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Introduction

Early identification of Alzheimer’s disease (AD) is needed both for clinical trials and in clinical practice. In this study, we compared brief cognitive tests and cerebrospinal fluid (CSF) biomarkers in predicting conversion from mild cognitive impairment (MCI) to AD.

Methods

At a memory clinic, 133 patients with MCI were followed until development of dementia or until they had been stable over a mean period of 5.9 years (range 3.2–8.8 years). The Mini-Mental State Examination (MMSE), the clock drawing test, total tau, tau phosphorylated at Thr181 (P-tau) and amyloid-β1–42 (Aβ42) were assessed at baseline.

Results

During clinical follow-up, 47% remained cognitively stable and 53% developed dementia, with an incidence of 13.8%/year. In the group that developed dementia the prevalence of AD was 73.2%, vascular dementia 14.1%, dementia with Lewy bodies (DLB) 5.6%, progressive supranuclear palsy (PSP) 4.2%, semantic dementia 1.4% and dementia due to brain tumour 1.4%. When predicting subsequent development of AD among patients with MCI, the cognitive tests classified 81% of the cases correctly (AUC, 0.85; 95% CI, 0.77–0.90) and CSF biomarkers 83% (AUC, 0.89; 95% CI, 0.82–0.94). The combination of cognitive tests and CSF (AUC, 0.93; 95% CI 0.87 to 0.96) was significantly better than the cognitive tests (p = 0.01) and the CSF biomarkers (p = 0.04) alone when predicting AD.

Conclusions

The MMSE and the clock drawing test were as accurate as CSF biomarkers in predicting future development of AD in patients with MCI. Combining both instruments provided significantly greater accuracy than cognitive tests or CSF biomarkers alone in predicting AD.

Biomarkers of brain Aβ amyloid deposition can be measured either by cerebrospinal fluid Aβ42 or Pittsburgh compound B positron emission tomography imaging. Our objective was to evaluate the ability of Aβ load and neurodegenerative atrophy on magnetic resonance imaging to predict shorter time-to-progression from mild cognitive impairment to Alzheimer’s dementia and to characterize the effect of these biomarkers on the risk of progression as they become increasingly abnormal. A total of 218 subjects with mild cognitive impairment were identified from the Alzheimer’s Disease Neuroimaging Initiative. The primary outcome was time-to-progression to Alzheimer’s dementia. Hippocampal volumes were measured and adjusted for intracranial volume. We used a new method of pooling cerebrospinal fluid Aβ42 and Pittsburgh compound B positron emission tomography measures to produce equivalent measures of brain Aβ load from either source and analysed the results using multiple imputation methods. We performed our analyses in two phases. First, we grouped our subjects into those who were ‘amyloid positive’ (n = 165, with the assumption that Alzheimer's pathology is dominant in this group) and those who were ‘amyloid negative’ (n = 53). In the second phase, we included all 218 subjects with mild cognitive impairment to evaluate the biomarkers in a sample that we assumed to contain a full spectrum of expected pathologies. In a Kaplan–Meier analysis, amyloid positive subjects with mild cognitive impairment were much more likely to progress to dementia within 2 years than amyloid negative subjects with mild cognitive impairment (50 versus 19%). Among amyloid positive subjects with mild cognitive impairment only, hippocampal atrophy predicted shorter time-to-progression (P < 0.001) while Aβ load did not (P = 0.44). In contrast, when all 218 subjects with mild cognitive impairment were combined (amyloid positive and negative), hippocampal atrophy and Aβ load predicted shorter time-to-progression with comparable power (hazard ratio for an inter-quartile difference of 2.6 for both); however, the risk profile was linear throughout the range of hippocampal atrophy values but reached a ceiling at higher values of brain Aβ load. Our results are consistent with a model of Alzheimer’s disease in which Aβ deposition initiates the pathological cascade but is not the direct cause of cognitive impairment as evidenced by the fact that Aβ load severity is decoupled from risk of progression at high levels. In contrast, hippocampal atrophy indicates how far along the neurodegenerative path one is, and hence how close to progressing to dementia. Possible explanations for our finding that many subjects with mild cognitive impairment have intermediate levels of Aβ load include: (i) individual subjects may reach an Aβ load plateau at varying absolute levels; (ii) some subjects may be more biologically susceptible to Aβ than others; and (iii) subjects with mild cognitive impairment with intermediate levels of Aβ may represent individuals with Alzheimer’s disease co-existent with other pathologies.

Objective

To characterize rates of regional Alzheimer disease (AD)–specific brain atrophy across the presymptomatic, mild cognitive impairment, and dementia stages.

Design

Multicenter case-control study of neuroimaging, cerebrospinal fluid, and cognitive test score data from the Alzheimer’s Disease Neuroimaging Initiative.

Setting

Research centers across the United States and Canada.

Patients

We examined a total of 317 participants with base-line cerebrospinal fluid biomarker measurements and 3T1-weighted magnetic resonance images obtained within 1 year.

Main Outcome Measures

We used automated tools to compute annual longitudinal atrophy in the hippocampus and cortical regions targeted in AD. We used Mini-Mental State Examination scores as a measure of cognitive performance. We performed a cross-subject analysis of atrophy rates and acceleration on individuals with an AD-like cerebrospinal fluid molecular profile.

Results

In presymptomatic individuals harboring indicators of AD, baseline thickness in AD-vulnerable cortical regions was significantly reduced compared with that of healthy control individuals, but baseline hippocampal volume was not. Across the clinical spectrum, rates of AD-specific cortical thinning increased with decreasing cognitive performance before peaking at approximately the Mini-Mental State Examination score of 21, beyond which rates of thinning started to decline. Annual rates of hippocampal volume loss showed a continuously increasing pattern with decreasing cognitive performance as low as the Mini-Mental State Examination score of 15. Analysis of the second derivative of imaging measurements revealed that AD-specific cortical thinning exhibited early acceleration followed by deceleration. Conversely, hippocampal volume loss exhibited positive acceleration across all study participants.

Conclusions

Alzheimer disease–specific cortical thinning and hippocampal volume loss are consistent with a sigmoidal pattern, with an acceleration phase during the early stages of the disease. Clinical trials should carefully consider the nonlinear behavior of these AD biomarkers.

The authors aim to study subjective ratings of clock drawing test by clinicians and determine interrater reliability and diagnostic accuracy. The clock drawing test has been advocated over the Mini-Mental State Examination as an office screening test for dementia, but use of the clock drawing test by neurologists and dementia specialist clinicians has not been validated. The authors conducted a study of clock drawing test scoring by dementia specialists. The authors randomly assigned 25 clocks from each of six predetermined groups based on consensus diagnosis (cognitive comparison subjects, subjects with a memory complaint but with normal neuropsychological testing, subjects with probable and possible mild cognitive impairment, and subjects with possible and probable Alzheimer’s disease) to dementia specialists for blinded scoring using a binary yes/no impairment system and a 0–10 scale as subjectively determined by each individual clinician rater. The authors collapsed the six groups into three (comparison subjects, mild cognitive impairment patients, and Alzheimer’s disease patients) and analyzed interrater reliability, sensitivity, and specificity for consensus diagnosis of mild cognitive impairment, and Alzheimer’s disease. The authors found excellent interrater reliability, sensitivity, and specificity for predicting consensus diagnosis. The 0–10 clock drawing test rating scale was more predictive of consensus diagnosis than the binary impairment scale. Based on the five clinicians’ average dichotomous rating, the clinicians differentiated comparison and Alzheimer’s disease participants with a sensitivity of 0.75 and a specificity of 0.81. For three of the four comparisons, a cutoff score of two or greater resulted in the maximization of sensitivity and specificity for differentiating diagnostic groups. A cutoff score of four or greater maximized sensitivity (0.54) and specificity (0.74) for differentiating Alzheimer’s disease from mild cognitive impairment. Based on rating systems, clock drawing test scoring by dementia clinicians had excellent interrater reliability and sensitivity for differentiating the mild Alzheimer’s disease subjects from comparison subjects. When utilizing a binary rating scale for the clock drawing test in the absence of clinical information, dementia specialist clinicians at the Boston Medical Center were moderately sensitive and highly specific in separating mild cognitive impairment from healthy comparison subjects. These dementia clinicians were also highly sensitive and less specific in differentiating mild cognitive impairment from Alzheimer’s disease.

Objectives

To evaluate a simple three step procedure to identify people in the general population who are in the preclinical phase of Alzheimer's disease and dementia.

Design

Three year population based cohort study.

Setting

Kungsholmen cohort, Stockholm, Sweden.

Participants

1435 people aged 75-95 years without dementia.

Assessments

Single question asking about memory complaints, assessment by mini-mental state examination, and neuropsychological testing.

Main outcome measure

Alzheimer's disease and dementia at three year follow up.

Results

None of the three instruments was sufficiently predictive of Alzheimer's disease and dementia when administered separately. After participants had been screened for memory complaints and global cognitive impairment, specific tests of word recall and verbal fluency had positive predictive values for dementia of 85-100% (95% confidence intervals range from 62% to 100%). However, only 18% of future dementia cases were identified in the preclinical phase by this three step procedure. Memory complaints were the most sensitive indicator of Alzheimer's disease and dementia in the whole population, but only half the future dementia cases reported memory problems three years before diagnosis.

Conclusion

This three step procedure, which simulates what might occur in clinical practice, has a high positive predictive value for dementia, although only a small number of future cases can be identified.

What is already known on this topicAlzheimer's disease is characterised by a preclinical phase, during which cognitive deficits are seen before diagnosisElderly people with subjective memory complaints and objective global cognitive impairment have a high risk of developing Alzheimer's disease and dementiaWhat this study addsThis three step procedure (self report of memory complaints, test of global cognitive functioning, and then domain specific cognitive tests) has a positive predictivity of 85-100% for Alzheimer's disease and dementia at three yearsHowever, only 18% of people in the preclinical phase can be identified using this procedureAbout half of the people in the preclinical phase of Alzheimer's disease and dementia do not report problems with their memory three years before diagnosis

Objective To evaluate a cognitive test, the TYM (“test your memory”), in the detection of Alzheimer’s disease.

Design Cross sectional study.

Setting Outpatient departments in three hospitals, including a memory clinic.

Participants 540 control participants aged 18-95 and 139 patients attending a memory clinic with dementia/amnestic mild cognitive impairment.

Intervention Cognitive test designed to use minimal operator time and to be suitable for non-specialist use.

Main outcome measures Performance of normal controls on the TYM. Performance of patients with Alzheimer’s disease on the TYM compared with age matched controls. Validation of the TYM with two standard tests (the mini-mental state examination (MMSE) and the Addenbrooke’s cognitive examination-revised (ACE-R)). Sensitivity and specificity of the TYM in the detection of Alzheimer’s disease.

Results Control participants completed the TYM with an average score of 47/50. Patients with Alzheimer’s disease scored an average of 33/50. The TYM score shows excellent correlation with the two standard tests. A score of ≤42/50 had a sensitivity of 93% and specificity of 86% in the diagnosis of Alzheimer’s disease. The TYM was more sensitive in detection of Alzheimer’s disease than the mini-mental examination, detecting 93% of patients compared with 52% for the mini-mental state exxamination. The negative and positive predictive values of the TYM with the cut off of ≤42 were 99% and 42% with a prevalence of Alzheimer’s disease of 10%. Thirty one patients with non-Alzheimer dementias scored an average of 39/50.

Conclusions The TYM can be completed quickly and accurately by normal controls. It is a powerful and valid screening test for the detection of Alzheimer’s disease.

Objective

To determine the temporal relationships of clinical, cognitive, Pittsburgh Compound-B (PiB) amyloid imaging, and cerebrospinal fluid (CSF) markers of Alzheimer’s disease (AD).

Design

A case report of a longitudinally assessed participant in a memory and aging study who had serial clinical and psychometric assessments over 6 years, in addition to PiB imaging and CSF biomarker assays, prior to coming to autopsy.

Setting

Alzheimer’s Disease Research Center

Findings

An 85-year old individual was cognitively normal at his initial and next 3 annual assessments. Decline in measures of episodic memory and, to a lesser degree, working memory began at about age 88 years. PiB-PET amyloid imaging was negative at age 88.5 years, but at age 89.5 years there was reduced amyloid-beta 42 (Aβ42) and elevated levels of tau in the CSF. At his 6th assessment, when he was 90 years old, he was diagnosed with very mild dementia of the Alzheimer type. After death at age 91 years, the autopsy revealed foci of frequent neocortical diffuse Aβ plaques, sufficient to fulfill Khachaturian neuropathologic criteria for AD, but neuritic plaques and neurofibrillary tangles were sparse. Postmortem biochemical analysis of the cerebral tissue confirmed that PiB-PET-binding was below the level needed for in vivo detection.

Conclusion

Clinical, cognitive, and CSF markers consistent with AD may precede detection of cerebral Aβ with amyloid imaging agents such as PiB, which primarily label fibrillar Aβ plaques.

Background

Cognitive dysfunction, including dementia and delirium, is prevalent in geriatric emergency department (ED) patients, but often remains undetected. One barrier to reliable identification of acutely or chronically impaired cognitive function is the lack of an acceptable screening tool. While multiple brief screening instruments have been derived, ED validation trials have not previously demonstrated tools that are appropriately sensitive for clinical use.

Objectives

The primary objective was to evaluate and compare the Ottawa 3DY (O3DY), Brief Alzheimer’s Screen (BAS), Short Blessed Test (SBT), and caregiver-completed AD8 (cAD8) diagnostic test performance for cognitive dysfunction in geriatric ED patients using the Mini Mental Status Exam (MMSE) as the criterion standard. A secondary objective was to assess the diagnostic accuracy for the cAD8 (which is an informant-based instrument) when used in combination with the other performance-based screening tools.

Methods

In an observational cross-sectional cohort study at one urban academic university-affiliated medical center, trained research assistants collected patients’ responses on the Confusion Assessment Method for the Intensive Care Unit, BAS, and SBT. When available, reliable caregivers completed the cAD8. The MMSE was then obtained. The O3DY was reconstructed from elements of the MMSE and the BAS. Consenting subjects were non-critically ill, English-speaking adults over age 65 years, who had not received potentially sedating medications prior to or during cognitive testing. Using an MMSE score ≤ 23 as the criterion standard for cognitive dysfunction, the sensitivity, specificity, likelihood ratios, and receiver operating characteristic area under the curve were computed. Venn diagrams were constructed to quantitatively compare the degree of overlap among positive test results between the performance-based instruments.

Results

The prevalence of cognitive dysfunction for the 163 patients enrolled with complete data collection was 37%, including 5.5% with delirium. Dementia was self-reported in 3%. Caregivers were available to complete the cAD8 for 56% of patients. The SBT, BAS, and O3DY each demonstrated 95% sensitivity, compared with 83% sensitivity for the cAD8. The SBT had a superior specificity of 65%. No combination of instruments with the cAD8 significantly improved diagnostic accuracy. The SBT provided the optimal overlap with the MMSE.

Conclusions

The SBT, BAS, and O3DY are three brief performance-based screening instruments to identify geriatric patients with cognitive dysfunction more rapidly than the MMSE. Among these three instruments, the SBT provides the best diagnostic test characteristics and overlap with MMSE results. The addition of the cAD8 to the other instruments does not enhance diagnostic accuracy.

Objective

Self-administered by spouses and other collateral informants, the nationally normed Older Adult Behavior Checklist (OABCL) provides standardized data on diverse aspects of older adult psychopathology and adaptive functioning. We tested the validity of the Older Adult Behavior Checklist (OABCL) scale scores in terms of associations with diagnoses of dementia of the Alzheimer’s type (DAT) and mood disorders (MD) and with 9 measures of psychopathology, cognitive performance, and adaptive functioning.

Method

Informants completed OABCLs for 727 60- to 97-year-olds recruited from a memory disorders clinic, geriatric psychiatry clinic, and community–dwelling seniors. OABCL scale scores were tested for associations with DAT and MD diagnoses, as well as with scores on the Neuropsychiatric Inventory, Mini-Mental State Exam (MMSE), Clock Drawing Test, Alzheimer’s Disease Assessment Scale, Geriatric Depression Scale, Clinical Dementia Rating, Dementia Severity Rating Scale, Trail Making Test Part A, and Instrumental Activities of Daily Living.

Results

OABCL scales had medium to large correlations with the 9 other indices of functioning and significantly augmented MMSE discrimination between patients with DAT vs. MD. OABCL scales also discriminated significantly between patients diagnosed with DAT vs. MD and both these groups vs. nonclinical subjects.

Conclusions

Multiple OABCL scales had medium to large associations with diverse indices of functioning based on other kinds of data. The nationally normed OABCL provides new ways to integrate informant and self-report data to improve assessment of older adults. Specifically, the OABCL can provide discrimination between those who qualify for diagnoses of DAT vs. MD vs. neither diagnosis.

Objective:

To re-examine proposed models of cognitive test performance that concluded separate factor structures were required for people with Alzheimer disease (AD) and older adults without dementia.

Methods:

Five models of cognitive test performance were compared using multistep confirmatory factor analysis in 115 individuals with autopsy-confirmed AD and 191 research participants without clinical dementia from longitudinal studies at the Washington University AD Research Center. The models were then cross-validated using independent samples of 323 people with clinically diagnosed dementia of the Alzheimer type and 212 cognitively healthy older adults.

Results:

After controlling for Alzheimer-specific changes in episodic memory, performance on the battery of tests used here was best represented in people both with and without dementia by a single model of one general factor and three specific factors (verbal memory, visuospatial ability, and working memory). Performance by people with dementia was lower on the general factor than it was by those without dementia. Larger variances associated with the specific factors in the group with dementia indicated greater individual differences in the pattern of cognitive deficits in the stage of AD.

Conclusions:

A hybrid model of general and specific cognitive domains simplifies cognitive research by allowing direct comparison of normal aging and Alzheimer disease performance. The presence of a general factor maximizes detection of the dementia, whereas the specific factors reveal the heterogeneity of dementia’s associated cognitive deficits.

GLOSSARY

= Alzheimer disease;

= Block Design;

= Boston Naming Test;

= Benton Visual Retention Test;

= Clinical Dementia Rating;

= confirmatory factor analysis;

= comparative fit index;

= dementia of the Alzheimer type;

= Digit Span Backward;

= Digit Span Forward;

= Digit Symbol;

= information;

= Lewy bodies;

= Logical Memory;

= Mental Control;

= National Institute on Aging;

= Paired Associate Learning;

= root mean square error of approximation;

= tests of invariance;

= Trailmaking A;

= Word Fluency.

Purpose of review

This review describes the evolution of the clinical criteria for Alzheimer’s disease over the past 25 years, with special emphasis on those recently published that have incorporated the use of biomarkers.

Recent findings

One of the most important advances in the knowledge of Alzheimer’s disease was the development of cerebrospinal fluid, PET and MRI biomarkers. These have shown that the Alzheimer’s disease is present in cognitively normal individuals, suggesting that there is a long incubation process that precedes the onset of the symptoms. Although there are diagnostic criteria for Alzheimer’s disease, the National Institute on Aging and the Alzheimer’s Association has proposed a set of diagnostic criteria oriented to provide a unified vision of the pathological process from preclinical, to mild cognitive impairment, and to full-blown dementia. These new criteria take advantage of different biomarkers to support the clinical diagnosis of the different stages of the disease.

Summary

The new guidelines provide a definition of the dementia syndrome and core diagnostic features to be used in research and clinical practice, although they caution about the use of biomarkers, since they still require validation, and the longitudinal interaction and dynamics of these biomarkers in relationship to the manifestation of the symptoms are not fully understood.

Alzheimer's disease (AD) is the most common form of dementia that affects several million people worldwide. The major neuropathological hallmarks of AD are the presence of extracellular amyloid plaques that are composed of Aβ40 and Aβ42 and intracellular neurofibrillary tangles (NFT), which is composed of hyperphosphorylated protein Tau. While the amyloid plaques and NFT could define the disease progression involving neuronal loss and dysfunction, significant cognitive decline occurs before their appearance. Although significant advances in neuroimaging techniques provide the structure and physiology of brain of AD cases, the biomarker studies based on cerebrospinal fluid (CSF) and plasma represent the most direct and convenient means to study the disease progression. Biomarkers are useful in detecting the preclinical as well as symptomatic stages of AD. In this paper, we discuss the recent advancements of various biomarkers with particular emphasis on CSF biomarkers for monitoring the early development of AD before significant cognitive dysfunction.

Background:

Extrapyramidal motor symptoms precede dementia in Parkinson disease (PDD) by many years, whereas dementia occurs early in dementia with Lewy bodies (DLB). Despite this clinical distinction, the neuropsychological and neuropathologic features of these conditions overlap. In addition to widespread distribution of Lewy bodies, both diseases have variable burdens of neuritic plaques and neurofibrillary tangles characteristic of Alzheimer disease (AD).

Objectives:

To determine whether amyloid deposition, as assessed by PET imaging with the β-amyloid–binding compound Pittsburgh Compound B (PiB), can distinguish DLB from PDD, and to assess whether regional patterns of amyloid deposition correlate with specific motor or cognitive features.

Methods:

Eight DLB, 7 PDD, 11 Parkinson disease (PD), 15 AD, and 37 normal control (NC) subjects underwent PiB-PET imaging and neuropsychological assessment. Amyloid burden was quantified using the PiB distribution volume ratio.

Results:

Cortical amyloid burden was higher in the DLB group than in the PDD group, comparable to the AD group. Amyloid deposition in the PDD group was low, comparable to the PD and NC groups. Relative to global cortical retention, occipital PiB retention was lower in the AD group than in the other groups. For the DLB, PDD, and PD groups, amyloid deposition in the parietal (lateral and precuneus)/posterior cingulate region was related to visuospatial impairment. Striatal PiB retention in the DLB and PDD groups was associated with less impaired motor function.

Conclusions:

Global cortical amyloid burden is high in dementia with Lewy bodies (DLB) but low in Parkinson disease dementia. These data suggest that β-amyloid may contribute selectively to the cognitive impairment of DLB and may contribute to the timing of dementia relative to the motor signs of parkinsonism.

GLOSSARY

= Automated Anatomic Labeling;

= Alzheimer disease;

= Alzheimer’s Disease Research Center;

= American version of the National Adult Reading Test;

= analysis of covariance;

= Blessed Dementia Scale;

= cerebral amyloid angiopathy;

= Clinical Dementia Rating;

= Clinical Dementia Rating Sum of Boxes;

= dementia with Lewy bodies;

= distribution volume ratio;

= Cued Selective Reminding Test;

= Free Selective Reminding Test;

= Hoehn and Yahr;

= Massachusetts General Hospital;

= Mini-Mental State Examination;

= normal control;

= neurofibrillary tangle;

= Neuropsychiatric Inventory Questionnaire;

= not significant;

= Parkinson disease;

= Parkinson disease dementia;

= Pittsburgh Compound B;

= region of interest;

= Statistical Parametric Mapping;

= UK Parkinson’s Disease Society Brain Bank Research Center;

= United Parkinson’s Disease Rating Scale;

= Wechsler Adult Intelligence Scale–Revised.

The Alzheimer’s Disease Neuroimaging Initiative (ADNI) beginning in October 2004, is a 6-year re-search project that studies changes of cognition, function, brain structure and function, and biomarkers in elderly controls, subjects with mild cognitive impairment, and subjects with Alzheimer’s disease (AD). A major goal is to determine and validate MRI, PET images, and cerebrospinal fluid (CSF)/blood biomarkers as predictors and outcomes for use in clinical trials of AD treatments. Structural MRI, FDG PET, C-11 Pittsburgh compound B (PIB) PET, CSF measurements of amyloid β (Aβ) and species of tau, with clinical/cognitive measurements were performed on elderly controls, subjects with mild cognitive impairment, and subjects with AD. Structural MRI shows high rates of brain atrophy, and has high statistical power for determining treatment effects. FDG PET, C-11 Pittsburgh compound B PET, and CSF measurements of Aβ and tau were significant predictors of cognitive decline and brain atrophy. All data are available at UCLA/LONI/ADNI, without embargo. ADNI-like projects started in Australia, Europe, Japan, and Korea. ADNI provides significant new information concerning the progression of AD.

Alzheimer’s disease is known to be the most common form of dementia in the elderly. It is clinically characterized by impairment of cognitive functions, as well as changes in personality, behavioral disturbances and an impaired ability to perform activities of daily living. To date, there are no effective ways to cure or reverse the disease. Genetic studies of early-onset familial Alzheimer’s disease cases revealed causative mutations in the genes encoding β-amyloid precursor protein and the γ-secretase-complex components presenilin-1 and presenilin-2, supporting an important role of β-amyloid in the pathogenesis of Alzheimer’s disease. Compromised function of the choroid plexus and defective cerebrospinal fluid production and turnover, with diminished clearance of β-amyloid, may play an important role in late-onset forms of Alzheimer’s disease. If reduced cerebrospinal fluid turnover is a risk factor for Alzheimer’s disease, then therapeutic strategies to improve cerebrospinal fluid flow are reasonable. However, the role of deficient cerebrospinal fluid dynamics in Alzheimer’s disease and the relevance of choroidal proteins as potential therapeutic targets to enhance cerebrospinal fluid turnover have received relatively little research attention. In this paper, we discuss several choroidal proteins, such as Na+-K+ ATPase, carbonic anhydrase, and aquaporin 1, that may be targets for pharmacological up-regulation of cerebrospinal fluid formation. The search for potentially beneficial drugs useful to ameliorate Alzheimer’s disease by facilitating cerebrospinal fluid production and turnover may be an important area for future research. However, the ultimate utility of such modulators in the management of Alzheimer’s disease remains to be determined. Here, we hypothesize that caffeine, the most commonly used psychoactive drug in the world, may be an attractive therapeutic candidate for treatment of Alzheimer’s disease since long-term caffeine consumption may augment cerebrospinal fluid production. Other potential mechanisms of cognitive protection by caffeine have been suggested by recent studies.

Objective

To determine whether preclinical Alzheimer’s disease (AD), as detected by the amyloid imaging agent Pittsburgh Compound B (PIB) in cognitively normal older adults, is associated with risk of symptomatic AD.

Design

A longitudinal cohort study of cognitively normal older adults assessed with positron emission tomography (PET) to determine the mean cortical binding potential for PIB and followed with annual clinical and cognitive assessments for progression to very mild dementia of the Alzheimer type (DAT).

Setting

Alzheimer’s Disease Research Center

Participants

One hundred and fifty-nine participants with mean age of 71.5 y in a longitudinal study of memory and aging had a PET PIB scan when cognitively normal with Clinical Dementia Rating (CDR) of 0.

Outcome Measure

Progression from CDR 0 status to CDR 0.5 (very mild dementia).

Results

Twenty-three participants progressed to CDR 0.5 at follow-up assessment (range: 1–5 assessments after PET PIB). Of these, 9 also were diagnosed with DAT. Higher MCBP values for PIB (hazard ratio 4.85, 95% CI, 1.22–19.01, p = .02) and age (hazard ratio 1.14, 95% CI 1.02–1.28, p = .03) predicted progression to CDR 0.5 DAT. The CDR 0.5 DAT group showed decline in three cognitive domains (episodic memory, semantic memory, and visuospatial performance) and had volume loss in the parahippocampal gyrus (includes entorhinal cortex) compared with individuals who remained CDR 0.

Conclusions

Preclinical AD, as detected by PET PIB, is not benign as it is associated with progression to symptomatic AD.

Objectives:

Diagnostic challenges exist for differentiating HIV dementia from Alzheimer disease (AD) in older HIV-infected (HIV+) individuals. Similar abnormalities in brain amyloid-β42 (Αβ42) metabolism may be involved in HIV-associated neuropathology and AD. We evaluated the amyloid-binding agent 11C-Pittsburgh compound B (11C-PiB), a biomarker for Αβ42 deposition, in cognitively unimpaired HIV+ (n = 10) participants and matched community controls without dementia (n = 20).

Methods:

In this case-control study, all participants had an 11C-PiB scan within 2 years of concomitant CSF studies and neuropsychometric testing. Statistical differences between HIV+ and community controls for demographic and clinical values were assessed by χ2 tests. Participants were further divided into either low (<500 pg/mL) or normal (≥500 pg/mL) CSF Αβ42 groups with Student t tests performed to determine if regional differences in fibrillar amyloid plaque deposition varied with CSF Αβ42.

Results:

Regardless of CSF Αβ42 level, none of the HIV+ participants had fibrillar amyloid plaques as assessed by increased 11C-PiB mean cortical binding potential (MCBP) or binding potential within 4 cortical regions. In contrast, some community controls with low CSF Αβ42 (<500 pg/mL) had high 11C-PiB MCBP with elevated binding potentials (>0.18 arbitrary units) within cortical regions.

Conclusions:

Cognitively unimpaired HIV+ participants, even with low CSF Αβ42 (<500 pg/mL), do not have 11C-PiB parameters suggesting brain fibrillar amyloid deposition. The dissimilarity between unimpaired HIV+ and preclinical AD may reflect differences in Aβ42 production and/or formation of diffuse plaques. Future longitudinal studies of HIV+ participants with low CSF Aβ42 and normal 11C-PiB are required.

GLOSSARY

= amyloid-β42;

= Alzheimer disease;

= antiretroviral therapy;

= Clinical Dementia Rating;

= CNS Highly Activated Retroviral Therapy Effects Research;

= global deficit score;

= HIV-associated neurocognitive disorder;

= lumbar puncture;

= mean cortical binding potential;

= Pittsburgh compound B;

= region of interest;

= Washington University in St. Louis.

Plasma sphingolipids have been shown to predict cognitive impairment and hippocampal volume loss, but there is little research in patients with Alzheimer’s disease dementia (AD). In this study we sought to determine whether plasma ceramides, dihydroceramides (DHCer), sphingomyelins (SM), or dihydrosphingomyelin (DHSM) levels and ratios of SM/ceramide or DHSM/DHCer were predictive of progression in AD. Probable AD patients (n=120) were enrolled in the Alzheimer’s Disease and Memory Disorders Center at Baylor College of Medicine. Plasma sphingolipids were assessed using ESI/MS/MS. Linear mixed effects models were used to examine the relation between baseline plasma sphingolipid levels and cross-sectional and longitudinal performance on the Mini-Mental State Exam (MMSE), Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and Clinical Dementia Rating-Sum of Boxes (CDR-Sum). Participants were followed a mean of 4.2 visits and 2.3 years. There were no cross-sectional associations. In longitudinal analyses, high levels of DHCer and ceramide were associated with greater progression, but findings did not reach significance (p>0.05). In contrast, higher plasma levels of SM, DHSM, SM/ceramide and DHSM/DHCer ratios were associated with less progression on the MMSE and ADAS-Cog; the ratios were the strongest predictors of clinical progression. Compared to the lowest tertiles, the highest tertiles of DHSM/DHCer and SM/ceramide ratios declined 1.35 points (p=0.001) and 1.19 (p=0.004) less per year on the MMSE and increased 3.18 points (p=0.001) and 2.42 (p=0.016) less per year on the ADAS-Cog. These results suggest that increased SM/ceramide and DHSM/DHCer ratios dose-dependently predict slower progression among AD patients and may be sensitive blood-based biomarkers for clinical progression.

Background:

Early screenings involving biomarkers and use of potential disease-modifying therapies (DMTs) may have significant humanistic implications for treatment strategies in Alzheimer’s disease.

Methods:

Markov models simulated transitions of patient cohorts beginning in predementia, a hypothetical early stage of Alzheimer’s disease marked by objective cognitive impairment/memory complaints without functional impairment, and followed for 10 years. Hypothetical cohorts of 10,000 patients included those who were treated with standard of care (donepezil) upon reaching mild–moderate Alzheimer’s disease, a DMT in predementia, and a DMT in mild-moderate Alzheimer’s disease. Transition probabilities were based on data from the Alzheimer’s Disease Neuroimaging Initiative and published clinical data, and estimated for the hypothetical DMT. In each disease stage (predementia, mild, moderate, or severe), time was computed and costs were estimated using literature review and published data, and published data provided mortality rates. The impact of screening was evaluated using positive predictive value (patients identified as predementia truly at risk for transition to dementia).

Results:

Earlier treatment yielded modest gains in total life-years; however, the distribution was skewed towards milder disease. Assuming a 25% reduction in the annual risk of progression, treating predementia patients with DMT increased life-years in predementia to mild states on average from 3.2 to 4.2, while life-years spent in moderate-to-severe Alzheimer’s disease decreased from 2.6 to 2.2. Average time in the community increased from 4.4 to 5.4 years, while time in long-term care declined from 1.3 to 0.9 years. This impact grows as the advantage of the novel agent increases. Screening accuracy had significant implications for cost-effectiveness.

Conclusion:

If screening can accurately identify predementia patients at risk for progression, earlier treatment with DMTs has the potential benefit to patients of prolonging time in milder disease, reducing time spent with more severe disease, increasing time in the community, and reducing time in long-term care.

The National Institute on Aging and the Alzheimer’s Association charged a workgroup with the task of developing criteria for the symptomatic predementia phase of Alzheimer’s disease (AD), referred to in this article as mild cognitive impairment due to AD. The workgroup developed the following two sets of criteria: (1) core clinical criteria that could be used by healthcare providers without access to advanced imaging techniques or cerebrospinal fluid analysis, and (2) research criteria that could be used in clinical research settings, including clinical trials. The second set of criteria incorporate the use of biomarkers based on imaging and cerebrospinal fluid measures. The final set of criteria for mild cognitive impairment due to AD has four levels of certainty, depending on the presence and nature of the biomarker findings. Considerable work is needed to validate the criteria that use biomarkers and to standardize biomarker analysis for use in community settings.

The Philadelphia Brief Assessment of the Cognition (PBAC) is a brief dementia-screening instrument. The PBAC assesses five cognitive domains: working memory/executive control; lexical retrieval/language; visuospatial/visuoconstructional operations; verbal/visual episodic memory; and behavior/social comportment. A revised version of the PBAC was administered to 198 participants including patients with Alzheimer’s disease (AD) (n=46) and four groups of patients with frontotemporal dementia (FTD) syndromes: behavioral-variant FTD (bvFTD; n=65), semantic-variant primary progressive aphasia (PPA) (svPPA; n=22), non-fluent/agrammatic-variant PPA (nfaPPA; n=23), and corticobasal syndrome (CBS; n=42), and a group of normal controls (n=15). The total PBAC score was highly correlated with the MMSE. The criterion validity of the PBAC was assessed relative to standard neuropsychological test performance. Using standard neuropsychological test performance as a criterion, the total PBAC score accurately identified the presence and severity of dementia. Intra-class correlations between PBAC subscales and standard neuropsychological tests were highly significant. PBAC subscales demonstrated good clinical utility in distinguishing AD and FTD subtypes using receiver operating characteristic analysis and standard diagnostic performance statistics to determine optimal subscale cut scores. The PBAC is a valid tool and able to assesses differential patterns neuropsychological/behavioral impairment in a broad range of neurodegenerative conditions.

Objective

To identify biomarker patterns typical for Alzheimer disease (AD) in an independent, unsupervised way, without using information on the clinical diagnosis.

Design

Mixture modeling approach.

Setting

Alzheimer’s Disease Neuroimaging Initiative database.

Patients or Other Participants

Cognitively normal persons, patients with AD, and individuals with mild cognitive impairment.

Main Outcome Measures

Cerebrospinal fluid–derived β-amyloid protein 1–42, total tau protein, and phosphorylated tau181P protein concentrations were used as biomarkers on a clinically well-characterized data set. The outcome of the qualification analysis was validated on 2 additional data sets, 1 of which was autopsy confirmed.

Results

Using the US Alzheimer’s Disease Neuroimaging Initiative data set, a cerebrospinal fluid β-amyloid protein 1–42/phosphorylated tau181P biomarker mixture model identified 1 feature linked to AD, while the other matched the “healthy” status. The AD signature was found in 90%, 72%, and 36% of patients in the AD, mild cognitive impairment, and cognitively normal groups, respectively. The cognitively normal group with the AD signature was enriched in apolipoprotein E ε4 allele carriers. Results were validated on 2 other data sets. In 1 study consisting of 68 autopsy-confirmed AD cases, 64 of 68 patients (94% sensitivity) were correctly classified with the AD feature. In another data set with patients (n = 57) with mild cognitive impairment followed up for 5 years, the model showed a sensitivity of 100% in patients progressing to AD.

Conclusions

The mixture modeling approach, totally independent of clinical AD diagnosis, correctly classified patients with AD. The unexpected presence of the AD signature in more than one-third of cognitively normal subjects suggests that AD pathology is active and detectable earlier than has heretofore been envisioned.

Background: Anosognosia is a common manifestation of Alzheimer's disease. There is an association between impaired awareness and frontal-executive cognitive deficits. Anosognosia is also correlated with decreased metabolism in the right hemisphere, particularly in frontal lobe regions.

Objective: To investigate pathological correlates of anosognosia in Alzheimer's disease.

Design: 41 subjects followed longitudinally in the University of Pittsburgh memory disorders clinic and with necropsy verified Alzheimer's disease were divided into two groups, based on previous clinical assessment: +Aware (n = 23) and –Aware (n = 18). A subset analysis matching subjects for dementia severity using mini-mental state examination scores was also carried out (13 +Aware; 13 –Aware). Histopathological data from necropsy brain tissue consisted of senile plaque (SP) and neurofibrillary tangle (NFT) counts (regional density) from four different brain regions in the right and left hemispheres: superior and middle frontal gyri (SMF), superior temporal isocortex (ST), the prosubiculum of the hippocampus (PRO), and the entorhinal cortex (EC).

Results: SP density was greater in the right PRO region of –Aware subjects (F = 6.54, p = 0.015) than +Aware subjects. Significant differences between SP or NFT density were not observed in any other regions. In the subset analysis matching for dementia severity, SP density was again greater in the right PRO region of –Aware subjects than in the other regions (F = 12.72, p = 0.002).

Conclusions: Increased SP density in the right PRO region suggests that selective pathological involvement of this area contributes to awareness deficits in Alzheimer's disease. The putative role of the PRO in self appraisal may reflect its interconnections with other medial temporal and prefrontal regions.

Background:

PET imaging using [18F]fluorodeoxyglucose (FDG) and [11C]Pittsburgh compound B (PIB) have been proposed as biomarkers of Alzheimer disease (AD), as have CSF measures of the 42 amino acid β-amyloid protein (Aβ1-42) and total and phosphorylated tau (t-tau and p-tau). Relationships between biomarkers and with disease severity are incompletely understood.

Methods:

Ten subjects with AD, 11 control subjects, and 34 subjects with mild cognitive impairment from the Alzheimer’s Disease Neuroimaging Initiative underwent clinical evaluation; CSF measurement of Aβ1-42, t-tau, and p-tau; and PIB-PET and FDG-PET scanning. Data were analyzed using continuous regression and dichotomous outcomes with subjects classified as “positive” or “negative” for AD based on cutoffs established in patients with AD and controls from other cohorts.

Results:

Dichotomous categorization showed substantial agreement between PIB-PET and CSF Aβ1-42 measures (91% agreement, κ = 0.74), modest agreement between PIB-PET and p-tau (76% agreement, κ = 0.50), and minimal agreement for other comparisons (κ <0.3). Mini-Mental State Examination score was significantly correlated with FDG-PET but not with PIB-PET or CSF Aβ1-42. Regression models adjusted for diagnosis showed that PIB-PET was significantly correlated with Aβ1-42, t-tau, and p-tau181p, whereas FDG-PET was correlated only with Aβ1-42.

Conclusions:

PET and CSF biomarkers of Aβ agree with one another but are not related to cognitive impairment. [18F]fluorodeoxyglucose-PET is modestly related to other biomarkers but is better related to cognition. Different biomarkers for Alzheimer disease provide different information from one another that is likely to be complementary.

GLOSSARY

β1-42 = 42 amino acid β-amyloid protein;

= Alzheimer disease;

= Alzheimer’s Disease Neuroimaging Initiative;

= Clinical Dementia Rating;

= confidence interval;

= [18F]fluorodeoxyglucose;

= mild cognitive impairment;

= Mini-Mental State Examination;

= magnetic resonance;

= [11C]Pittsburgh compound B;

= phosphorylated tau;

= receiver operating characteristic;

= region of interest;

= standardized uptake value ratio;

= total tau;

= Wechsler Memory Scale–Revised.

OBJECTIVE: To examine neuropsychological and neuropsychiatric differences between patients with probable Alzheimer's disease and patients with Parkinson's disease and dementia. METHODS: Thirty three patients with probable Alzheimer's disease and 33 patients with Parkinson's disease and dementia were matched for age, sex, and mini mental state examination scores and given a battery of neuropsychological and neuropsychiatric tests. RESULTS: Patients with Parkinson's disease with dementia had a significantly higher prevalence of major depression than patients with Alzheimer's disease; patients with Alzheimer's disease showed more severe anosognosia and disinhibition than patients with Parkinson's disease. Whereas no significant between group differences were found on tests of memory and language, demented patients with Parkinson's disease had a significantly greater impairment on a test of visual reasoning than patients with Alzheimer's disease. CONCLUSION: There were significant psychiatric differences between patients with Alzheimer's disease and demented patients with Parkinson's disease, but neuropsychological differences were restricted to a single cognitive domain.