We investigated a simple imaging sign for Alzheimer's disease (AD), using diffusion tensor imaging (DTI). We hypothesized that a reduction in fractional anisotropy (FA) in the fornix could be utilized as an imaging sign.
Twenty-three patients with AD, 24 patients with amnestic mild cognitive impairment (aMCI), and 25 control participants (NC) underwent DTI at baseline and one year later. The diagnosis was re-evaluated one year and three years after the initial scan. A color-scaled FA map was used to visually identify the FA reduction (“fornix sign”). We investigated whether the fornix sign could differentiate AD from NC, and could predict progression from aMCI to AD or NC to aMCI. We also quantified FA of the fornix to validate the fornix sign.
The fornix sign was identical to the lack of any voxels with an FA > 0.52 within the fornix. The fornix sign differentiated AD from NC with specificity of 1.0 and sensitivity of 0.56. It predicted conversion from NC to aMCI with specificity of 1.0 and sensitivity of 0.67, and from aMCI to AD with specificity of 0.94 and sensitivity of 0.83.
The fornix sign is a promising predictive imaging sign of AD.
fornix sign; fractional anisotropy; diffusion tensor imaging; Alzheimer's disease; mild cognitive impairment
Previous studies have shown that high serum ceramides are associated with memory impairment and hippocampal volume loss, but have not examined dementia as an outcome. The aim of this study was to examine whether serum ceramides and sphingomyelins (SM) were associated with an increased risk of all-cause dementia and Alzheimer disease (AD).
Participants included 99 women without dementia aged 70–79, with baseline serum SM and ceramides, enrolled in a longitudinal population-based study and followed for up to 6 visits over 9 years. Baseline lipids, in tertiles, were examined in relation to all-cause dementia and AD using discrete time Cox proportional survival analysis. Lipids were analyzed using electrospray ionization tandem mass spectrometry.
Twenty-seven (27.3%) of the 99 women developed incident dementia. Of these, 18 (66.7%) were diagnosed with probable AD. Higher baseline serum ceramides, but not SM, were associated with an increased risk of AD; these relationships were stronger than with all-cause dementia. Compared to the lowest tertile, the middle and highest tertiles of ceramide d18:1–C16:0 were associated with a 10-fold (95% confidence interval [CI] 1.2–85.1) and 7.6-fold increased risk of AD (95% CI 0.9–62.1), respectively. The highest tertiles of ceramide d18:1–C24:0 (hazard ratio [HR] = 5.1, 95% CI 1.1–23.6) and lactosylceramide (HR = 9.8, 95% CI 1.2–80.1) were also associated with risk of AD. Total and high-density lipoprotein cholesterol and triglycerides were not associated with dementia or AD.
Results from this preliminary study suggest that particular species of serum ceramides are associated with incident AD and warrant continued examination in larger studies.
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
This paper examines the multiple atlas random diffeomorphic orbit model in Computational Anatomy (CA) for parameter estimation and segmentation of subcortical and ventricular neuroanatomy in magnetic resonance imagery. We assume that there exist multiple magnetic resonance image (MRI) atlases, each atlas containing a collection of locally-defined charts in the brain generated via manual delineation of the structures of interest. We focus on maximum a posteriori estimation of high dimensional segmentations of MR within the class of generative models representing the observed MRI as a conditionally Gaussian random field, conditioned on the atlas charts and the diffeomorphic change of coordinates of each chart that generates it. The charts and their diffeomorphic correspondences are unknown and viewed as latent or hidden variables. We demonstrate that the expectation-maximization (EM) algorithm arises naturally, yielding the likelihood-fusion equation which the a posteriori estimator of the segmentation labels maximizes. The likelihoods being fused are modeled as conditionally Gaussian random fields with mean fields a function of each atlas chart under its diffeomorphic change of coordinates onto the target. The conditional-mean in the EM algorithm specifies the convex weights with which the chart-specific likelihoods are fused. The multiple atlases with the associated convex weights imply that the posterior distribution is a multi-modal representation of the measured MRI. Segmentation results for subcortical and ventricular structures of subjects, within populations of demented subjects, are demonstrated, including the use of multiple atlases across multiple diseased groups.
Better tools for assessing cognitive impairment in the early stages of Alzheimer’s disease (AD) are required to enable diagnosis of the disease before substantial neurodegeneration has taken place and to allow detection of subtle changes in the early stages of progression of the disease. The National Institute on Aging and the Alzheimer’s Association convened a meeting to discuss state of the art methods for cognitive assessment, including computerized batteries, as well as new approaches in the pipeline. Speakers described research using novel tests of object recognition, spatial navigation, attentional control, semantic memory, semantic interference, prospective memory, false memory and executive function as among the tools that could provide earlier identification of individuals with AD. In addition to early detection, there is a need for assessments that reflect real-world situations in order to better assess functional disability. It is especially important to develop assessment tools that are useful in ethnically, culturally and linguistically diverse populations as well as in individuals with neurodegenerative disease other than AD.
The fornix is the predominant outflow tract of the hippocampus, a brain region known to be affected early in the course of Alzheimer’s disease (AD). The aims of the present study were to: 1) examine the cross-sectional relationship between fornix DTI measurements (fractional anisotropy (FA), and mean (MD), axial (DA) and radial (DR) diffusivities), hippocampal volume, and memory performance, and 2) compare fornix DTI measures to hippocampal volumes as predictors of progression and transition from amnestic mild cognitive impairment (MCI) to AD dementia.
23 MCI participants with baseline hippocampal volumetry and diffusion tensor imaging received detailed evaluations at baseline, 3, 6, 12 months, and 2.5 years. Six participants converted to AD over the follow-up. Fornix and posterior cingulum DTI measurements and hippocampal volumes were ascertained using manual measures. Random effects models assessed each of the neuroimaging measures as predictors of decline on the MMSE, CDR-Sum of boxes and Memory z-scores; ROC analyses examined the predictive value for conversion to AD.
There was a significant correlation between fornix FA and hippocampal volumes. However, only the fornix measurements (FA, MD, DR, DA) were cross-sectionally correlated with memory z-scores. Both fornix FA and hippocampal volumes were predictive of memory decline. Individually, fornix FA and MD and hippocampal volumes were very good predictors of progression with likelihood ratios>83, and better than 90% accuracy.
Fornix FA both cross-sectionally correlated with and longitudinally predicted memory decline and progression to AD. Manually-drawn fornix ROI shows comparable promise to hippocampal volume as a predictive biomarker of progression and warrants replication in a larger study.
Fornix; Hippocampus; Mild Cognitive Impairment; Biomarker; Diffusion tensor imaging
Neuropsychiatric symptoms (NPS) occur frequently in mild cognitive impairment (MCI) and Alzheimer’s dementia (AD). We examined the relationship between NPS and white matter integrity in these conditions. Twenty two individuals with MCI and 23 with mild AD underwent clinical assessments including the Neuropsychiatric Inventory Questionnaire and 3.0 Tesla magnetic resonance scans. Fractional anisotropy (FA) was measured in the following manually-drawn regions of interest (ROI): fornix, cingulum bundle, splenium, and cerebral peduncles (control region). The probability of having NPS by tertile of ROI FA was assessed using logistic regression. Because associations were similar within MCI and AD groups, the two groups were combined. Compared to those in the highest tertile, participants within the lowest anterior cingulum (AC) FA tertile were more likely to exhibit irritability, agitation, dysphoria, apathy, and nighttime behavioral disturbances (p<0.05). After adjusting for MMSE, participants in the lowest vs. highest tertile of AC FA were more likely to report irritability (OR: 7.21, p=0.041). Using DTI, low AC FA was associated with increased odds of irritability in mild AD and MCI participants. Further imaging studies are necessary to elucidate the role of the AC in the pathophysiology of NPS in AD and MCI.
Diffusion tensor imaging; Alzheimer’s disease; Mild cognitive impairment; Neuropsychiatric symptoms
To determine whether cerebrospinal fluid (CSF) biomarkers for Alzheimer disease fluctuate significantly over time in a cohort of older, mildly symptomatic individuals.
Biomarker validation in a clinical cohort.
University hospital inpatient unit.
Ten patients admitted for CSF drainage for diagnostic purposes.
Main Outcome Measures
The CSF levels of Aβ1–40, Aβ1–42, tau, and phosphorylated tau on threonine 181 (p-tau181) were measured every 6 hours for 24 or 36 hours.
The mean coefficient of variation values for each biomarker assessed in our 10 patients were 5.5% (95% CI, 3.8%–10.0%) for Aβ1–42, 12.2% (9.0%–24.2%) for Aβ1–40, 8.2% (5.7%–15.1%) for total tau, and 11.9% (8.5%–23.0%) for p-tau181. These values are only slightly higher than the variability in the assay. In addition, no significant circadian fluctuation in any Alzheimer disease biomarker was observed given the limitations of our sampling frequency.
In a cohort of elderly patients, little fluctuation in the levels of important Alzheimer disease biomarkers in lumbar CSF is seen as a function of time.
This study explores the longitudinal relationship between patient characteristics and use of four drug classes (antihypertensives, antidepressants, antipsychotics, and hormones) that showed significant changes in use rates over time in patients with Alzheimer’s disease (AD). Patient/caregiver-reported prescription medication usage was categorized by drug class for 201 patients from the Predictors Study. Patient characteristics included use of cholinesterase inhibitors and/or memantine, function, cognition, living situation, baseline age, and gender. Assessment interval, year of study entry, and site were controlled for. Before adjusting for covariates, use increased for antihypertensives (47.8% to 62.2%), antipsychotics (3.5% to 27.0%), and antidepressants (32.3% to 40.5%); use of hormones decreased (19.4% to 5.4%). After controlling for patient characteristics, effects of time on the use of antidepressants were no longer significant. Antihypertensive use was associated with poorer functioning, concurrent use of memantine, and older age. Antipsychotic use was associated with poorer functioning and poorer cognition. Antidepressant use was associated with younger age, poorer functioning, and concurrent use of cholinesterase inhibitors and memantine. Hormone use was associated with being female and younger age. Findings suggest accurate modeling of the AD treatment paradigm for certain subgroups of patients should include antihypertensives and antipsychotics in addition to cholinesterase inhibitors and memantine.
Alzheimer’s disease; antihypertensive; antidepressant; antipsychotic; hormone; longitudinal studies
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.
Mild cognitive impairment; AD dementia; Diagnosis
DTI is one of the most effective MR tools for the investigation of the brain anatomy. In addition to the gray matter, histopathological studies indicate that white matter is also a good target for both the early diagnosis of AD and for monitoring disease progression, which motivates us to use DTI to study AD patients in vivo. There are already a large amount of studies reporting significant differences between AD patients and controls, as well as to predict progression of disease in symptomatic non-demented individuals. Application of these findings in clinical practice remains to be demonstrated.
Alzheimer’s disease; mild cognitive impairment; white matter; diffusion tensor imaging; clinical application
The Clinical Dementia Rating (CDR) and CDR-Sum-of-Boxes (CDR-SB) can be utilized to grade mild but clinically important cognitive symptoms. However, sensitive clinical interview formats are lengthy.
To develop a brief instrument for obtaining CDR scores, and to assess its reliability and cross-sectional validity.
Using legacy data from expanded interviews conducted among 347 community-dwelling, older adults in a longitudinal study, we identified 60 questions about cognitive functioning in daily life–out of a possible 131– using clinical judgment, inter-item correlations, and principal components analysis. Items were selected in one cohort (n=147), and a computer algorithm for generating CDR scores was developed in this same cohort and re-run in a replication cohort (n=200) to evaluate how well the 60 items retained information from the original 131. Then, short interviews based on the 60 items were administered to 50 consecutively-recruited elders, with no or mild cognitive symptoms, at an Alzheimer Disease Research Center. CDR scores based on short interviews were compared with those from independent long interviews.
In the replication cohort, agreement between short and long CDR interviews ranged from κ =0.65–0.79, with κ =0.76 for Memory; κ =0.77 for global CDR; ICC (intra-class correlation coefficient) for CDR-SB=0.89. In the cross-sectional validation, short interview scores were slightly lower than those from long interviews, but good agreement was observed: κ ≥ 0.70 for global CDR and Memory; ICC for CDR-SB=0.73.
The SIST-M is a brief, reliable and sensitive instrument for obtaining CDR scores in persons with symptoms along the spectrum of mild cognitive change.
Alzheimer disease; mild cognitive impairment; Clinical Dementia Rating; instrument; questionnaire; clinical interview
This study examined in detail patterns of cholinesterase inhibitors (ChEIs) and memantine use and explored the relationship between patient characteristics and such use. Patients with probable Alzheimer disease AD (n = 201) were recruited from the Predictors Study in 3 academic AD centers and followed from early disease stages for up to 6 years. Random effects logistic regressions were used to examine effects of patient characteristics on ChEIs/memantine use over time. Independent variables included measures of function, cognition, comorbidities, the presence of extrapyramidal signs, psychotic symptoms, age, sex, and patient’s living situation at each interval. Control variables included assessment interval, year of study entry, and site. During a 6-year study period, rate of ChEIs use decreased (80.6% to 73.0%) whereas memantine use increased (2.0% to 45.9%). Random effects logistic regression analyses showed that ChEI use was associated with better function, no psychotic symptoms, and younger age. Memantine use was associated with better function, poorer cognition, living at home, later assessment interval, and later year of study entry. Results suggest that high rate of ChEI use and increasing memantine use over time are consistent with current practice guidelines of initiation of ChEIs in mild-to-moderate AD patients and initiation of memantine in moderate-to-severe patients.
Alzheimer disease; cholinesterase inhibitors; memantine; longitudinal studies
To examine the effect of specific “CSF profiles” on the rate of cognitive decline, disease progression, and risk of conversion to Alzheimer's disease (AD) dementia in patients with amnestic mild cognitive impairment (MCI).
Total tau (t-tau), tau phosphorylated at threonine 181 (p-tau181), and β-amyloid 1-42 peptide (Aβ42) were immunoassayed in CSF samples obtained from MCI patients enrolled in the Alzheimer's Disease Neuroimaging Initiative. Patients were then stratified by “CSF profiles”: (1) normal t-tau and Aβ42 levels (i.e., normal–t-tauAβ42), (2) normal t-tau but abnormal Aβ42 (i.e., abnormal–Aβ42), (3) abnormal t-tau but normal Aβ42 (i.e., abnormal–t-tau), and (4) abnormal t-tau and Aβ42 (i.e., abnormal–t-tauAβ42).
Fifty-eight sites in the US and Canada.
One hundred ninety-five MCI patients.
Main Outcome Measures
A composite cognitive measure, the CDR-Sum of Boxes, and conversion to AD.
MCI patients with a CSF profile of abnormal–Aβ42 or abnormal–t-tauAβ42 experienced a faster rate of decline on the composite cognitive measure and the CDR-Sum of Boxes compared to those with normal–t-tauAβ42. They also had a greater risk of converting to AD relative to the normal–t-tauAβ42 group. In contrast, those with a CSF profile of abnormal–t-tau did not differ from the normal–t-tauAβ42 group on any outcome. These findings were generally replicated when the sample was reclassified by patterns of p-tau181 and Aβ42 abnormalities.
β-amyloid abnormalities, but not tau alterations, are associated with cognitive deterioration, disease progression, and increased risk of conversion to AD dementia in patients with MCI. Patients with abnormal levels of Aβ42 may be prime targets for drug treatment and clinical trials in MCI.
CSF; MCI; cognitive decline; disease progression; conversion to AD
The ability to form associations between previously unrelated items of information, such as names and faces, is an essential aspect of episodic memory function. The neural substrate that determines success vs. failure in learning these associations remains to be elucidated. Using event-related functional MRI during the encoding of novel face-name associations, we found that successfully remembered face-name pairs showed significantly greater activation in the anterior hippocampal formation bilaterally and left inferior prefrontal cortex, compared to pairs that were forgotten. Functional connectivity analyses revealed significant correlated activity between the right and left hippocampus and neocortical regions during successful, but not attempted, encoding. These findings suggest that anterior regions of the hippocampal formation, in particular, are crucial for successful associative encoding and that the degree of coordination between hippocampal and neocortical activity may predict the likelihood of subsequent memory.
Most estimates of the cost of informal caregiving in patients with Alzheimer’s disease (AD) remain cross-sectional. Longitudinal estimates of informal caregiving hours and costs are less frequent and are from assessments covering only short periods of time. The objectives of this study were to estimate long-term trajectories of the use and cost of informal caregiving for patients with AD and the effects of patient characteristics on the use and cost of informal caregiving. The sample is drawn from the Predictors Study, a large, multicenter cohort of patients with probable AD, prospectively followed annually for up to 7 years in three university-based AD centers in the United States (n = 170). Generalized linear mixed models were used to estimate the effects of patient characteristics on use and cost of informal caregiving. Patients’ clinical characteristics included cognitive status (Mini-Mental State Examination), functional capacity (Blessed Dementia Rating Scale (BDRS)), comorbidities, psychotic symptoms, behavioral problems, depressive symptoms, and extrapyramidal signs. Results show that rates of informal care use and caregiving hours (and costs) increased substantially over time but were related differently to patients’ characteristics. Use of informal care was significantly associated with worse cognition, worse function, and higher comorbidities. Conditional on receiving informal care, informal caregiving hours (and costs) were mainly associated with worse function. Each additional point on the BDRS increased informal caregiving costs 5.4%. Average annual informal cost was estimated at $25,381 per patient, increasing from $20,589 at baseline to $43,030 in Year 4.
informal care; costs; Alzheimer’s disease; longitudinal study
Arterial spin labeling (ASL) MRI is becoming a popular method for measuring perfusion due to its ability of generating perfusion maps non-invasively. This allows for frequent repeat scanning, which is especially useful for follow-up studies. However, limited information is available regarding the reliability and reproducibility of ASL perfusion measurements. Here, the reliability and reproducibility of pulsed ASL (PASL) was investigated in an elderly population to determine the variation in perfusion among cognitively normal individuals in different brain structures. Intra-class correlation coefficients (ICC) and within-subject variation coefficients (wsCV) were used to estimate reliability and reproducibility over a period of one year. Twelve cognitively normal subjects (75.5±5.3 years old, six male and six female) were scanned four times (at 0, 3, 6 and 12 months). No significant difference in cerebral blood flow (CBF) was found over this period. CBF values ranged from 46–53 ml/100g/min in the medial frontal gyrus (MFG) and from 40–44 ml/100g/min over all gray matter regions in the superior part of the brain. Data obtained from the first two scans were processed by two readers and showed high reliability (ICC>0.97) and reproducibility (wsCV <6%). However, over the total period of one year, reliability reduced to a moderate level (ICC = 0.63–0.74) with wsCVs of gray matter, left MFG, right MFG of13.5%, 12.3% , and 15.4%, respectively. In conclusion, measurement of CBF with pulsed ASL provided good agreement between inter-raters. A moderate level of reliability was obtained over a one-year period, which was attributed to variance in slice positioning and coregistration. As such pulsed ASL has the potential to be used for CBF comparison in longitudinal studies.
Perfusion; arterial spin labeling; cerebral blood flow; reliability; reproducibility
There is widespread evidence that memory deteriorates with aging, however the exact mechanisms that underlie these changes are not well understood. Given the growing size of the aging population, there is an imperative to study age-related neurocognitive changes in order to better parse healthy from pathological aging. Using a behavioral paradigm that taxes pattern separation (the ability to differentiate novel yet similar information from previously learned information and thus avoid interference), we investigated age-related neural changes in the human hippocampus using high-resolution (1.5 mm isotropic) BOLD fMRI. Recent evidence from animal studies suggests that hyperactivity in the CA3 region of the hippocampus may underlie behavioral deficits in pattern separation in aged rats. Here, we report evidence that is consistent with findings from the animal studies. We found a behavioral impairment in pattern separation in a sample of healthy older adults compared to young controls. We also found a related increase in CA3/dentate gyrus activity levels during an fMRI contrast that stresses pattern separation abilities. In a detailed analysis of behavior, we also found that the pattern of impairment was consistent with the predictions of the animal model, where larger changes in the input (greater dissimilarity) were required in order for elderly adults to successfully encode new information as distinct from previously learned information. These findings are also consistent with recent fMRI and behavioral reports in healthy aging, and further suggest that a specific functional deficit in the CA3/dentate network contributes to memory difficulties with aging.
fMRI; recognition memory; aging; medial temporal lobe; computational model
A blood-based biomarker of Alzheimer disease (AD) would be superior to CSF and neuroimaging measures in terms of cost, invasiveness and feasibility for repeated measures. We previously reported 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 one year.
Participants 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 one year later. Plasma ceramides were assayed at baseline using HPLC-coupled electrospray ionization tandem mass spectrometry.
While all saturated ceramides were lower in MCI compared to AD at baseline, Ceramides C22:0 and C24:0 were significantly lower in the MCI group compared to both NC and AD groups (p<0.01). Ceramide levels did not differ (p>0.05) 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 one year later.
Results 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.
Ceramides; Lipids; Biomarker; Plasma; Mild cognitive impairment; Hippocampal volume
Background: Alterations of the gray and white matter have been identified in Alzheimer’s disease (AD) by structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). However, whether the combination of these modalities could increase the diagnostic performance is unknown. Methods: Participants included 19 AD patients, 22 amnestic mild cognitive impairment (aMCI) patients, and 22 cognitively normal elderly (NC). The aMCI group was further divided into an “aMCI-converter” group (converted to AD dementia within 3 years), and an “aMCI-stable” group who did not convert in this time period. A T1-weighted image, a T2 map, and a DTI of each participant were normalized, and voxel-based comparisons between AD and NC groups were performed. Regions-of-interest, which defined the areas with significant differences between AD and NC, were created for each modality and named “disease-specific spatial filters” (DSF). Linear discriminant analysis was used to optimize the combination of multiple MRI measurements extracted by DSF to effectively differentiate AD from NC. The resultant DSF and the discriminant function were applied to the aMCI group to investigate the power to differentiate the aMCI-converters from the aMCI-stable patients. Results: The multi-modal approach with AD-specific filters led to a predictive model with an area under the receiver operating characteristic curve (AUC) of 0.93, in differentiating aMCI-converters from aMCI-stable patients. This AUC was better than that of a single-contrast-based approach, such as T1-based morphometry or diffusion anisotropy analysis. Conclusion: The multi-modal approach has the potential to increase the value of MRI in predicting conversion from aMCI to AD.
Alzheimer’s disease; pre-dementia phase; mild cognitive impairment; white matter; magnetic resonance imaging; diffusion tensor imaging; multi-modal disease-specific spatial filtering
Functional magnetic resonance imaging (fMRI) studies have observed hyperactivity in the hippocampal region in individuals with Mild Cognitive Impairment (MCI). However, the actual source of such hyperactivity is not well understood. Studies of aged rats observed similar hyperactive signals in the CA3 region of the hippocampus that correlated with spatial memory deficits and, in particular, with their ability to represent novel environments as being distinct from familiar ones (pattern separation). In this study, we tested the hypothesis that patients with amnestic MCI (aMCI) have deficits in pattern separation, along with hyperactive fMRI BOLD activity in the CA3 region of the hippocampus. We used high-resolution fMRI during a continuous recognition task designed to emphasize pattern separation. We conducted hippocampal subfield-level region of interest analyses to test for dysfunctional activity in aMCI patients. We found that patients showed impaired performance on trials that taxed their pattern separation abilities. We also observed hyperactive BOLD signals in the CA3/dentate and hypoactive signals in the entorhinal cortex during the separation condition. In a high-resolution morphometric analysis of hippocampal subfields, aMCI patients also had smaller CA3/dentate and CA1 volumes (no difference in the subiculum). The CA3/dentate region bilaterally also exhibited the largest shape deformations in aMCI patients, suggesting that this locus is affected early in the course of the disease. These findings suggest that structural and functional changes in the CA3/dentate region of the hippocampus contribute to the deficits in episodic memory that are observed in patients with aMCI. The functional hyperactivity may be evidence for a dysfunctional encoding mechanism, consistent with the predictions of computational models of hippocampal learning.
Delusions and hallucinations are common in Alzheimer disease (AD) and there are conflicting reports regarding their ability to predict cognitive decline, functional decline, and institutionalization. According to all previous literature, they are not associated with mortality.
To examine whether the presence of delusions or hallucinations has predictive value for important outcomes in AD.
Design, Setting, and Participants
A total of 456 patients with AD at early stages (mean Folstein Mini-Mental State Examination [MMSE] score of 21 of 30 at entry) were recruited and followed up semiannually for up to 14 years (mean, 4.5 years) in 5 university-based AD centers in the United States and Europe. Using the Columbia University Scale for Psychopathology in AD (administered every 6 months, for a total of 3266 visit-assessments, average of 7.2 per patient), the presence of delusions and hallucinations was extracted and examined as time-dependent predictors in Cox models. The models controlled for cohort effect, recruitment center, informant status, sex, age, education, a comorbidity index, baseline cognitive and baseline functional performance, behavioral symptoms, and use of neuroleptics and cholinesterase inhibitors.
Main Outcome Measures
Cognitive (Columbia MMSE score of ≤20/57 [approximate Folstein MMSE score of ≤10/30]), functional (Blessed Dementia Rating Scale [parts I and II] score of ≥10), institutionalization equivalent index, and death.
During the full course of follow-up, 38% of patients reached the cognitive, 41% the functional, 54% the institutionalization, and 49% the mortality end point. Delusions were noted for 34% of patients at baseline and 70% at any evaluation. Their presence was associated with increased risk for cognitive (risk ratio [RR], 1.50; 95% confidence interval [CI], 1.07-2.08) and functional decline (RR, 1.41; 95% CI, 1.02-1.94). Hallucinations were present in 7% of patients at initial visit and in 33% at any visit. Their presence was associated with increased risk for cognitive decline (RR, 1.62; 95% CI, 1.06-2.47), functional decline (RR, 2.25; 95% CI, 1.54-2.27), institutionalization (RR, 1.60; 95% CI, 1.13-2.28), and death (RR, 1.49; 95% CI, 1.03-2.14).
Delusions and hallucinations are very common in AD and predict cognitive and functional decline. Presence of hallucinations is also associated with institutionalization and mortality.
The posteromedial cortices and other regions of the “default network” are particularly vulnerable to the pathology of Alzheimer disease (AD). In this study, we performed fMRI to investigate whether the presence of apolipoprotein E (APOE) ε4 allele and degree of memory impairment were associated with dysfunction of these brain regions. Seventy-five elderly subjects ranging from cognitively normal to mild AD, divided into ε4 carriers and non-carriers, underwent fMRI during a memory encoding task. Across all subjects, posteromedial and ventral anterior cingulate cortices (key components of the default network) as well as right middle and inferior prefrontal regions demonstrated reduced task-induced deactivation in the ε4 carriers relative to non-carriers. Even among cognitively normal subjects, ε4 carriers demonstrated reduced posteromedial deactivation compared to non-carriers, in the same regions which demonstrated failure of deactivation in AD patients. Greater failure of posteromedial deactivation was related to worse memory performance (delayed recall) across all subjects and within the range of cognitively normal subjects. In summary, the posteromedial cortical fMRI response pattern is modulated both by the presence of APOE ε4 and episodic memory capability. Altered fMRI activity of the posteromedial areas of the brain default network may be an early indicator of risk for AD.
Alzheimer disease; apolipoprotein E (APOE); cognitive aging; functional magnetic resonance imaging (fMRI); mild cognitive impairment (MCI); memory
The relationship between engagement in pleasant activities as rated by the patient and as rated by the caregiver from the patient's perspective was examined using structural equation modeling in a sample of patients (N = 277) diagnosed with mild to moderate Alzheimer's disease. The two activity participation ratings were only moderately related to one another. Furthermore, depression was the only significant predictor of the patient-rated activity participation, whereas severity of depression, degree of personality change, level of dependence, and cognition were all significant predictors of caregiver-rated activity participation. These findings suggest that caregivers consider a wider range of variables when evaluating the patient's engagement in activities than does the patient. Predictors of patient-rated activity participation did not differ as a function of age or cognition.
Activities; Alzheimer's disease; Invariance analyses; Structural equation modeling