Pittsburgh compound B retention and progression of cognitive status – a meta‐analysis

Our aim was to conduct a meta‐analysis of longitudinal studies assessing the association between Pittsburgh compound B (PiB) retention and the progression of cognitive status in healthy elderly, in patients with mild cognitive impairment (MCI) and in patients with Alzheimer's disease (AD). PubMed, MEDLINE, Embase and the Cochrane Library up to April 2013 were searched for studies reporting PiB retention at baseline and conversion of clinical status at follow‐up, with manual searches of bibliographies of key retrieved articles and relevant reviews. Two independent reviewers extracted data on individual numbers with PiB positive or negative status at baseline and corresponding numbers of patients with cognitive decline at follow‐up (conversion from healthy elderly to MCI or AD, or from MCI to AD, or a Mini‐Mental State Examination decline >3 for AD patients). Relative risks were pooled using fixed‐effects or random‐effects models as appropriate. Associations were tested in subgroups representing three different phases of AD. Publication bias was evaluated with funnel plots. Twelve cohort studies including 1275 participants were included with a follow‐up period ranging from 1 to 3.8 years. The pooled adjusted relative risks were 3.75 (95% confidence interval 2.76–5.09; P for heterogeneity 0.16; fixed‐effects model) for disease progression, 1.73 (0.63–4.75; P for heterogeneity 0.27; fixed‐effects model) for AD patients (four studies), 4.03 (2.68–6.07; P for heterogeneity 0.49; fixed‐effects model) for MCI patients (eight studies) and 3.67 (2.25–5.99; P for heterogeneity 0.26; fixed‐effects model) for disease progression in healthy elderly (six studies). Baseline PiB positive status is associated with a significantly increased risk of cognitive progression in healthy elderly and MCI patients.     

A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer's disease

There is increasing evidence that subjective cognitive decline (SCD) in individuals with unimpaired performance on cognitive tests may represent the first symptomatic manifestation of Alzheimer's disease (AD). The research on SCD in early AD, however, is limited by the absence of common standards. The working group of the Subjective Cognitive Decline Initiative (SCD-I) addressed this deficiency by reaching consensus on terminology and on a conceptual framework for research on SCD in AD. In this publication, research criteria for SCD in pre-mild cognitive impairment (MCI) are presented. In addition, a list of core features proposed for reporting in SCD studies is provided, which will enable comparability of research across different settings. Finally, a set of features is presented, which in accordance with current knowledge, increases the likelihood of the presence of preclinical AD in individuals with SCD. This list is referred to as SCD plus.     

Discriminating Alzheimer's disease progression using a new hippocampal marker from T1‐weighted MRI: The local surface roughness

Hippocampal atrophy is one of the main hallmarks of Alzheimer's disease (AD). However, there is still controversy about whether this sign is a robust finding during the early stages of the disease, such as in mild cognitive impairment (MCI) and subjective cognitive decline (SCD). Considering this background, we proposed a new marker for assessing hippocampal atrophy: the local surface roughness (LSR). We tested this marker in a sample of 307 subjects (normal control (NC) = 70, SCD = 87, MCI = 137, AD = 13). In addition, 97 patients with MCI were followed‐up over a 3‐year period and classified as stable MCI (sMCI) (n = 61) or progressive MCI (pMCI) (n = 36). We did not find significant differences using traditional markers, such as normalized hippocampal volumes (NHV), between the NC and SCD groups or between the sMCI and pMCI groups. However, with LSR we found significant differences between the sMCI and pMCI groups and a better ability to discriminate between NC and SCD. The classification accuracy of the LSR for NC and SCD was 68.2%, while NHV had a 57.2% accuracy. In addition, the classification accuracy of the LSR for sMCI and pMCI was 74.3%, and NHV had a 68.3% accuracy. Cox proportional hazards models adjusted for age, sex, and education were used to estimate the relative hazard of progression from MCI to AD based on hippocampal markers and conversion times. The LSR marker showed better prediction of conversion to AD than NHV. These results suggest the relevance of considering the LSR as a new hippocampal marker for the AD continuum.     

Predictors of future cognitive decline in persons with mild cognitive impairment

This study sought first to identify individual items of the Mini-Mental State Examination (MMSE) and demographic variables at baseline that predicted the trajectories of cognitive change among patients with mild cognitive impairment (MCI), and second to quantify the risk of cognitive decline in such patients based on their pattern of failure of MMSE items. 187 MCI patients were evaluated serially with the MMSE for up to 3.5 years. Patients who followed a declining cognitive trajectory differed from the stable reference group in their baseline profile of MMSE test performance. Patient age and performance on delayed recall, constructional praxis, attention, and orientation to time and floor predicted future cognitive decline with good accuracy (79.9%) and specificity (86.4%), and moderate sensitivity (67.2%). These results are presented in the form of a simple clinical tool for quantifying risk of future cognitive decline in MCI.     

CSF tau protein phosphorylated at threonine 231 correlates with cognitive decline in MCI subjects

In this longitudinal study of 77 patients with mild cognitive impairment (MCI), the authors analyzed whether levels of tau protein phosphorylated at threonine 231 (p-tau(231)) in CSF correlate with progression of cognitive decline. High CSF p-tau(231) levels at baseline, but not total tau protein levels, correlated with cognitive decline and conversion from MCI to AD. Independently, old age and APOE-epsilon 4 carrier status were predictive as well. Our data indicate that an increased p-tau(231) level is a potential risk factor for cognitive decline in patients with MCI.     

The dual role of cognitive reserve in subjective cognitive decline and mild cognitive impairment: a 7-year follow-up study

Journal of Neurology - The aim of this study was to evaluate the effect of cognitive reserve (CR), in progression from subjective cognitive decline (SCD) to mild cognitive impairment (MCI) and...     

Evaluation of a computerized test system to screen for mild cognitive impairment

Background: Mild cognitive impairment (MCI) refers to the clinical condition between normal aging and Alzheimer's disease (AD) and has a high probability of developing into AD. Early detection of MCI is important because early detection and appropriate follow‐up treatment can prevent the disease from progressing. Therefore, MCI is an important candidate for screening and possible intervention. Methods: We have developed a computerized screening test system to identify cognitive decline. This system consists of six tests (age and year‐of‐birth validity test, three‐word memory test, time orientation test, first modified delayed‐recall test, visual working memory test and second modified delayed‐recall test). The scores obtained from three groups (MCI patients, AD patients and healthy control subjects) were analyzed to evaluate the sensitivity and specificity required for the screening of MCI. Results: The system was well accepted by the patients. All of the test procedures were completed within 5 min. Significant group differences in all test results were found. The system has sensitivity and specificity values of 82% and 87%, respectively, when used as a screen for MCI. Conclusion: The system is useful for the screening of cognitive disorders.     

Plasma ceramides are altered in mild cognitive impairment and predict cognitive decline and hippocampal volume loss

BackgroundA blood-based biomarker of Alzheimer's disease (AD) would be superior to cerebrospinal fluid (CSF) and neuroimaging measures in terms of cost, invasiveness, and feasibility for repeated measures. We previously reported that blood ceramides varied in relation to timing of memory impairment in a population-based study. The present objective was to examine whether plasma ceramides varied by AD severity in a well-characterized clinic sample and were associated with cognitive decline and hippocampal volume loss over 1 year.MethodsParticipants included 25 normal controls (NC), 17 amnestic Mild Cognitive Impairment (MCI), and 21 early probable AD. A thorough neuropsychological battery and neuroimaging with hippocampal volume determination were conducted at baseline and 1 year later. Plasma ceramides were assayed at baseline using high performance liquid chromatography coupled electrospray ionization tandem mass spectrometry.ResultsAlthough all saturated ceramides were lower in MCI compared with AD at baseline, ceramides C22:0 and C24:0 were significantly lower in the MCI group compared with both NC and AD groups (P < .01). Ceramide levels did not differ (P > .05) in AD versus NC. There were no cross-sectional associations between ceramides C22:0 and C24:0 and either cognitive performance or hippocampal volume among any group. However, among the MCI group, higher baseline ceramide C22:0 and C24:0 levels were predictive of cognitive decline and hippocampal volume loss 1 year later.ConclusionResults suggest that very long-chain plasma ceramides C22:0 and C24:0 are altered in MCI and predict memory loss and right hippocampal volume loss among subjects with MCI. These plasma ceramides may be early indicators of AD progression.     

Rate of progression of cognitive decline in Alzheimer's disease: effect of butyrylcholinesterase K gene variation

OBJECTIVE: To determine whether individuals with Alzheimer's disease (AD) and the K variant allele of butyrylcholinesterase have a slower rate of cognitive decline than those without the K variant allele of butyrylcholinesterase. METHOD: The cognitive status of 339 community based subjects with AD was assessed with the Mini Mental State Examination at baseline and yearly over a three year follow up period. The rates of cognitive decline of subjects with and without the K variant allele were compared. RESULT: Presence of the K allele was associated with a slower average rate of cognitive decline in subjects with severe AD. CONCLUSIONS: This finding is consistent with the suggestion that the K variant of butyrylcholinesterase has an important role in disease progression in AD, and this may have implications for treatment.     

Clinical trials in mild cognitive impairment: lessons for the future

Mild cognitive impairment (MCI) is an operational definition for a cognitive decline in individuals with a greater risk of developing dementia. The amnestic subtype of MCI is of particular interest because these individuals most likely progress to Alzheimer's disease (AD). Currently hypothesised therapeutic approaches in MCI are mainly based on AD treatment strategies. Long term secondary prevention randomised clinical trials have been completed in amnestic MCI populations, encompassing agents with various mechanisms of action: acetylcholinesterase inhibitors (donepezil, rivastigmine, galantamine), antioxidants (vitamin E), anti-inflammatories (rofecoxib), and nootropics (piracetam). The design of clinical trials in MCI is influenced by study objectives and definition of primary end points: time to clinical diagnosis of dementia, and AD in particular, or symptom progression. As none of the drugs previously shown to have clinical efficacy in AD trials or benefit in everyday practice have met the primary objectives of the respective trials, design of future clinical trials in MCI should be further developed particularly as regards the selection of more homogeneous samples at entry, optimal treatment duration, and multidimensional and reliable outcomes.     

FDG-PET measurement is more accurate than neuropsychological assessments to predict global cognitive deterioration in patients with mild cognitive impairment

The accurate prediction, at a pre-dementia stage of Alzheimer’s disease (AD), of the subsequent clinical evolution of patients would be a major breakthrough from both therapeutic and research standpoints. Amnestic mild cognitive impairment (MCI) is presently the most common reference to address the pre-dementia stage of AD. However, previous longitudinal studies on patients with MCI assessing neuropsychological and PET markers of future conversion to AD are sparse and yield discrepant findings, while a comprehensive comparison of the relative accuracy of these two categories of measure is still lacking. In the present study, we assessed the global cognitive decline as measured by the Mattis scale in 18 patients with amnestic MCI over an 18-month follow-up period, studying which subtest of this scale showed significant deterioration over time. Using baseline measurements from neuropsychological evaluation of memory and PET, we then assessed significant markers of global cognitive change, that is, percent annual change in the Mattis scale total score, and searched for the best predictor of this global cognitive decline. Altogether, our results revealed significant decline over the 18-month follow-up period in the total score and the verbal initiation and memory-recall subscores of the Mattis scale. The percent annual change in the total Mattis score significantly correlated with age and baseline performances in delayed episodic memory recall as well as semantic autobiographical and category word fluencies. Regarding functional imaging, significant correlations were also found with baseline PET values in the right temporo-parietal and medial frontal areas. Age and right temporo-parietal PET values were the most significant predictors of subsequent global cognitive decline, and the only ones to survive stepwise regression analyses. Our findings are consistent with previous works showing predominant delayed recall and semantic memory impairment at a pre-dementia stage of AD, as well as early metabolic defects in the temporo-parietal associative cortex. However, they suggest that only the latter predictor is specifically and accurately associated with subsequent cognitive decline in patients with MCI within 18 months of first assessment.     

FDG-PET measurement is more accurate than neuropsychological assessments to predict global cognitive deterioration in patients with mild cognitive impairment

The accurate prediction, at a pre-dementia stage of Alzheimer's disease (AD), of the subsequent clinical evolution of patients would be a major breakthrough from both therapeutic and research standpoints. Amnestic mild cognitive impairment (MCI) is presently the most common reference to address the pre-dementia stage of AD. However, previous longitudinal studies on patients with MCI assessing neuropsychological and PET markers of future conversion to AD are sparse and yield discrepant findings, while a comprehensive comparison of the relative accuracy of these two categories of measure is still lacking. In the present study, we assessed the global cognitive decline as measured by the Mattis scale in 18 patients with amnestic MCI over an 18-month follow-up period, studying which subtest of this scale showed significant deterioration over time. Using baseline measurements from neuropsychological evaluation of memory and PET, we then assessed significant markers of global cognitive change, that is, percent annual change in the Mattis scale total score, and searched for the best predictor of this global cognitive decline. Altogether, our results revealed significant decline over the 18-month follow-up period in the total score and the verbal initiation and memory-recall subscores of the Mattis scale. The percent annual change in the total Mattis score significantly correlated with age and baseline performances in delayed episodic memory recall as well as semantic autobiographical and category word fluencies. Regarding functional imaging, significant correlations were also found with baseline PET values in the right temporo-parietal and medial frontal areas. Age and right temporo-parietal PET values were the most significant predictors of subsequent global cognitive decline, and the only ones to survive stepwise regression analyses. Our findings are consistent with previous works showing predominant delayed recall and semantic memory impairment at a pre-dementia stage of AD, as well as early metabolic defects in the temporo-parietal associative cortex. However, they suggest that only the latter predictor is specifically and accurately associated with subsequent cognitive decline in patients with MCI within 18 months of first assessment.     

Impaired cerebral glucose metabolism and cognitive functioning predict deterioration in mild cognitive impairment

The objective of this study was to assess whether reduced glucose metabolism (rCMRGlu) and cognitive functioning could predict development of Alzheimer's disease (AD) in subjects with mild cognitive impairment (MCI). Twenty MCI patients underwent baseline and follow-up investigations of rCMRGlu, as measured by PET, and cognitive function measured by neuropsychological test assessments. Subjects were clinically followed up with an average interval of 36.5 months. Two groups were obtained after the second clinical assessment. Nine patients were diagnosed as AD and classified as progressive MCI (P-MCI), whereas 11 patients remained clinically stable and were classified as stable MCI (S-MCI). There were no differences in demographic variables or baseline MMSE between the two subgroups. Logistic regression indicated the two variables that most effectively predicted future development of AD were rCMRGlu from the left temporoparietal area and performance on the block design. These combined measures gave an optimal 90% correct classification rate, whereas only rCMRGlu or neuropsychology alone gave 75% and 65% correct classification, respectively. Measures of temporoparietal cerebral metabolism and visuospatial function may aid in predicting the evolution to AD for patients with MCI.     

A two-year follow-up of cognitive deficits and brain perfusion in mild cognitive impairment and mild Alzheimer's disease

The 15-Objects Test (15-OT) provides useful gradation of visuoperceptual impairment from normal aging through Alzheimer's disease (AD) and correlates with temporo-parietal perfusion. The objectives of this study were to analyze progression of 15-OT performance in mild cognitive impairment (MCI) and AD, and its correlates with cognition and single photon emission computerized tomography (SPECT), as well as to examine neuropsychological and SPECT differences between the MCI patients who developed AD and those who did not. From the initial 126 participants (42/group), 38 AD, 39 MCI, and 38 elderly controls (EC) were reassessed (SPECT: 35 AD, 33 MCI, 35 EC) after two years. The progression of cognitive and SPECT scores during this period was compared between groups, and baseline data between converters and non-converters. The 15-OT was the only measure of progression that differed between the three groups; worsening scores on 15-OT were associated with worsening in verbal and visual retention, and decreased perfusion on left postsubicular area. In the MCI patients, cerebral perfusion fell over the two years in medial-posterior cingulate and fronto-temporo-parietal regions; AD showed extensive changes involving almost all cerebral regions. No SPECT changes were detected in controls. At baseline, the MCI patients who developed AD differed from non-converters in verbal recognition memory, but not in SPECT perfusion. In conclusion, SPECT and 15-OT appear to provide a potential measure to differentiate between normal aging, MCI, and AD. Worsening on 15-OT was related to decreased perfusion in postsubicular area; but further longitudinal studies are needed to determine the contribution of 15-OT as a predictor of AD from MCI.     

Complexity changes in preclinical Alzheimer’s disease: An MEG study of subjective cognitive decline and mild cognitive impairment

ObjectiveTo analyse magnetoencephalogram (MEG) signals with Lempel-Ziv Complexity (LZC) to identify the regions of the brain showing changes related to cognitive decline and Alzheimeŕs Disease (AD).MethodsLZC was used to study MEG signals in the source space from 99 participants (36 male, 63 female, average age: 71.82 ± 4.06) in three groups (33 subjects per group): healthy (control) older adults, older adults with subjective cognitive decline (SCD), and adults with mild cognitive impairment (MCI). Analyses were performed in broadband (2–45 Hz) and in classic narrow bands (theta (4–8 Hz), alpha (8–12 Hz), low beta (12–20 Hz), high beta (20–30 Hz), and, gamma (30–45 Hz)).ResultsLZC was significantly lower in subjects with MCI than in those with SCD. Moreover, subjects with MCI had significantly lower MEG complexity than controls and SCD subjects in the beta frequency band. Lower complexity was correlated with smaller hippocampal volumes.ConclusionsBrain complexity – measured with LZC – decreases in MCI patients when compared to SCD and healthy controls. This decrease is associated with a decrease in hippocampal volume, a key feature in AD progression.SignificanceThis is the first study to date characterising the changes of brain activity complexity showing the specific spatial pattern of the alterations as well as the morphological correlations throughout preclinical stages of AD.     

Mild cognitive impairment: a cross-national comparison

OBJECTIVE: The main aim of this collaborative study was to assess the comparability of the most commonly used criteria for mild cognitive impairment (MCI) by comparing the cognitive performance of patients with MCI from the Mayo Clinic (USA) and the Karolinska Institutet (Sweden). METHODS: Standardised neuropsychological test scores were used to compare the two samples from the two institutions with regard to the number of cognitive domains in which performance was below 1.5 SD. Possible predictors for the conversion from MCI to Alzheimer's disease (AD) were assessed. RESULTS: When the two institutions were considered together in the Cox proportional hazard model, the number of affected cognitive domains below 1.5 SD was a significant predictor of time to AD diagnosis with age, education, and APOE epsilon4 genotype entered into the same model as covariates. The number of affected cognitive areas remained as a significant predictor when the institutions were considered separately. The logistic regression model of conversion to AD showed that only tests assessing learning and retention were predictors of developing AD. CONCLUSIONS: Differences in population as well as in methodology of case ascertainment as well as other aspects may account for the observed variability between samples of patients with MCI. The number of impaired cognitive factors at baseline can predict the progression from MCI to AD. Furthermore, tests assessing learning and retention are the best predictors for progression to AD.     

Clinical predictors of cognitive decline in patients with mild cognitive impairment: the Chongqing aging study

Mild cognitive impairment (MCI) is considered as the early stage of dementia which currently has no effective treatments. Reducing progression of cognitive decline at the MCI stage could be an important strategy for preventing conversion to dementia. The goal of this work was to screen for clinical predictors indicating the prognosis of MCI comprehensively; therefore, we assumed vascular risk factors (VRFs), carotid stenosis, and white matter changes (WMC) to be independent predictors. A total of 257 patients with MCI underwent collection of VRF information, neuropsychological evaluation, computed tomography angiography (CTA) to investigate carotid stenosis, and magnetic resonance imaging (MRI) to identify severity of WMC. After a 3-year follow-up period, the neuropsychological evaluation, CTA, and MRI were repeated to assess the progression of cognitive decline, carotid stenosis, and WMC. The conversion rate from MCI to dementia was 11.65% per year, and the conversion rate from MCI to Alzheimer's disease was 7.05% per year in our cohort. Cognitive decline (in terms of changes in Mini Mental State Examination scores) was associated with diabetes mellitus (p = 0.004), baseline WMC severity (p < 0.001), baseline carotid stenosis (p < 0.001), and WMC severity change (p < 0.001). Besides, diabetes, baseline WMC severity, baseline moderate-to-severe carotid stenosis, and carotid stenosis change during follow-up were predictors of conversion from MCI to dementia. Given the potential clinical predictors, our findings could imply that controlling blood glucose, removing carotid stenosis, and improving cerebral perfusion could be effective measures to delay cognitive decline in patients with MCI and prevent conversion from MCI to dementia.     

Cognitive decline and amyloid accumulation in patients with mild cognitive impairment

Background/Aims: The relationship between baseline (11)C-Pittsburgh compound B ((11)C-PIB) uptake and cognitive decline during a 2-year follow-up was studied in 9 patients with mild cognitive impairment (MCI) who converted to Alzheimer's disease (AD) and 7 who remained with MCI. Methods: (11)C-PIB PET scan was conducted at baseline and cognitive assessment both at baseline and at follow-up. To obtain quantitative regional values of (11)C-PIB uptake, automated region of interest analysis was done using spatially normalized parametric ratio (region-to-cerebellar cortex) images. Results: At baseline, there were statistically significant differences in (11)C-PIB uptake, but not in cognitive test performances between the converters and nonconverters. Memory and executive function declined only in the converters during follow-up. In the converters, lower baseline frontal (11)C-PIB uptake was associated with faster decline in verbal learning. Higher baseline uptake in the caudate nucleus was related to faster decline in memory consolidation, and higher temporal uptake was associated with decline in executive function. Conclusion: Higher (11)C-PIB uptake in the caudate nucleus and temporal lobe was related to decline in memory and executive functions, whereas lower frontal uptake was related to decline in verbal learning. The results indicate that in prodromal AD, frontal amyloid accumulation reaches its maximum in the MCI stage, characterized by memory problems without full-blown dementia.     

Aβ and cognitive change: Examining the preclinical and prodromal stages of Alzheimer's disease

BackgroundHigh β-amyloid (Aβ) is associated with faster memory decline in healthy individuals and adults with mild cognitive impairment (MCI). However, longer prospective studies are required to determine if Aβ-related memory decline continues and whether it is associated with increased rate of disease progression.MethodsHealthy controls (HCs; n = 177) and adults with MCI (n = 48) underwent neuroimaging for Aβ and cognitive assessment at baseline. Cognition was reassessed 18 and 36 months later.ResultsCompared with low-Aβ HCs, high-Aβ HC and MCI groups showed moderate decline in episodic and working memory over 36 months. Those with MCI with low Aβ did not show any cognitive decline. Rates of disease progression were increased in the high-Aβ HC and MCI groups.ConclusionsIn healthy individuals, high Aβ likely indicates that Alzheimer's disease (AD)-related neurodegeneration has begun. Once commenced, the rate of decline in cognitive function remains constant across the preclinical and prodromal stages of AD.