Progressive Mild Cognitive Impairment Group Research Articles

Synaptic Molecular and Neurophysiological Markers Are Independent Predictors of Progression in Alzheimer's Disease.

Background:Cerebrospinal fluid (CSF) neurogranin and quantitative electroencephalography (qEEG) are potential molecular and functional markers of synaptic pathology in Alzheimer’s disease (AD). Synaptic markers have emerged as candidate prognostic indicators of AD since synaptic degeneration was shown to be an early event and the best correlate of cognitive deficits in patients along the disease continuum.Objective:The present study investigated the association between CSF neurogranin and qEEG measures as well as their potential to predict clinical deterioration in mild cognitive impairment (MCI) patients.Methods:Patients diagnosed with MCI (n = 99) underwent CSF conventional AD biomarkers and neurogranin analysis and resting-state EEG recordings. The study population was further stratified into stable (n = 41) and progressive MCI (n = 31), based on the progression to AD dementia during two years follow-up. qEEG analysis included computation of global field power and global field synchronization in four conventional frequency bands.Results:CSF neurogranin levels were associated with theta power and synchronization in the progressive MCI group. CSF neurogranin and qEEG measures were significant predictors of progression to AD dementia, independent of baseline amyloid status in MCI patients. A combination of CSF neurogranin with global EEG power in theta and global EEG synchronization in beta band exhibited the highest classification accuracy as compared to either of these markers alone.Conclusion:qEEG and CSF neurogranin are independent predictors of progression to AD dementia in MCI patients. Molecular and neurophysiological synaptic markers may have additive value in a multimodal diagnostic and prognostic approach to dementia.

Common Variants in ABI3 Influence Cerebrospinal Fluid Total Tau Levels and Cognitive Decline in Progressive Mild Cognitive Impairment Patients.

A potential role for ABI3 gene has been suggested in the risk of Alzheimer's disease (AD), but the detailed mechanism before typical AD onset was unclear. In this study, we investigated the associations of ABI3 common variants with cerebrospinal fluid biomarkers and cognitive function scores among non-demented elderly from the ADNI database. We found that, in the progressive mild cognitive impairment group, rs5978930 was associated with total tau levels and rs16947151 was associated with cognitive function scores at baseline and over time, suggesting that ABI3 variants may be associated with cognitive decline and may influence AD onset through tau pathology.

Identifying the Alteration Patterns of Brain Functional Connectivity in Progressive Mild Cognitive Impairment Patients: A Longitudinal Whole-Brain Voxel-Wise Degree Analysis.

Patients with mild cognitive impairment (MCI) are at high risk for developing Alzheimer’s disease (AD), while some of them may remain stable over decades. The underlying mechanism is still not fully understood. In this study, we aimed to explore the connectivity differences between progressive MCI (PMCI) and stable MCI (SMCI) individuals on a whole-brain scale and on a voxel-wise basis, and we also aimed to reveal the differential dynamic alteration patterns between these two disease subtypes. The resting-state functional magnetic resonance images of PMCI and SMCI patients at baseline and year-one were obtained from the Alzheimer’s Disease Neuroimaging Initiative dataset, and the progression was determined based on a 3-year follow-up. A whole-brain voxel-wise degree map that was calculated based on graph-theory was constructed for each subject, and then the cross-sectional and longitudinal analyses on the degree maps were performed between PMCI and SMCI patients. In longitudinal analyses, compared with SMCI group, PMCI group showed decreased long-range degree in the left middle occipital/supramarginal gyrus, while the short-range degree was increased in the left supplementary motor area and middle frontal gyrus and decreased in the right middle temporal pole. A significant longitudinal alteration of decreased short-range degree in the right middle occipital was found in PMCI group. Taken together with previous evidence, our current findings may suggest that PMCI, compared with SMCI, might be a “severe” presentation of disease along the AD continuum, and the rapidly reduced degree in the right middle occipital gyrus may have indicative value for the disease progression. Moreover, the cross-sectional comparison results and corresponding receiver-operator characteristic-curves analyses may indicate that the baseline degree difference is not a good predictor of disease progression in MCI patients. Overall, these findings may provide objective evidence and an indicator to characterize the progression-related brain connectivity changes in MCI patients.

Association of Cerebrospinal Fluid Neurofilament Light Concentration With Alzheimer Disease Progression.

The extent to which large-caliber axonal degeneration contributes to Alzheimer disease (AD) progression is unknown. Cerebrospinal fluid (CSF) neurofilament light (NFL) concentration is a general marker of damage to large-caliber myelinated axons. To test whether CSF NFL concentration is associated with cognitive decline and imaging evidence of neurodegeneration and white matter change in AD. A commercially available immunoassay was used to analyze CSF NFL concentration in a cohort of patients with AD (n = 95) or mild cognitive impairment (MCI) (n = 192) and in cognitively normal individuals (n = 110) from the Alzheimer's Disease Neuroimaging Initiative. The study dates were January 2005 to December 2007. The NFL analysis was performed in November 2014. Correlation was investigated among baseline CSF NFL concentration and longitudinal cognitive impairment, white matter change, and regional brain atrophy within each diagnostic group. Cerebrospinal fluid NFL concentration (median [interquartile range]) was higher in the AD dementia group (1479 [1134-1842] pg/mL), stable MCI group (no progression to AD during follow-up; 1182 [923-1687] pg/mL), and progressive MCI group (MCI with progression to AD dementia during follow-up; 1336 [1061-1693] pg/mL) compared with control participants (1047 [809-1265] pg/mL) (P < .001 for all) and in the AD dementia group compared with the stable MCI group (P = .01). In the MCI group, a higher CSF NFL concentration was associated with faster brain atrophy over time as measured by changes in whole-brain volume (β = -4177, P = .003), ventricular volume (β = 1835, P < .001), and hippocampus volume (β = -54.22, P < .001); faster disease progression as reflected by decreased Mini-Mental State Examination scores (β = -1.077, P < .001) and increased Alzheimer Disease Assessment Scale cognitive subscale scores (β = 2.30, P < .001); and faster white matter intensity change (β = 598.7, P < .001). Cerebrospinal fluid NFL concentration is increased by the early clinical stage of AD and is associated with cognitive deterioration and structural brain changes over time. This finding corroborates the contention that degeneration of large-caliber axons is an important feature of AD neurodegeneration.

Cerebrospinal fluid neurogranin: relation to cognition and neurodegeneration in Alzheimer's disease.

Synaptic dysfunction is linked to cognitive symptoms in Alzheimer's disease. Thus, measurement of synapse proteins in cerebrospinal fluid may be useful biomarkers to monitor synaptic degeneration. Cerebrospinal fluid levels of the postsynaptic protein neurogranin are increased in Alzheimer's disease, including in the predementia stage of the disease. Here, we tested the performance of cerebrospinal fluid neurogranin to predict cognitive decline and brain injury in the Alzheimer's Disease Neuroimaging Initiative study. An in-house immunoassay was used to analyse neurogranin in cerebrospinal fluid samples from a cohort of patients who at recruitment were diagnosed as having Alzheimer's disease with dementia (n = 95) or mild cognitive impairment (n = 173), as well as in cognitively normal subjects (n = 110). Patients with mild cognitive impairment were grouped into those that remained cognitively stable for at least 2 years (stable mild cognitive impairment) and those who progressed to Alzheimer's disease dementia during follow-up (progressive mild cognitive impairment). Correlations were tested between baseline cerebrospinal fluid neurogranin levels and baseline and longitudinal cognitive impairment, brain atrophy and glucose metabolism within each diagnostic group. Cerebrospinal fluid neurogranin was increased in patients with Alzheimer's disease dementia (P < 0.001), progressive mild cognitive impairment (P < 0.001) and stable mild cognitive impairment (P < 0.05) compared with controls, and in Alzheimer's disease dementia (P < 0.01) and progressive mild cognitive impairment (P < 0.05) compared with stable mild cognitive impairment. In the mild cognitive impairment group, high baseline cerebrospinal fluid neurogranin levels predicted cognitive decline as reflected by decreased Mini-Mental State Examination (P < 0.001) and increased Alzheimer's Disease Assessment Scale-cognitive subscale (P < 0.001) scores at clinical follow-up. In addition, high baseline cerebrospinal fluid neurogranin levels in the mild cognitive impairment group correlated with longitudinal reductions in cortical glucose metabolism (P < 0.001) and hippocampal volume (P < 0.001) at clinical follow-up. Furthermore, within the progressive mild cognitive impairment group, elevated cerebrospinal fluid neurogranin levels were associated with accelerated deterioration in Alzheimer's Disease Assessment Scale-cognitive subscale (β = 0.0017, P = 0.01). These data demonstrate that cerebrospinal fluid neurogranin is increased already at the early clinical stage of Alzheimer's disease and predicts cognitive deterioration and disease-associated changes in metabolic and structural biomarkers over time.

EPA-0190 – Novel upstream markers of amyloid precursor protein processing in the diagnosis and prognosis of alzheimer's disease

To assess cerebrospinal fluid (CSF) β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) activity in relation to Alzheimer's disease (AD) and to correlate the enzyme activity with protein markers of APP metabolism and axonal degeneration. BACE1 activity and protein concentrations were measured and analysed in 342 participants of the AD Neuroimaging Initiative, including 99 normal controls, 75 stable mild cognitive impairment (MCI), 87 progressive MCI and 79 AD dementia cases. All statistical analyses were Bonferroni corrected for multiple comparisons. No significant differences between controls and any of the three patient groups were detected for BACE1 activity and soluble APP (sAPP)β concentrations in CSF. Significant correlations with BACE1 activity were found for CSF APPβ and total tau in all four groups; and for CSF phosphorylated tau181 in all groups but the progressive MCI group. There were no correlations for CSF amyloid β (Aβ) 1–42 nor for plasma Aβ 1–42 and Aβ 1–40 . The consistent correlation between BACE1 activity and sAPPβ supports their role as biomarkers of target engagement in clinical trials on BACE1 inhibition.

Cerebrospinal fluid BACE1 activity and markers of amyloid precursor protein metabolism and axonal degeneration in Alzheimer's disease

ObjectiveThe objective of this study was to assess cerebrospinal fluid (CSF) β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) activity in relation to Alzheimer's disease (AD) and to correlate the enzyme activity with protein markers of APP metabolism and axonal degeneration. MethodsBACE1 activity and protein concentrations were measured and analyzed in 342 participants of the Alzheimer's Disease Neuroimaging Initiative, including 99 normal control, 75 stable mild cognitive impairment (MCI), 87 progressive MCI, and 79 AD dementia cases. All statistical analyses were Bonferroni corrected for multiple comparisons. ResultsNo significant differences between controls and any of the three patient groups were detected for BACE1 activity and soluble APPβ (sAPPβ) concentrations in CSF. Significant correlations with BACE1 activity were found for CSF APPβ and total tau in all four groups and for CSF phosphorylated tau181 in all groups but the progressive MCI group. There were no correlations for CSF amyloid β (Aβ)1-42 or for plasma Aβ1-42 and Aβ1-40. ConclusionsThe consistent correlation between BACE1 activity and sAPPβ supports their role as biomarkers of target engagement in clinical trials on BACE1 inhibition.

Cortical Thickness in Frontotemporal Dementia, Mild Cognitive Impairment, and Alzheimer's Disease

Cortical thickness analysis has been proposed as a potential diagnostic measure in memory disorders. In this retrospective study, we compared the cortical thickness values of 24 patients with frontotemporal dementia (FTD) to those of 25 healthy controls, 45 symptomatic subjects with stable mild cognitive impairment (S-MCI), 15 subjects with progressive mild cognitive impairment (P-MCI), and 36 patients with Alzheimer's disease (AD). The patterns of regions of thinning in FTD when compared to controls and also S-MCI patients showed similar trends; thinning of the bilateral frontal poles and bilateral medial temporal lobe structures, especially the anterior part of the gingulum, the uncus, and parahippocampal gyri. Cortical thinning in FTD was also found on the boundary regions of parietal and occipital lobes. In the P-MCI group compared to FTD, the trend of thinning in small distinct areas of the parietal and occipital lobes was observed. The FTD and AD groups did not differ statistically, but we found trends toward thinning in FTD of the left cingulate gyrus, and the left occipitotemporal gyri, and in AD of the inferior parietal, occipitoparietal, and the pericalcarine regions, more in the right hemisphere. In FTD, increased slowness in the executive test (Trail-Making A) correlated with the thinner cortex, whereas the language tests showed the lower scores, the thinner cortex in the left hemisphere. Cortical thickness might be a tool for detecting subtle changes in brain atrophy in screening of dementia prior to the development of diffuse or lobar atrophies.

Evolution of Global and Local Grey Matter Atrophy on Serial MRI Scans During the Progression from MCI to AD

Mild cognitive impairment (MCI) often represents a prodromal form of dementia, conferring a significantly higher risk of converting to probable Alzheimer's disease (AD). The aim of this study is to characterise the differences of grey matter (GM) distribution and dynamics between progressive and stable MCI subjects during a 2 year period preceding the conversion to AD. We included 48 stable MCI and 12 progressive MCI cases based on the availability of 3 serial scans acquired with approximately 1 year scan interval. For the progressive MCI group, the third scan was acquired at the time of the clinical diagnosis of AD, while the first two scans were acquired approximately 2 and 1 years earlier. For the stable MCI group, the three scans were acquired at approximately 1 year intervals during a period free from significant cognitive decline. We used longitudinal voxel-based morphometry (VBM) for mapping the progression of GM loss over time. For the progressive MCI group, the cross-sectional analysis revealed areas of lower GM volumes in the parahippocampal gyrus, precuneus and posterior cingulate 12 months before the AD diagnosis. For the longitudinal VBM analysis the progressive MCI group revealed increased GM loss in cortical regions belonging to the temporal neocortex, parahippocampal cortex, and cingulate gyrus. The frontal lobe, insula and the cerebellum were also affected. This accelerated atrophy may offer new insights into the understanding of neurodegenerative pathology and the clinical relevance of these changes remains to be verified by subsequent studies.

Cortical Thickness Analysis to Detect Progressive Mild Cognitive Impairment: A Reference to Alzheimer’s Disease

Background/Aims: Mild cognitive impairment (MCI) is associated with an increased risk of Alzheimer’s disease (AD). It would be advantageous to be able to distinguish the characteristics of those MCI patients with a high probability to progress to AD if one wishes to monitor the disease development and treatment. Methods: We assessed the baseline MRI and maximum of 7 years clinical follow-up data of 60 MCI subjects in order to examine differences in cortical thickness (CTH) between the progressive MCI (P-MCI) and stable MCI (S-MCI) subjects. CTH was measured using an automatic computational surface-based method. During the follow-up, 15 MCI subjects converted to AD on average 1.9 ± 1.3 years after the baseline examination, while 45 MCI subjects remained stable. Results: The P-MCI group displayed significantly reduced CTH bilaterally in the superior and middle frontal, superior, middle and inferior temporal, fusiform and parahippocampal regions as well as the cingulate and retrosplenial cortices and also in the right precuneal and paracentral regions compared to S-MCI subjects. Conclusions: Analysis of CTH could be used in conjunction with neuropsychological testing to identify those subjects with imminent conversion from MCI to AD several years before dementia diagnosis.

APOLIPOPROTEIN E GENOTYPE FREQUENCIES IN A PROSPECTIVE STUDY OF SPORADIC LATE -ONSET DEMENTIA.

Background and Significance The correlation of apolipoprotein E (ApoE) genotype frequencies with the development of sporadic progressive late-onset dementia has been demonstrated in several studies. In particular, the risk effect of the ApoE 4 allele in the development of Alzheimer9s disease (AD) has been well documented. Over the past 4 years we have studied a cohort of 76 patients with mild cognitive impairment (MCI) and 28 controls and followed the cognitive course of these cases with serial psychometric examinations and MRI sequences that include susceptibility weighted imaging (SWI) to determine iron content. Serial blood samples have been collected for multiple systems of analysis, and this report deals with the analysis of patient DNA for identification of ApoE genotype. The aim of this study is to correlate the identified ApoE allelic frequencies in these cases with progression from MCI to mild AD. Methods The subjects consist of a community-based cohort of 76 MCI and 28 cognitively normal participants studied with IRB approval. Classifications of MCI were based on the Mayo Clinic rating criteria, and all cases had psychometric examinations to diagnose them as normal, MCI, and progressive MCI (PMCI) or AD. Patient DNA was extracted using standard techniques and the 270 bp polymorphic region of ApoE was amplified by PCR with primers that have previously been used. The DNA digestion was carried out with HhaI endonucleases and the resulting samples were visualized on both 4% agarose and 0.8% acrylamide gels for identification of the three different isoforms of ApoE. Results and Conclusions The frequency of the genotypes for ApoE 2, 3, and 4 for the normal control population were 4.1% E2, 77.1% E3, and 14.5% E4. The stable MCI population frequencies were 9.1% E2, 75% E3, and 15.9% E4. However, the frequencies for the PMCI group were 0% E2, 75% E3, and 25% E4. These results confirm the role of ApoE 4 as a risk factor for AD. In addition, it appears that the ApoE 2 allele may be protective against the development of dementia. We are in the process now of doing additional studies to assess the relevance of patient genotypes to developing AD and brain microhemorrhages as indicated by SWI studies.

Cerebrospinal fluid tau protein and periventricular white matter lesions in patients with mild cognitive impairment: implications for 2 major pathways.

Mild cognitive impairment (MCI) may be a heterogeneous condition rather than a uniform disease entity. To develop reliable tools that aid in identifying patients at risk of developing Alzheimer disease (AD) among heterogeneous populations with MCI to maximize the benefits of emerging therapies for AD. A 2-year prospective study. Clinical follow-up in an outpatient memory clinic. Seventy-two consecutive older patients with memory complaints. Cerebrospinal fluid tau levels, severity of periventricular and deep white matter lesions, silent brain infarction on magnetic resonance imaging, plasma homocysteine levels, apolipoprotein E genotype, and other vascular risk factors were assessed at baseline. Fifty-seven patients were diagnosed as having amnestic MCI. Forty-one patients with (AD-converted MCI group) or without (progressive MCI group) conversion to dementia and AD progressed over time, whereas the other 16 patients remained cognitively stable (stable MCI group). The stable MCI group was characterized by normal cerebrospinal fluid tau levels and a high grade of periventricular white matter lesions (PWMLs). The progressive MCI and AD-converted MCI groups had increased cerebrospinal fluid tau levels and low grades of PWMLs. A logistic regression model showed that age was significantly associated with developing PWMLs (P =.03; odds ratio, 1.15; 95% confidence interval, 1.0-1.3). Tau-related AD pathologic conditions and possibly ischemic PWMLs represent 2 major etiologies in the development of MCI, reflecting heterogeneity in the clinical progression. Because the progressive type of MCI may be a primary target of clinical trials that aim at secondary prevention of dementia, these patients should be identified by appropriate biomarkers and neuroimaging techniques.