Probable Alzheimer's Disease Group Research Articles

Serum neurofilament light chain and inflammatory cytokines as biomarkers for early detection of mild cognitive impairment

To investigate the association between serum neurofilament light chain (NfL) levels, inflammatory cytokines, and cognitive function to assess their utility in the early detection of mild cognitive impairment (MCI). We conducted a cross-sectional study involving 157 community-dwelling individuals aged 55 years and above, categorized into healthy controls, MCI, and probable Alzheimer's disease (AD). Serum levels of NfL, inflammatory cytokines, and AD pathology markers were measured using enzyme-linked immunosorbent assay (ELISA). Correlations between these biomarkers and cognitive function were analyzed, and the diagnostic performance of the cognitive assessment scales and serum biomarker concentrations was evaluated using receiver operating characteristic (ROC) curve analysis. Serum NfL levels were significantly elevated in MCI and probable AD groups compared to healthy controls. Positive correlations were found between serum NfL and inflammatory cytokines IL-1β, IL-6, and Aβ40. Combining serum NfL with p-tau217 and the Boston Naming Test significantly enhanced the predictive accuracy for MCI. However, combining serum NfL with inflammatory markers did not improve MCI prediction accuracy. Elevated serum NfL is associated with cognitive impairment and inflammatory markers, suggesting its potential as a peripheral serum biomarker for MCI detection. The combination of serum NfL with p-tau217 and cognitive tests could offer a more accurate prediction of MCI, providing new insights for AD treatment strategies.

Association Between Hippocampal Volume and African Neuropsychology Memory Tests in Adult Individuals with Probable Alzheimer's Disease in Democratic Republic of Congo.

Western studies indicate potential associations between hippocampal volume and memory in the trajectory of Alzheimer's disease (AD). However, limited availability of neuroimaging technology and neuropsychological tests appropriate for sub-Saharan African (SSA) countries makes it difficult to establish neuroanatomical associations of hippocampus and memory in this locale. This study examined hippocampal volumes and memory in healthy control (HC) and probable AD groups in the Democratic Republic of Congo (DRC). Forty-six subjects with probable AD and 29 HC subjects were screened using the Community Instrument for Dementia and the Alzheimer Questionnaire. Participants underwent neuroimaging in Kinshasa, DRC, and memory was evaluated using the African Neuropsychology Battery (ANB). Multiple linear regression was used to determine associations between hippocampal volumes and memory. Patients with probable AD performed significantly worse than HCs on ANB memory measures, and exhibited greater cerebral atrophy, which was significantly pronounced in the medial temporal lobe region (hippocampus, entorhinal cortex). Both AD and HC subjects exhibited high rates of white matter hyperintensities compared to international base rate prevalence, which was significantly worse for probable AD. Both also exhibited elevated rates of microhemorrhages. Regression analysis demonstrated a significant association between hippocampal volume and ANB memory tests. Hippocampal atrophy discriminated probable AD from the HC group. This study establishes the feasibility of conducting neuroimaging research in the SSA, demonstrates many known neuroimaging findings in probable AD patients hold up using culturally appropriate memory tasks, and suggest cardiovascular problems are a greater issue in SSA than in Western countries.

Correlation of blood-brain barrier leakage with cerebral small vessel disease including cerebral microbleeds in Alzheimer's disease.

Blood-brain barrier (BBB) damage is considered an important part of Alzheimer's disease (AD) progression, and cerebral small-vessel disease (CSVD) is commonly associated with AD. However, the relationship between BBB damage, small cerebrovascular lesions, especially cerebral microbleeds (CMBs), and amyloid and tau biomarkers remains controversial. Therefore, our study aimed to further investigate their association in our cohort of patients with AD. A total of 139 individuals were divided into probable AD (18F-florbetapir PET positive, n = 101) and control group (cognitively normal, n = 38). The levels of cerebrospinal fluid (CSF) and plasma t-tau, p-tau181, Aβ40, Aβ42, and albumin were measured using corresponding commercial assay kits, and the CSF/plasma albumin ratio (Qalb), an indicator of BBB dysfunction, was calculated. CSVD burden and the number of CMBs were defined using magnetic resonance imaging. Patients with AD had higher Qalb (p = 0.0024), higher numbers of CMBs (p = 0.03), and greater CSVD burden (p < 0.0001). In the AD group, CMBs and CSVD correlated with a higher Qalb (p = 0.03), and the numbers of CMBs negatively correlated with CSF Aβ42 (p = 0.02). Blood-brain barrier damage was accompanied by a more severe burden of CSVD, including CMB, in patients with AD.

Coagulation and cognitive function - science behind the scenes

Cardiovascular risk factors and proteins that regulate endothelial cell function have been suggested to contribute to the development of Alzheimer's disease (AD)-related dementia. The aim of the study was to investigate a relationship between vascular endothelial growth factor (VEGF), VEGF-interacting protein, neuropilin-1, and blood coagulation/anticoagulation proteins with cognitive decline associated with AD. Plasma levels of different proteins were measured in healthy volunteers (N=193), patients with mild cognitive impairment (N=126) and patients with probable AD (N=365).Fibrinogen and coagulation factor XI were the highest in the probable AD group and were significantly different only from the values in the healthy volunteers group (p = 0.035 and p = 0.002, respectively). Coagulation factor X, coagulation factor Xa and protein C were the lowest in the probable AD group and the differences were significant only when compared with the values in the healthy volunteers group (p = 0.043, p = 0.003 and p = 0.008, respectively). There was significant, non-parametric correlation between VEGF and neuropilin-1 and coagulation/anticoagulation proteins: neuropilin-1 and protein C (r = - 0.274, p = 0.000), neuropilin-1 and fibrinogen (r = 0.209, p = 0.000), neuropilin-1 and coagulation factor X (r = - 0.220, p = 0.000), neuropilin-1 and coagulation factor Xa (r = - 0.247, p = 0.000), VEGF and protein C (r = - 0.191, p = 0.000).Our results demonstrate significant differences in plasma levels of some coagulation/anticoagulation proteins between AD patients and healthy individuals, indicating a specific pattern of hypercoagulability risk in the AD patients.

Associating Type 2 Diabetes Risk Factor Genes and FDG-PET Brain Metabolism in Normal Aging and Alzheimer's Disease.

Background: Several studies have linked type 2 diabetes (T2D) to an increased risk of developing Alzheimer’s disease (AD). This has led to an interest in using antidiabetic treatments for the prevention of AD. However, the underlying mechanisms explaining the relationship between T2D and AD have not been completely elucidated.Objective: Our objective was to examine cerebral 18F-fluorodeoxyglucose (FDG) uptake during normal aging and in AD patients in regions associated with diabetes genetic risk factor expression to highlight which genes may serve as potential targets for pharmaceutical intervention.Methods: We calculated regional glucose metabolism differences in units of standardized uptake values (SUVR) for 386 cognitively healthy adults and 335 clinically probable AD patients. We then proceeded to extract gene-expression data from the publicly available Allen Human Brain Atlas (HBA) database. We used the nearest genes to 46 AD- and T2D-associated SNPs previously identified in the literature, and mapped their expression to the same 34 cortical regions in which we calculated SUVRs. SNPs with a donor consistency of 0.40 or greater were selected for further analysis. We evaluated the associations between SUVR and gene-expression across the brain.Results: Of the 46 risk-factor genes, 15 were found to be significantly correlated with FDG-PET brain metabolism in healthy adults and probable AD patients after correction for multiple comparisons. Using multiple regression, we found that five genes explained a total of 72.5% of the SUVR variance across the healthy adult group regions, while four genes explained a total of 79.3% of the SUVR variance across the probable AD group regions. There were significant differences in whole-brain SUVR as a function of allele frequencies for two genes.Conclusions: These results highlight the association between risk factor genes for T2D and regional glucose metabolism during both normal aging and in probable AD. Highlighted genes were associated with mitochondrial stability, vascular maintenance, and glucose intolerance. Pharmacological intervention of these pathways has the potential to improve glucose metabolism during normal again as well as in AD patients.

Altered Expression of Long Non-coding RNAs in Peripheral Blood Mononuclear Cells of Patients with Alzheimer's Disease.

Long non-coding RNAs (lncRNAs) are involved in many neurological conditions, and neurodegenerative disorders including Alzheimer's disease (AD) regulate gene expression at transcriptional, post-transcriptional, and epigenetic levels. However, the roles of lncRNAs in the pathogenesis of AD remain unclear. In this study, we aimed to determine the expression of lncRNAs and also mRNAs in AD which may alter expression and contribute to the pathogenesis of the disease. Peripheral blood samples were obtained from patients admitted to the Neurology Department of Pamukkale University Medical Faculty (23 patients with AD, 33 control groups). Total RNA obtained from peripheral blood mononuclear cells (PBMC) of subjects with probable AD (n = 4) and healthy control groups (n = 4) was examined to determine the altered expression of lncRNAs and mRNAs in AD were evaluated by microarray analysis. Five lncRNAs with the highest end-to-end fold change (fc ≥ 2.0, p < 0.05) were identified and confirmed by quantitative real-time polymerase chain reaction (qRT-PCR). In our study, the profiles of lncRNAs and mRNAs that may be associated with Alzheimer's disease were determined. A total of 14 lncRNAs and 35 mRNAs were determined as upregulated, and 20 lncRNAs and 73 mRNAs determined as downregulated as a result of microarray analysis in patients with AD compared with control groups (fold change ≥ 2.0, p < 0.05). From lncRNAs, expression of lncRNA TTC39C-AS1, lnc-AL445989.1-2, LINC01420, lnc-CSTB-1, and LOC401557 was confirmed by qRT-PCR. When assessed by KEGG analysis of AD PBMC lncRNA and mRNA profiles, TNF signaling pathway, PI3K/AKT, Ras, and MAPK pathways; glutamatergic, dopaminergic, and cholinergic synapses; GABA, and neurotrophin signaling pathways are found to be significant. This is the first known study to investigate lncRNA profiles in AD PBMCs. We think that these results may open a door to the understanding of AD pathogenesis targeted by lncRNAs.

Brain PET amyloid and neurodegeneration biomarkers in the context of the 2018 NIA-AA research framework: an individual approach exploring clinical-biomarker mismatches and sociodemographic parameters.

[18F]FDG-PET and [11C]PIB-PET are validated as neurodegeneration and amyloid biomarkers of Alzheimer's disease (AD). We used a PET staging system based on the 2018 NIA-AA research framework to compare the proportion of amyloid positivity (A+) and hypometabolism ((N)+) in cases of mild probable AD, amnestic mild cognitive impairment (aMCI), and healthy controls, incorporating an additional classification of abnormal [18F]FDG-PET patterns and investigating the co-occurrence of such with A+, exploring [18F]FDG-PET to generate hypotheses in cases presenting with clinical-biomarker "mismatches." Elderly individuals (N = 108) clinically classified as controls (N = 27), aMCI (N = 43) or mild probable AD (N = 38) were included. Authors assessed their A(N) profiles and classified [18F]FDG-PET neurodegenerative patterns as typical or non-typical of AD, performing re-assessments of images whenever clinical classification was in disagreement with the PET staging (clinical-biomarker "mismatches"). We also investigated associations between "mismatches" and sociodemographic and educational characteristics. AD presented with higher rates of A+ and (N)+. There was also a higher proportion of A+ and (N)+ individuals in the aMCI group in comparison to controls, however without statistical significance regarding the A staging. There was a significant association between amyloid positivity and AD (N)+ hypometabolic patterns typical of AD. Non-AD (N)+ hypometabolism was seen in all A- (N)+ cases in the mild probable AD and control groups and [18F]FDG-PET patterns classified such individuals as "SNAP" and one as probable frontotemporal lobar degeneration. All A- (N)- cases in the probable AD group had less than 4years of formal education and lower socioeconomic status (SES). The PET-based staging system unveiled significant A(N) differences between AD and the other groups, whereas aMCI and controls had different (N) staging, explaining the cognitive impairment in aMCI. [18F]FDG-PET could be used beyond simple (N) staging, since it provided alternative hypotheses to cases with clinical-biomarker "mismatches." An AD hypometabolic pattern correlated with amyloid positivity. Low education and SES were related to dementia in the absence of biomarker changes.

The probable role of insulin resistance and SIRT1 proteins in the Alzheimer's disease.

Recent evidence suggests that insulin resistance may play an important role in the pathogenesis of Alzheimer's disease (AD). In this study, the probable role of insulin resistance in the pathogenesis of AD was investigated in patients with Type 2 Diabetes Mellitus (T2DM). Serum amyloid beta (Aβ) (1-42), insulin like growth factor-1 (IGF-1), sirtuin1 (SIRT1) and leptin protein levels were measured in serum samples of control (n = 26), probable AD (n = 26), and probable AD+T2DM patients (n = 12) using ELISA method. Mini mental state examination (MMSE) was performed to the patient and control groups. Serum IGF-1 significantly increased in the probable AD+T2DM group as compared to the control and probable AD groups (p ˂ 0.05). The levels of serum leptin significantly decreased in the probable AD and AD+T2DM groups as compared to the control (p ˂ 0.05). There were no statistically significant differences in serum Aβ (1-42) and SIRT1 levels among groups (p > 0.05). The significant decrease in serum leptin levels in AD patients may indicate that it may be a therapeutic marker in AD. The level of serum Aβ peptide and SIRT1 proteins can vary depending on the stage of the disease. Therefore, this study should be supported by more comprehensive studies in terms of the number of patients in advanced stage (Tab. 1, Fig. 4, Ref. 29).

Alzheimer's Disease Diagnosis: Discrepancy between Clinical, Neuroimaging, and Cerebrospinal Fluid Biomarkers Criteria in an Italian Cohort of Geriatric Outpatients: A Retrospective Cross-sectional Study.

The role of cerebrospinal fluid (CSF) biomarkers, and neuroimaging in the diagnostic process of Alzheimer's disease (AD) is not clear, in particular in the older patients. The aim of this study was to compare the clinical diagnosis of AD with CSF biomarkers and with cerebrovascular damage at neuroimaging in a cohort of geriatric patients. Retrospective analysis of medical records of ≥65-year-old patients with cognitive impairment referred to an Italian geriatric outpatient clinic, for whom the CSF concentration of amyloid-β (Aβ), total Tau (Tau), and phosphorylated Tau (p-Tau) was available. Clinical diagnosis (no dementia, possible and probable AD) was based on the following two sets of criteria: (1) the Diagnostic Statistical Manual of Mental Disorders (DSM-IV) plus the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) and (2) the National Institute on Aging-Alzheimer's Association (NIA-AA). The Fazekas visual scale was applied when a magnetic resonance imaging scan was available. We included 94 patients, mean age 77.7 years, mean Mini Mental State Examination score 23.9. The concordance (kappa coefficient) between the two sets of clinical criteria was 70%. The mean CSF concentration (pg/ml) (±SD) of biomarkers was as follows: Aβ 687 (±318), Tau 492 (±515), and p-Tau 63 (±56). There was a trend for lower Aβ and higher Tau levels from the no dementia to the probable AD group. The percentage of abnormal liquor according to the local cutoffs was still 15 and 21% in patients without AD based on the DSM-IV plus NINCDS-ADRDA or the NIA-AA criteria, respectively. The exclusion of patient in whom normotensive hydrocephalus was suspected did not change these findings. A total of 80% of patients had the neuroimaging report describing chronic cerebrovascular damage, while the Fazekas scale was positive in 45% of patients overall, in 1/2 of no dementia or possible AD patients, and in about 1/3 of probable AD patients, with no difference across ages. We confirmed the expected discrepancy between different approaches to the diagnosis of AD in a geriatric cohort of patients with cognitive impairment. Further research is needed to understand how to interpret this discrepancy and provide clinicians with practical guidelines.

BACE1 levels are increased in plasma of Alzheimer's disease patients compared with matched cognitively healthy controls.

BACE1 is the secretase that acts in Aβ production in Alzheimer's disease (AD). We investigated mRNA expression in total blood and the levels of plasma protein BACE1 in AD patients compared with cognitively healthy subjects. Probable AD (n = 47) and non-AD control group (n = 32) were evaluated for mRNA expression for BACE1 using reverse transcription-qPCR. A subsample of n = 21 AD and n = 20 non-AD had plasma BACE1 levels analyzed, using ELISA. No differences were found on BACE1 mRNA between groups. However, higher levels of BACE1 were detected in plasma of AD patients. Blood-based diagnostic tools are desired to improve AD diagnosis. BACE1 plasma levels could provide an additional diagnostic tool for AD in association with neuropsychological tests.

Spectral Analysis of EEG in Familial Alzheimer's Disease with E280A Presenilin-1 Mutation Gene.

To evaluate the hypothesis that quantitative EEG (qEEG) analysis is susceptible to detect early functional changes in familial Alzheimer's disease (AD) preclinical stages. Three groups of subjects were selected from five extended families with hereditary AD: a Probable AD group (18 subjects), an asymptomatic carrier (ACr) group (21 subjects), with the mutation but without any clinical symptoms of dementia, and a normal group of 18 healthy subjects. In order to reveal significant differences in the spectral parameter, the Mahalanobis distance (D 2) was calculated between groups. To evaluate the diagnostic efficiency of this statistic D 2, the ROC models were used. The ROC curve was summarized by accuracy index and standard deviation. The D 2 using the parameters of the energy in the fast frequency bands shows accurate discrimination between normal and ACr groups (area ROC = 0.89) and between AD probable and ACr groups (area ROC = 0.91). This is more significant in temporal regions. Theses parameters could be affected before the onset of the disease, even when cognitive disturbance is not clinically evident. Spectral EEG parameter could be firstly used to evaluate subjects with E280A Presenilin-1 mutation without impairment in cognitive function.

Nonamnestic mild cognitive impairment progresses to dementia with Lewy bodies

To determine the rate of progression of mild cognitive impairment (MCI) to dementia with Lewy bodies (DLB). We followed 337 patients with MCI in the Mayo Alzheimer's Disease Research Center (range 2-12 years). Competing risks survival models were used to examine the rates of progression to clinically probable DLB and Alzheimer disease (AD). A subset of patients underwent neuropathologic examination. In this clinical cohort, 116 remained as MCI, while 49 progressed to probable DLB, 162 progressed to clinically probable AD, and 10 progressed to other dementias. Among nonamnestic MCI, progression rate to probable DLB was 20 events per 100 person-years and to probable AD was 1.6 per 100 person-years. Among amnestic MCI, progression rate to probable AD was 17 events per 100 person-years, and to DLB was 1.5 events per 100 person-years. In 88% of those who developed probable DLB, the baseline MCI diagnosis included attention and/or visuospatial deficits. Those who developed probable DLB were more likely to have baseline daytime sleepiness and subtle parkinsonism. In 99% of the clinically probable AD group, the baseline MCI diagnosis included memory impairment. Neuropathologic confirmation was obtained in 24 of 30 of those with clinically probable AD, and in 14 of 18 of those with clinically probable DLB. In a clinical sample, patients with nonamnestic MCI were more likely to develop DLB, and those with amnestic MCI were more likely to develop probable AD.

Using Positron Emission Tomography and Florbetapir F 18 to Image Cortical Amyloid in Patients With Mild Cognitive Impairment or Dementia Due to Alzheimer Disease

To characterize quantitative florbetapir F 18 (hereafter referred to as simply florbetapir) positron emission tomographic (PET) measurements of fibrillar β-amyloid (Aβ) burden in a large clinical cohort of participants with probable Alzheimer disease (AD) or mild cognitive impairment (MCI) and older healthy controls (OHCs). Cerebral-to-whole-cerebellar florbetapir standard uptake value ratios (SUVRs) were computed. Mean cortical SUVRs were compared. A threshold of SUVRs greater than or equal to 1.17 was used to reflect pathological levels of amyloid associated with AD based on separate antemortem PET and postmortem neuropathology data from 19 end-of-life patients. Similarly, a threshold of SUVRs greater than 1.08 was used to signify the presence of any identifiable Aβ because this was the upper limit from a separate set of 46 individuals 18 to 40 years of age who did not carry apolipoprotein E (APOE) ε4. Multiple research imaging centers. A total of 68 participants with probable AD, 60 participants with MCI, and 82 OHCs who were 55 years of age or older. Main Outcome Measure Florbetapir-PET activity. All of the participants (ie, those with probable AD or MCI and those who were OHCs) differed significantly in mean (SD) cortical florbetapir SUVRs (1.39 [0.24], 1.17 [0.27], and 1.05 [0.16], respectively; P < 1.0 × 10⁻⁷), in percentage meeting levels of amyloid associated with AD by SUVR criteria (80.9%, 40.0%, and 20.7%, respectively; P < 1.0 × 10⁻⁷), and in percentage meeting SUVR criteria for the presence of any identifiable Aβ (85.3%, 46.6%, and 28.1%, respectively; P < 1.0 × 10⁻⁷). Among OHCs, the percentage of florbetapir positivity increased linearly by age decile (P = .05). For the 54 OHCs with available APOE genotypes, APOE ε4 carriers had a higher mean (SD) cortical SUVR than did noncarriers (1.14 [0.2] vs 1.03 [0.16]; P = .048). The findings of our analysis confirm the ability of florbetapir-PET SUVRs to characterize amyloid levels in clinically probable AD, MCI, and OHC groups using continuous and binary measures of fibrillar Aβ burden. It introduces criteria to determine whether an image is associated with an intermediate-to-high likelihood of pathologic AD or with having any identifiable cortical amyloid level above that seen in low-risk young controls.

ApoE E4 is a Susceptibility Factor in Amnestic But Not Aphasic Dementias

The goal of this study was to determine if the apolipoprotein ε gene, which is a well-established susceptibility factor for Alzheimer disease (AD) pathology in typical amnestic dementias, may also represent a risk factor in the language-based dementia, primary progressive aphasia (PPA). Apolipoprotein E genotyping was obtained from 149 patients with a clinical diagnosis of PPA, 330 cognitively healthy individuals (NC), and 179 patients with a clinical diagnosis of probable Alzheimer's disease (PrAD). Allele frequencies were compared among the groups. Analyses were also completed by sex and in 2 subsets of PPA patients: 1 in which the patients were classified by subtype (logopenic, agrammatic, and semantic) and another in which pathologic data were available. The allele frequencies for the PPA group (ε2:5%, ε3:79.5%, and ε4:15.4%) showed a distribution similar to the NC group, but significantly different from the PrAD group. The presence of an ε4 allele did not influence the age of symptom onset or aid in the prediction of AD pathology in PPA. These data show that ε4 polymorphism, which is a well-known risk factor for AD pathology in typical amnestic dementias, has no similar relationship to the clinical syndrome of PPA or its association with AD pathology.

Sex differences in grey matter atrophy patterns among AD and aMCI patients: Results from ADNI

We used longitudinal magnetic resonance imaging (MRI) data to determine whether there are any gender differences in grey matter atrophy patterns over time in 197 individuals with probable Alzheimer's disease (AD) and 266 with amnestic mild cognitive impairment (aMCI), compared with 224 healthy controls participating in the Alzheimer's Disease Neuroimaging Initiative (ADNI). While previous research has differentiated probable AD and aMCI groups from controls in brain atrophy, it is unclear whether and how sex plays a role in patterns of change over time. Using regional volumetric maps, we fit longitudinal models to the grey matter data collected at repeated occasions, seeking differences in patterns of volume change over time by sex and diagnostic group in a voxel-wise analysis. Additionally, using a region-of-interest approach, we fit longitudinal models to the global volumetric data of predetermined brain regions to determine whether this more conventional approach is sufficient for determining sex and group differences in atrophy. Our longitudinal analyses revealed that, of the various grey matter regions investigated, males and females in the AD group and the aMCI group showed different patterns of decline over time compared to controls in the bilateral precuneus, bilateral caudate nucleus, right entorhinal gyrus, bilateral thalamus, bilateral middle temporal gyrus, left insula, and right amygdala. As one of the first investigation to model more than two time points of structural MRI data over time, our findings add insight into how AD and aMCI males and females differ from controls and from each other over time.

Characterizing Alzheimer's disease using a hypometabolic convergence index

This article introduces a hypometabolic convergence index (HCI) for the assessment of Alzheimer's disease (AD); compares it to other biological, cognitive and clinical measures; and demonstrates its promise to predict clinical decline in mild cognitive impairment (MCI) patients using data from the AD Neuroimaging Initiative (ADNI). The HCI is intended to reflect in a single measurement the extent to which the pattern and magnitude of cerebral hypometabolism in an individual's fluorodeoxyglucose positron emission tomography (FDG-PET) image correspond to that in probable AD patients, and is generated using a fully automated voxel-based image-analysis algorithm. HCIs, magnetic resonance imaging (MRI) hippocampal volume measurements, cerebrospinal fluid (CSF) assays, memory test scores, and clinical ratings were compared in 47 probable AD patients, 21 MCI patients who converted to probable AD within the next 18 months, 76 MCI patients who did not, and 47 normal controls (NCs) in terms of their ability to characterize clinical disease severity and predict conversion rates from MCI to probable AD. HCIs were significantly different in the probable AD, MCI converter, MCI stable and NC groups ( p = 9e−17) and correlated with clinical disease severity. Using retrospectively characterized threshold criteria, MCI patients with either higher HCIs or smaller hippocampal volumes had the highest hazard ratios (HRs) for 18-month progression to probable AD (7.38 and 6.34, respectively), and those with both had an even higher HR (36.72). In conclusion, the HCI, alone or in combination with certain other biomarker measurements, has the potential to help characterize AD and predict subsequent rates of clinical decline. More generally, our conversion index strategy could be applied to a range of imaging modalities and voxel-based image-analysis algorithms.

The Role of Neuropsychology in Distinguishing the Posterior Cortical Atrophy Syndrome and Alzheimer's Disease

This study investigated the neuropsychological hallmarks of posterior cortical atrophy (PCA). Seventeen patients with PCA, 17 patients with probable Alzheimer's disease (PAD), and 17 healthy age-matched subjects underwent neuropsychological testing for abstract reasoning, visuospatial abilities, memory, language, executive functions, praxes, and attention. The PCA patients were significantly more impaired in visual perception, spatial memory, visual attention, and visuospatial reasoning compared to the PAD patients who were relatively more impaired in episodic memory. In the PCA group, no test score correlated with disease duration or age of clinical onset, whereas, in the PAD group, several scores correlated with disease duration. Compared to the healthy subjects, both patient groups showed multiple cognitive deficits. Thus, PCA is characterised by distinctive visuospatial deficits that reflect the distribution of brain damage and contrast with the memory impairment of PAD patients. Specific neuropsychological tests may contribute to early identification of cortical dementia for diagnostic and research purposes.

Single voxel magnetic resonance spectroscopy at 3 Tesla in a memory disorders clinic: Early right hippocampal NAA/Cr loss in mildly impaired subjects

In this study, we use magnetic resonance spectroscopy (MRS) at 3 Tesla to measure N-acetyl aspartate (NAA), myo-inositol (mI) and choline (Cho) to creatine (Cr) ratios in R (right) and L (left) hippocampi (H) in 8 mildly memory impaired (MMI), 6 probable Alzheimer's Disease (PRAD), and 17 control subjects. NAA/Cr was significantly reduced in the RH in the MMI group and bilaterally in the PRAD group vs. controls. No other metabolite differences were noted between the three groups. Five MMI subjects have converted to PRAD in follow-up. These findings suggest that RH NAA/Cr ratios measured at 3 Tesla may be a sensitive marker of future progression to dementia in a clinically defined population with isolated memory complaints.

P2-037: Categorical and correlational analyses of baseline fluorodeoxyglucose positron emission tomography images from the Alzheimer's disease neuroimaging initiative

Alzheimer's disease (AD) is characterized by regional reductions in fluorodeoxyglucose positron emission tomography (PET) measurements of the cerebral metabolic rate for glucose (CMRgl), which are correlated with clinical severity, progressive and apparent before the onset of dementia or mild cognitive impairment (MCI). We have been using statistical parametric mapping (SPM) to analyze PET data from probable AD patients, amnestic MCI (aMCI) patients and normal controls (NC) from the AD Neuroimaging Initiative (ADNI). Our objective was to characterize patterns of cerebral hypometabolism in probable AD and aMCI, and correlate lower Mini-Mental State Examination (MMSE) scores with lower regional CMRgl in both the overall cohort of probable AD, aMCI and NC subjects and the probable AD group. Baseline PET images from 298 subjects, including 74 probable AD (age 70±10, MMSE 23.5±2.2), 142 aMCI (age 67±12, MMSE 27.1±1.7) and 82 NC (69±10 years old, MMSE 28.9±1.1), were analyzed on a voxel-by-voxel basis using SPM5. ANOVA with pair-wise comparisons contrasted regional CMRgl in the three subject groups. Linear regression correlated lower MMSE scores with lower CMRgl in the overall cohort and probable AD group. Compared to NC, the probable AD and aMCI groups each had lower CMRgl bilaterally in previously characterized posterior cingulate, precuneus, and parietotemporal regions (P<0.05 corrected for multiple comparisons), and occipital cortex, hippocampus, parahippocampal gyrus and fusiform gyrus (uncorrected P<0.005). Compared to NC, the probable AD group had lower CMRgl in frontal regions (corrected P<0.05). In the overall cohort, lower MMSE scores were correlated with lower CMRgl in the posterior cingulate, precuneus, parietotemporal and frontal regions (P<0.05, corrected for multiple comparisons). In the probable AD group, lower MMSE scores were correlated with lower CMRgl in left frontal and temporal regions (uncorrected P<0.001). Findings from this large multi-center study confirm the previously characterized pattern of regional hypometabolism in AD and aMCI and implicate additional brain regions. Furthermore, they confirm the previously characterized correlation between severity of clinical impairment in a combined group of patients and controls, but suggest strongest correlations between clinical severity of frontal and temporal regions by the time AD patients satisfy criteria for dementia.

Using a Rasch scale to characterize the clinical features of patients with a clinical diagnosis of uncertain, probable, or possible Alzheimer disease at intake.

This study examined the clinical features of patients with clinical diagnoses of probable Alzheimer disease (AD), possible AD, and uncertain. Case study comparing three groups of AD patients diagnosed at their initial visit to an Alzheimer outpatient clinic. Southern Illinois University School of Medicine's Center for Alzheimer Disease and Related Disorders (CADRD) assessment sites (20) in rural Illinois. 300 patients assessed at CADRD between January 1, 1994 and July 1, 2000. Patients were given an extensive clinical battery consisting of physical and neurologic examination, mental status testing including the Mini-Mental State Exam (MMSE), Short Blessed Dementia (SBD) and Blessed Dementia Scale (ADL), medical history evaluation, and laboratory tests. Other data included age at visit, gender, and medical history variables. Mean MMSE, SBD, and ADL scores differed significantly between groups (p's < 0.01). In all three cognitive tests, the uncertain group was the least impaired while the probable AD group was the most impaired. A Rasch model indicated that only the cognitive measures were useful in discriminating between the three diagnostic groups. In general, probable AD patients were distinguished from possible AD patients by the severity of their dementia as measured by the MMSE, ADL and SBD as well as Hachinski-Ischemic Score (HIS) scores. A Rasch model did well at predicting group membership based upon dementia measures only. The uncertain group differed from the AD groups in age and dementia severity as measured by the MMSE, ADL and SBD. Noting differences between this and previous studies, we speculate disparity may be related to differences in population ethnicity.