild cognitive impairment and hypercholesterolemia. We quantified cholesterol precursors and metabolites and AD biomarkers of Aβ and tau in both plasma and cerebrospinal fluid at baseline and after the 12-week treatment period. We found a modest but significant inhibition of brain cholesterol biosynthesis after simvastatin treatment, as indexed by a decrease of cerebrospinal fluid lathosterol and plasma 24S-hydroxycholesterol. Despite this effect, there were no changes in AD biomarkers. Our findings indicate that simvastatin treatment can affect brain cholesterol metabolism within 12 weeks, but did not alter molecular indices of AD pathology during this short-term treatment.
Alzheimer disease; simvastatin; cholesterol; biomarker
The purpose of this study was to conduct a systematic review of the literature of cardiovascular factors pertaining to incident Alzheimer disease (AD).
A systematic literature review was conducted of all studies of cardiovascular risk factors for incident AD listed in PUBMED in English from 2000–2007. Risk factors included hypertension, diabetes, exercise, alcohol intake, smoking, B complex vitamins, homocysteine, stroke, atrial fibrillation, APOE, lipids, and diet. Inclusion criteria consisted of diagnoses of incident AD and longitudinal studies with cohorts of 500 or more.
Individual clinically defined risk factors such as hypertension and diabetes were not significantly associated with increased risk for AD. The strength of the association for hypertension could be considerably strengthened by changing criteria such as midlife measurements or using higher cutoffs for systolic blood pressure. APOE ε4 was the most consistent risk factor. Interactions between risk factors modify risk particularly for hypertension and diabetes. Interactions modifying risk were also found for exercise and physical function, APOE ε4, diabetes and cholesterol.
In this review the evidence that single clinically defined cardiovascular risk factors are significantly associated with incident Alzheimer disease is inconsistent at best. The strength of the association of cardiovascular risk factors and AD can be influenced greatly by changing the parameters of measurement of risk factors and by identifying interactions between the factors.
incident Alzheimer disease; cardiovascular risk factors; interactions
Spouses are often the first providers of informal care when their partners develop dementia. We used The National Longitudinal Caregiver Study (NLCS, 4 annual surveys, 1999 to 2002) and identified 3 distinct longitudinal patterns (trajectory classes) of total daily caregiving time provided by the wife to her husband using Generalized growth mixture models (GGMM). About 56.4% of the sample (N=828) was found to have an increase in the trajectory of total daily caregiving time (mean 252 min/d at baseline, rising to 471 min/d at time 4). Four hundred forty-four (30.3%) caregivers had a trajectory described by a moderate increase in caregiving time (an increase from a mean of 464 min/d at baseline to 533 at wave 4), whereas 195 (13.3%) had a sharply declining trajectory (a decline from a mean of 719 min/d at baseline to 421 at wave 4). There was no significant difference in the duration (time since onset) of caregiving at baseline for these 3 trajectories. GGMM are well suited for the identification of distinct trajectory classes. Here they show that there are large differences in caregiving time provided to persons with dementia, who seem to be quite similar.
informal caregiving; longitudinal methods; burden of Alzheimer disease/dementia
For more than three decades, recruitment and retention of African Americans for research in Alzheimer's disease have been regarded as difficult undertakings with poor results. The typical explanation for failure to respond to research participation options is widespread mistrust of research and the biomedical community. Mistrust is a reasonable response given the historical reality of malfeasance, victimization, and mistreatment over the course of the research participation history of African Americans. The challenges are real but there are opportunities for successful recruitment and retention of African Americans for research including research on Alzheimer's disease. Participation, however, comes with specific terms and considerations. Two of the most prominent criteria for research recruitment and retention are the transparency and accountability of the investigator which may determine how he or she proceeds from the start of the process throughout the steps of recruitment, retention and subsequent follow-up with the community.
Alzheimer's; Recruitment; Retention; Minorities; Mistrust; Guidelines
The present investigation worked to understand whether patients with mild Alzheimer's disease (AD) could use general or self-referential mental imagery to improve their recognition of visually presented words. Experiment 1 showed that, unlike healthy controls, patients generally did not benefit from either type of imagery. To help determine whether the patients' inability to benefit from mental imagery at encoding was due to poor memory or due to an impairment in mental imagery, subjects then performed four imagery tasks, with varying imagery and cognitive demands. Experiment 2 showed that patients successfully performed basic visual imagery, but degraded semantic memory, coupled with visuospatial and executive functioning deficits, impaired their ability to perform more complex types of imagery. Given that patients with AD can perform basic mental imagery, our results suggest that episodic memory deficits likely prevent AD patients from storing or retrieving general mental images generated during encoding. Overall, the results of both experiments suggest that neurocognitive deficits do not allow patients with AD to perform complex mental imagery, which may be most beneficial to improving memory. However, our data also suggest that intact basic mental imagery and rehearsal could possibly be helpful if used in a rehabilitation multi-session intervention approach.
mental imagery; visual imagery; recognition memory; cognitive rehabilitation
Anticipatory grief is the process of experiencing normal phases of bereavement in advance of the loss of a significant person. To date, anticipatory grief has been examined in family caregivers to individuals who have had Alzheimer’s Disease (AD) an average of 3 to 6 years. Whether such grief is manifested early in the disease trajectory (at diagnosis) is unknown. Using a cross-sectional design, we examined differences in the nature and extent of anticipatory grief between family caregivers of persons with a new diagnosis of mild cognitive impairment (MCI, n=43) or AD (n=30). We also determined whether anticipatory grief levels were associated with caregiver demographics, caregiving burden, depressive symptoms and marital quality. Mean anticipatory grief levels were high in the total sample, with AD caregivers endorsing significantly more anticipatory grief than MCI caregivers. In general, AD caregivers endorsed difficulty functioning whereas MCI caregivers focused on themes of “missing the person” they once knew. Being a female caregiver, reporting higher levels of objective caregiving burden and higher depression levels each bore independent, statistically significant relationships with anticipatory grief. Given these findings, family caregivers of individuals with mild cognitive deficits or a new AD diagnosis may benefit from interventions specifically addressing anticipatory grief.
Anticipatory grief; dementia caregiving; mild cognitive impairment
The evidence relating obesity measured with body mass index (BMI) in the elderly to late onset Alzheimer’ disease (LOAD) is conflicting. Central obesity in middle age is related to a higher risk of LOAD, but data in the elderly are lacking. We explored whether measures of central obesity, waist circumference (WC), and waist to hip ratio (WHR) were better predictors of LOAD compared to BMI in the elderly. Participants were 1459 persons aged 65 years and older without dementia at baseline, with follow-up, and with anthropometric data from a longitudinal study of aging in New York City. Proportional Hazards regression was used for multivariable analyses relating BMI, WC, and WHR to LOAD. There were 145 cases of AD in 5,734 person-years of follow-up. Only WHR was related to higher LOAD risk (HR of the 4th quartile compared to the first =2.5; 95% CI = 1.3, 4.7) after adjustment for age, sex, education, ethnic group, APOE-ε4, type 2 diabetes, hypertension, non-HDL cholesterol, HDL cholesterol and stroke. Measures of central obesity, particularly WHR, are better predictors of cardiovascular outcomes compared to BMI. Our results support the notion that central obesity is related to a higher risk of LOAD.
obesity; body mass index; waist circumference; waist to hip ratio; Alzheimer’s disease
Frontotemporal lobar degeneration due to mutations in the progranulin gene (PGRN) presents a high variability both in the clinical phenotype and age of onset of disease. Factors that influence this variability remain largely unknown. The aim of our study was to determine whether selected genetic variables modify age at onset of disease in our series of 21 patients with a single splicing mutation (c.709-1G>A) in the PGRN gene, all of whom were of Basque descent. In our analysis, we included the following genetic variables: PGRN rs5848 and rs9897526 polymorphisms, APOE and MAPT genotypes and PRNP codon 129 polymorphism. We found no association between PGRN polymorphisms, APOE and MAPT genotypes and age at onset of the disease; while we report evidence for an association between PRNP codon 129 polymorphism and age at onset of disease in frontotemporal dementia-PGRN(+) patients. MM homozygous carriers presented onset of disease on average 8.5 years earlier than patients who carried at least one valine on their PRNP codon 129 (MV or VV). The biological justification for this association remains speculative.
APOE; PRNP codon 129; frontotemporal dementia; frontotemporal lobar degeneration; progranulin; prion protein gene
Little is known regarding factors associated with soluble amyloid beta peptide (Aβ) concentrations in humans at late midlife, when Aβ is likely most critical to Alzheimer disease pathogenesis. We examined the association between insulin, insulin-related factors, and plasma Aβ at late midlife. Plasma Aβ42, Aβ40, fasting insulin, and c-peptide were measured in 468 women without diabetes, aged 59–69 years (median 63 years). Prior to blood draw, participants reported body mass index, waist circumference, physical activity, alcohol intake, hypertension, and diabetes family history. Linear regression was used to calculate age-adjusted mean differences in Aβ42 to Aβ40 ratio, and Aβ42 levels, by insulin and insulin-related factors. The ratio of Aβ42 to Aβ40 was statistically significantly lower in women with diabetes family history, and Aβ42 was significantly lower with less physical activity, greater waist circumference, hypertension, and diabetes family history (p<0.05 for all). Aβ42 to Aβ40 ratio, and Aβ42 levels, appeared lower with higher c-peptide levels (p-trend=0.07 and 0.06, respectively), although these were not statistically significant. In summary, insulin-related factors appear associated with lower plasma Aβ42 to Aβ40 ratio, and Aβ42, at late mid-life, consistent with increased brain sequestration of Aβ42 (relative to Aβ40), suggesting insulin merits focus in strategies to prevent dementia.
amyloid beta peptide; insulin; epidemiology
To examine the association of midlife report of crisis following parental death (CFPD) during childhood and adolescence, with dementia at old age.
In 1965, 9362 male participants of the Israel Ischemic Heart disease (IIHD) study were asked whether they have experienced CFPD (paternal or maternal) during the following ages: 0–6. 7–12. 13–18 or >18 years. Dementia was assessed over three decades later in 1889 survivors of the original cohort, 1,652 of whom were assessed for CFPD in 1965.
Controlling for age, the estimated odds for dementia relative to individuals who reported crisis following paternal parental death (CFPR-P) at the age of 18 and above, were 3.06 (95%CI 1.42–6.61), 2.15 (95% CI 0.87–5.31) and 2.35 (95%CI 1.05–5.28) for those who reported CFPD-P at the ages of 0–6, 7–12 and 13–18 respectively. Odds for dementia were 0.60 (95% CI 0.32–1.11) for participants who reported CFPD-P at ages of 18 and above, compared to participants who did not report such a crisis. Similar results were obtained for the association of crisis reported following maternal parental death (CFPD-M) at different age groups and dementia.
CFPD during childhood is associated with increased risk for dementia in males who survived until old age.
crisis; parental death; childhood; dementia
Florbetapir F 18 (18F-AV-45) is a positron emission tomography (PET) imaging ligand for the detection of amyloid aggregation associated with Alzheimer’s disease. Earlier data showed that florbetapir F 18 binds with high affinity to β-amyloid plaques in human brain homogenates (Kd = 3.7 nM) and has favorable imaging pharmacokinetic properties, including rapid brain penetration and washout. The present study used human autopsy brain tissue to evaluate the correlation between in vitro florbetapir F 18 binding and β-amyloid density measured by established neuropathological methods.
The localization and density of florbetapir F 18 binding in frozen and formalin-fixed paraffin-embedded sections of postmortem brain tissue from 40 subjects with a varying degree of neurodegenerative pathology was assessed by standard florbetapir F 18 autoradiography and correlated with the localization and density of β-amyloid identified by silver staining, thioflavin S staining, and immunohistochemistry.
There were strong quantitative correlations between florbetapir F 18 tissue binding and both β-amyloid plaques identified by light microscopy (sliver staining and thioflavin S fluorescence) and by immunohistochemical measurements of β-amyloid using three antibodies recognizing different epitopes of the β-amyloid peptide (Aβ). Florbetapir F 18 did not bind to neurofibrillary tangles.
Florbetapir F 18 selectively binds β-amyloid in human brain tissue. The binding intensity was quantitatively correlated with the density of β-amyloid plaques identified by standard neuropathological techniques and correlated with the density of Aβ measured by immunohistochemistry. Since β-amyloid plaques are a defining neuropathological feature for Alzheimer’s disease, these results support the use of florbetapir F 18 as an amyloid PET ligand to identify the presence of AD pathology in patients with signs and symptoms of progressive late-life cognitive impairment.
PET imaging; Alzheimer’s disease; β-amyloid plaque; autoradiography; β-amyloid; amyloid PET imaging; florbetapir F 18; 18F-AV-45; postmortem