CSF Abeta42, tau and phosphorylated tau correlate with medial temporal lobe atrophy

Cerebrospinal fluid (CSF) biomarkers and medial temporal lobe (MTL) atrophy predict the progression of mild cognitive impairment (MCI) to Alzheimer's disease (AD). We investigated the association between the CSF biomarkers and MTL atrophy and the ability of these measures to predict AD in MCI patients in the same study population. The study included 21 MCI patients of whom eight progressed to AD during the study. CSF biomarkers were measured by using ELISA method and volumes of MTL structures were assessed by magnetic resonance imaging (MRI). Abeta42 levels were lower and tau and phospho-tau levels were higher in progressive subjects. The progressive subjects had lower volumes in all MRI measures. Tau and phospho-tau correlated inversely with hippocampal volumes and left entorhinal cortex volume in the whole study group. In the stable group, tau correlated with hippocampal volumes. Abeta42 had a negative correlation whereas phospho-tau exhibited a positive correlation with left hippocampal volume in the progressive group. These results indicate that both measures may reflect the ongoing neurodegenerative process in the progressive MCI patients. However, the order of the changes in the CSF biomarkers and MTL atrophy remain unclear due to a small number of studied subjects and study design.     

Differing patterns of temporal atrophy in Alzheimer's disease and semantic dementia

OBJECTIVE: To characterize and quantify the patterns of temporal lobe atrophy in AD vs semantic dementia and to relate the findings to the cognitive profiles. Medial temporal lobe atrophy is well described in AD. In temporal variant frontotemporal dementia (semantic dementia), clinical studies suggest polar and inferolateral temporal atrophy with hippocampal sparing, but quantification is largely lacking. METHODS: A volumetric method for quantifying multiple temporal structures was applied to 26 patients with probable AD, 18 patients with semantic dementia, and 21 matched control subjects. RESULTS: The authors confirmed the expected bilateral hippocampal atrophy in AD relative to controls, with involvement of the amygdala bilaterally and the right parahippocampal gyrus. Contrary to expectations, patients with semantic dementia had asymmetric hippocampal atrophy, more extensive than AD on the left. As predicted, the semantic dementia group showed more severe involvement of the temporal pole bilaterally and the left amygdala, parahippocampal gyrus (including the entorhinal cortex), fusiform gyrus, and the inferior and middle temporal gyri. Performance on semantic association tasks correlated with the size of the left fusiform gyrus, whereas naming appeared to depend upon a wider left temporal network. Episodic memory measures, with the exception of recognition memory for faces, did not correlate with temporal measures. CONCLUSIONS: Hippocampal atrophy is not specific for AD but is also seen in semantic dementia. Distinguishing the patients with semantic dementia was the severe global but asymmetric (left > right) atrophy of the amygdala, temporal pole, and fusiform and inferolateral temporal gyri. These findings have implications for diagnosis and understanding of the cognitive deficits in AD and semantic dementia.     

Structure and function of medial temporal and posteromedial cortices in early Alzheimer's disease

Medial temporal lobe (MTL) atrophy and posteromedial cortical hypometabolism are consistent imaging findings in Alzheimer's disease (AD). As the MTL memory structures are affected early in the course of AD by neurofibrillary tangle pathology, the posteromedial metabolic abnormalities have been postulated to represent remote effects of MTL alterations. In this study, we investigated with functional MRI (fMRI) the structure-function relationship between the MTL and posteromedial regions, including the retrosplenial, posterior cingulate and precuneal cortices, in 21 older controls (OCs), 18 subjects with amnestic mild cognitive impairment (MCI) and 16 AD patients during a word list learning task. In the voxel-based morphometric and volumetric analyses, the MCI subjects showed smaller entorhinal volume than OCs (P = 0.0001), whereas there was no difference in the hippocampal or posteromedial volume. AD patients, as compared with MCI patients, showed pronounced loss of volume in the entorhinal (P = 0.0001), hippocampal (P = 0.01) and posteromedial (P = 0.001) regions. The normal pattern of posteromedial fMRI task-induced deactivation during active encoding of words was observed bilaterally in the OCs, but only in restricted unilateral left posteromedial areas in the MCI and AD patients. Across all subjects, more extensive impairment of the retrosplenial and posterior cingulate function was significantly related to smaller entorhinal (P = 0.001) and hippocampal (P = 0.0002) volume. These findings demonstrate that entorhinal atrophy and posteromedial cortical dysfunction are early characteristics of prodromal AD, and precede and/or overwhelm atrophy of the hippocampus and posteromedial cortices. Disturbances in posteromedial cortical function are associated with morphological changes in the MTL across the continuum from normal aging to clinical AD.     

Plasma biomarkers for mild cognitive impairment and Alzheimer's disease

Purpose of review: With the move toward development of disease modifying treatments, there is a need for more specific diagnosis of early Alzheimer's disease (AD) and mild cognitive impairment (MCI), plasma biomarkers are likely to play an important role in this. We review the current state of knowledge on plasma biomarkers for MCI and AD, including unbiased proteomics and very recent longitudinal studies.Recent findings: With the use of proteomics methodologies, some proteins have been identified as potential biomarkers in plasma and serum of AD patients, including alpha-1-antitrypsin, complement factor H, alpha-2-macroglobulin, apolipoprotein J, apolipoprotein A-I. The findings of cross-sectional studies of plasma amyloid beta (Aβ) levels are conflicting, but some recent longitudinal studies have shown that low plasma Aβ1–42 or Aβ1–40 levels, or Aβ1–42/Aβ1–40 ratio may be markers of cognitive decline. Other potential biomarkers for MCI and AD reflecting a variety of pathophysiological processes have been assessed, including isoprostanes and homocysteine (oxidative stress), total cholesterol and ApoE4 allele (lipoprotein metabolism), and cytokines and acute phase proteins (inflammation). A panel of 18 signal proteins was reported as markers of MCI and AD.Summary: A variety of potential plasma biomarkers for AD and MCI have been identified, however the findings need replication in longitudinal studies. This area of research promises to yield interesting results in the near future.     

Episodic memory impairment in patients with Alzheimer’s disease is correlated with entorhinal cortex atrophy

The aims of this study were to investigate the pattern of cortical atrophy and the relationships between memory performances and the brain regions in Alzheimer's Disease (AD). optimized voxel-based morphometry (VBM) was applied to the MRI brain images of 18 probable AD and 18 healthy subjects (HS). Patients performed verbal and visuo-spatial episodic and shortterm memory tests. Contrasting of AD group with HS, and anatomobehavioural correlations were carried out in order to identify regional atrophic changes and neuro-cognitive aspects in AD group. We found evidence of gray matter (GM) volume reduction in AD in the medial temporal, parietal and frontal areas bilaterally and in the left anterior thalamic nuclei. Performance on the episodic memory delayed recall tests co-varied with GM volume in the left entorhinal cortex. The pattern of cortical atrophy likely reflects the heterogeneous level of dementia severity in our AD group. The anatomical region affected in the left hemisphere indicates a sufferance at multiple levels of the Polysynaptic Hippocampal Pathway, which is involved in declarative memory. Findings on the entorhinal cortex and the delayed memory scores support the role of the entorhinal cortex in episodic memory. Damage to the entorhinal cortex, deafferenting the hippocampus from neocortical inputs, interferes with episodic memory consolidation in AD patients.     

Plasma multianalyte profiling in mild cognitive impairment and Alzheimer disease

OBJECTIVES: While plasma biomarkers have been proposed to aid in the clinical diagnosis of Alzheimer disease (AD), few biomarkers have been validated in independent patient cohorts. Here we aim to determine plasma biomarkers associated with AD in 2 independent cohorts and validate the findings in the multicenter Alzheimer's Disease Neuroimaging Initiative (ADNI). METHODS: Using a targeted proteomic approach, we measured levels of 190 plasma proteins and peptides in 600 participants from 2 independent centers (University of Pennsylvania, Philadelphia; Washington University, St. Louis, MO), and identified 17 analytes associated with the diagnosis of very mild dementia/mild cognitive impairment (MCI) or AD. Four analytes (apoE, B-type natriuretic peptide, C-reactive protein, pancreatic polypeptide) were also found to be altered in clinical MCI/AD in the ADNI cohort (n = 566). Regression analysis showed CSF Aβ42 levels and t-tau/Aβ42 ratios to correlate with the number of APOE4 alleles and plasma levels of B-type natriuretic peptide and pancreatic polypeptide. CONCLUSION: Four plasma analytes were consistently associated with the diagnosis of very mild dementia/MCI/AD in 3 independent clinical cohorts. These plasma biomarkers may predict underlying AD through their association with CSF AD biomarkers, and the association between plasma and CSF amyloid biomarkers needs to be confirmed in a prospective study.     

Neuroimaging as a marker of the onset and progression of Alzheimer's disease

Several neuroimaging techniques are promising tools as early markers of brain pathology in Alzheimer's disease (AD). On structural MRI, atrophy of the entorhinal cortex is present already in mild cognitive impairment (MCI). In the autosomal dominant forms of AD, the rate of atrophy of medial temporal structures separates affected from control persons even 3 years before the clinical onset of cognitive impairment. The elevated annual rate of brain atrophy offers a surrogate tool for the evaluation of newer therapies using smaller samples, thereby saving time and resources. On functional MRI, activation paradigms activate a larger area of parieto-temporal association cortex in persons at higher risk for AD, whereas the entorhinal cortex activation is lesser in MCI. Similar findings have been detected with activation procedures and water (H(2)(15)O) PET. Regional metabolism in the entorhinal cortex, studied with FDG PET, seems to predict normal elderly who will deteriorate to MCI or AD. SPECT shows decreased regional perfusion in limbic areas, both in MCI and AD, but with a lower likelihood ratio than PET. Newer PET compounds allow for the determination in AD of microglial activation, regional deposition of amyloid and the evaluation of enzymatic activity in the brain of AD patients.     

Selective regional loss of exocytotic presynaptic vesicle proteins in Alzheimer's disease brains

We tested whether regional or selective alterations in presynaptic proteins occur in Alzheimer's disease (AD) and correlate with tests of cognitive function. We measured the levels of seven presynaptic proteins (synaptobrevin, synaptotagmin, SNAP-25, syntaxin, SV2, Rab3a, and synapsin I) by immunoblotting in postmortem tissue from four brain regions (hippocampus, entorhinal cortex, caudate nucleus, and occipital cortex). Three subject groups were studied: AD, possible/early AD (p-AD), and age-matched controls. Synaptobrevin and synaptotagmin were significantly reduced (29%, P<0.08; 38%, P<0. 07) in hippocampus in p-AD compared to controls. In definite AD compared to controls, selective regional reductions in vesicle proteins were found: synaptobrevin (46%, P<0.05), synaptotagmin (52%, P<0.01), and Rab3a (30%, P<0.05) in hippocampus; synaptobrevin (31%, P<0.01), synaptotagmin (15%, P<0.05), and Rab3a (44%, P<0.05) in entorhinal cortex. In contrast, the levels of two vesicle proteins (synapsin I and SV2) and two presynaptic membrane proteins (syntaxin and SNAP-25) were similar to controls. Synaptobrevin was the only vesicle protein reduced in AD in all four brain regions (occipital cortex 37%, P<0.05; caudate nucleus 31%, P<0.05). By univariate analysis of all cases, Mini-Mental State Examination, Blessed (BIMC) and Free Recall scores were strongly correlated with reduced levels of synaptic vesicle proteins synaptobrevin, synaptotagmin, and Rab3a in hippocampus and entorhinal cortex. These results suggest that there are selective and early defects in presynaptic vesicle proteins, but not synaptic plasma membrane proteins in AD and that defects correlate with cognitive dysfunction in this disease.     

Grey-matter atrophy in Alzheimer's disease is asymmetric but not lateralized

In Alzheimer's disease (AD), brain atrophy has been proposed to be left lateralized. Here, we reinvestigated the asymmetry and lateralization (i.e., asymmetry directed toward one hemisphere) of grey-matter (GM) distribution in 35 patients with AD, 24 patients with amnestic mild cognitive impairment (aMCI, a state of increased risk for AD), and 30 age-matched healthy controls (HC). We analyzed GM distribution by applying voxel-based morphometry (VBM) including analyses for asymmetry and lateralization. When comparing MCI with AD patients, VBM revealed GM loss in the entorhinal, temporoparietal, dorsofrontal, and occipital cortices as well as in the precuneus; when comparing HCs with MCI patients, we found similar differences, which were less pronounced especially within the temporoparietal cortex and precuneus. Analyses of regional asymmetry and regional lateralization as well as global lateralization did not yield significant results. However, lobar asymmetry of the temporal, parietal, and occipital lobes increased from HC to AD. Moreover, in aMCI and AD patients, performance of language-based neuropsychological tests correlated with lateralization of GM loss to the left hemisphere. We conclude that, in principle, brain atrophy in AD is asymmetric rather than lateralized. At the individual level however, asymmetry contributes to cognitive deficits.     

The Alzheimer's Disease Neuroimaging Initiative: Annual change in biomarkers and clinical outcomes

BackgroundThe Alzheimer's Disease Neuroimaging Initiative Phase 1 (ADNI-1) is a multisite prospective study designed to examine potential cerebrospinal fluid and imaging markers of Alzheimer's disease (AD) and their relationship to cognitive change. The objective of this study was to provide a global summary of the overall results and patterns of change observed in candidate markers and clinical measures over the first 2 years of follow-up.MethodsChange was summarized for 210 normal controls, 357 mild cognitive impairment, and 162 AD subjects, with baseline and at least one cognitive follow-up assessment. Repeated measures and survival models were used to assess baseline biomarker levels as predictors. Potential for improving clinical trials was assessed by comparison of precision of markers for capturing change in hypothetical trial designs.ResultsThe first 12 months of complete data on ADNI participants demonstrated the potential for substantial advances in characterizing trajectories of change in a range of biomarkers and clinical outcomes, examining their relationship and timing, and assessing the potential for improvements in clinical trial design. Reduced metabolism and greater brain atrophy in the mild cognitive impairment at baseline are associated with more rapid cognitive decline and a higher rate of conversion to AD. Use of biomarkers as study entry criteria or as outcomes could reduce the number of participants required for clinical trials.ConclusionsAnalyses and comparisons of ADNI data strongly support the hypothesis that measurable change occurs in cerebrospinal fluid, positron emission tomography, and magnetic resonance imaging well in advance of the actual diagnosis of AD.     

N-Methyl-D-aspartate receptor subunit proteins and their phosphorylation status are altered selectively in Alzheimer's disease

The N-methyl-D-aspartate (NMDA) receptor is a subtype of the ionotropic glutamate receptor that plays a pivotal role in synaptic mechanisms of learning and memory. We tested the hypothesis that NMDA receptor protein levels are abnormal in Alzheimer's disease (AD). By immunoblotting, we assessed levels of both non-phosphorylated and phosphorylated receptor subunit proteins from four separate regions of 16 post-mortem brains. Three patient groups with thorough pre-mortem neuropsychological testing were evaluated, including AD, early AD (p-AD), and control patients. Protein levels and phosphorylation status of NMDA receptor subunits NR1, NR2A and NR2B were correlated with measurements of cognitive performance. Selective regional reductions in NMDA receptor subunit protein levels were found in AD compared to controls, but protein levels in the p-AD group were similar to controls. Reductions of NR1 (53%, P<0.05) and NR2B (40%, P<0.05) were identified in hippocampus. Reductions of NR2A (39%, P<0.05) and NR2B (31%, P<0.01) were found in entorhinal cortex. No reductions were noted in occipital cortex and caudate. Phosphorylated NR2A (30%, P<0.05) and NR2B (56%, P<0.01) were selectively reduced in entorhinal cortex in AD when compared to controls. Both phosphorylated and non-phosphorylated NMDA receptor protein levels in entorhinal cortex correlated with Mini-Mental Status Examination (MMSE) and Blessed (BIMC) scores. The losses of phosphorylated and non-phosphorylated NMDA receptor subunit proteins correlated with changes in synaptobrevin levels (a presynaptic protein), but not with age or post-mortem interval. Our results demonstrate that NMDA receptor subunits are selectively and differentially reduced in areas of AD brain, and these abnormalities correlate with presynaptic alterations and cognitive deficits in AD.     

Impaired visual recognition memory in amnestic mild cognitive impairment is associated with mesiotemporal metabolic changes on magnetic resonance spectroscopic imaging

In the early stages of Alzheimer's disease (AD), neurofibrillary tangles develop in the mesial temporal lobe (MTL), first in the anterior subhippocampal (perirhinal/entorhinal) cortex and then in the hippocampal formation. This region plays a key role in visualrecognition memory (VRM). VRM has been reported to be impaired in patients with amnestic mild cognitive impairment (aMCI). The aim of the present study was to determine if an impairment of VRM is associated with metabolic changes in the MTL using magnetic resonance spectroscopic imaging and if evaluating VRM can contribute to the early diagnosis of AD. 28 patients with aMCI and 28 controls underwent a full neuropsychological assessment including an evaluation of VRM using the DMS48. NAA/mIno ratios, reduced in patients with AD and associated with the severity of pathological changes, were determined in the MTL. aMCI-patients were further divided into two subgroups according to their VRM performance. aMCI-patients showed decreased NAA/mIno levels in the right hippocampus compared with controls. aMCI-patients with impaired VRM showed decreased NAA/mIno ratios in the MTL bilaterally, including a region that sampled the left anterior subhippocampal cortex, compared to controls. No changes were found in aMCI patients with normal VRM. Performance on the DMS48 correlated with NAA/mIno levels in the anterior MTL. Clinical 6-year follow-up data (available for 78.6% of the aMCI-patients) indicates that impaired performance on the DMS48 could predict conversion to AD with a sensitivity and specificity of 81.8%. These findings provide further evidence that impaired VRM, as a hallmark of MTL dysfunction, may contribute to the early diagnosis of AD.     

Loss and atrophy of layer II entorhinal cortex neurons in elderly people with mild cognitive impairment

Layer II of the entorhinal cortex contains the cells of origin for the perforant path, plays a critical role in memory processing, and consistently degenerates in end-stage Alzheimer's disease. The extent to which neuron loss in layer II of entorhinal cortex is related to mild cognitive impairment without dementia has not been extensively investigated. We analyzed 29 participants who came to autopsy from our ongoing longitudinal study of aging and dementia composed of religious clergy (Religious Orders Study). All individuals underwent detailed clinical evaluation within 12 months of death and were categorized as having no cognitive impairment (n = 8), mild cognitive impairment (n = 10), or mild or moderate Alzheimer's disease (n = 11). Sections through the entorhinal cortex were immunoreacted with an antibody directed against a neuron-specific nuclear protein (NeuN). Stereological counts of NeuN-immunoreactive stellate cells, their volume, and the volume of layer II entorhinal cortex were estimated. Cases exhibiting no cognitive impairment averaged 639,625 +/- 184,600 layer II stellate neurons in the right entorhinal cortex. Individuals with mild cognitive impairment (63.5%; p < 0.0003) and mild or moderate Alzheimer's disease (46.06%; p < 0.0017) displayed significant losses of layer II entorhinal cortex neurons relative to those with no cognitive impairment but not relative to each other (p > 0.33). There was also significant atrophy of layer II entorhinal cortex neurons in individuals with mild cognitive impairment (24.1%) and Alzheimer's disease (25.1%). The volume of layer II was also reduced in individuals with mild cognitive impairment (26.5%), with a further reduction in those with Alzheimer's disease (46.4%). The loss and atrophy of layer II entorhinal cortex neurons significantly correlated with performance on clinical tests of declarative memory. Atrophy of layer II entorhinal cortex and the neurons within this layer significantly correlated with performance on the Mini Mental Status Examination. These data indicate that atrophy and loss of layer II entorhinal cortex neurons occur in elderly subjects with mild cognitive impairment prior to the onset of dementia and suggests that these changes are not exacerbated in early Alzheimer's disease.     

Cerebrospinal fluid profile in frontotemporal dementia and Alzheimer's disease

We assessed cerebrospinal fluid (CSF) levels of tau and other biomarkers of neurodegenerative disease. CSF tau levels vary widely in reports of frontotemporal dementia (FTD). CSF samples were assayed for tau, amyloid beta1-42 (A1-42), and the isoprostane 8,12-iso-iPF2a-VI (iP) prospectively in 64 patients with FTD, retrospectively in 26 autopsied cases with FTD or Alzheimer's disease (AD), and in 13 healthy seniors. To validate our observations in vivo, we correlated CSF tau levels with cortical atrophy in 17 FTD patients using voxel-based morphometry analyses of high-resolution magnetic resonance imaging. CSF levels of tau, Abeta1-42, and iP differed significantly in FTD compared with AD. Individual patient analyses showed that 34% of FD patients had significantly low levels of CSF tau, although this was never seen in AD. A discriminant analysis based on CSF levels of tau, Abeta1-42, and iP was able to classify 88.5% of these patients in a manner that corresponds to their clinical or autopsy diagnosis. Magnetic resonance imaging studies showed that CSF tau levels correlate significantly with right frontal and left temporal cortical atrophy, brain regions known to be atrophic in patients with autopsy-proved FTD. We conclude that CSF tau levels are significantly reduced in many patients with FTD.     

Core candidate neurochemical and imaging biomarkers of Alzheimer’s disease

BackgroundIn the earliest clinical stages of Alzheimer’s disease (AD) when symptoms are mild, clinical diagnosis can be difficult. AD pathology most likely precedes symptoms. Biomarkers can serve as early diagnostic indicators or as markers of preclinical pathologic change. Candidate biomarkers derived from structural and functional neuroimaging and those measured in cerebrospinal fluid (CSF) and plasma show the greatest promise. Unbiased exploratory approaches, eg, proteomics or cortical thickness analysis, could yield novel biomarkers. The objective of this article was to review recent progress in selected imaging and neurochemical biomarkers for early diagnosis, classification, progression, and prediction of AD.MethodsWe performed a survey of recent research, focusing on core biomarker candidates in AD.ResultsA number of in vivo neurochemistry and neuroimaging techniques, which can reliably assess aspects of physiology, pathology, chemistry, and neuroanatomy, hold promise as biomarkers. These neurobiologic measures appear to relate closely to pathophysiologic, neuropathologic, and clinical data, such as hyperphosphorylation of tau, amyloid beta (Aβ) metabolism, lipid peroxidation, pattern and rate of atrophy, loss of neuronal integrity, functional and cognitive decline, as well as risk of future decline. Current advances in the neuroimaging of mediotemporal, neocortical, and subcortical areas of the brain of mild cognitive impairment (MCI) and AD subjects are presented. CSF levels of Aβ42, tau, and hyperphosphorylated tau protein (p-tau) can distinguish subjects with MCI who are likely to progress to AD. They also show preclinical alterations that predict later development of early AD symptoms. Studies on plasma Aβ are not entirely consistent, but recent findings suggest that decreased plasma Aβ42 relative to Aβ40 might increase the risk of AD. Increased production of Aβ in aging is suggested by elevation of BACE1 protein and enzyme activity in the brain and CSF of subjects with MCI. CSF tau and p-tau are increased in MCI as well and show predictive value. Other biomarkers might indicate components of a cascade initiated by Aβ, such as oxidative stress or inflammation. These merit further study in MCI and earlier.ConclusionsA number of neuroimaging candidate markers are promising, such as hippocampus and entorhinal cortex volumes, basal forebrain nuclei, cortical thickness, deformation-based and voxel-based morphometry, structural and effective connectivity by using diffusion tensor imaging, tractography, and functional magnetic resonance imaging. CSF Aβ42, BACE1, total tau, and p-tau are substantially altered in MCI and clinical AD. Other interesting novel marker candidates derived from blood are being currently proposed (phase I). Biomarker discovery through proteomic approaches requires further research. Large-scale international controlled multicenter trials (such as the U.S., European, Australian, and Japanese Alzheimer’s Disease Neuroimaging Initiative and the German Dementia Network) are engaged in phase III development of the core feasible imaging and CSF biomarker candidates in AD. Biomarkers are in the process of implementation as primary outcome variables into regulatory guideline documents regarding study design and approval for compounds claiming disease modification.     

Variability in blood-based amyloid-beta assays: the need for consensus on pre-analytical processing

The objective of this study was to examine the diagnostic accuracy of imaging and CSF biomarkers in clinically ambiguous dementia (CAD). 69 patients were prospectively followed. The endpoint was clinical diagnosis at follow-up of 24 months based upon existing criteria. Medial temporal lobe atrophy score on MRI, distinctive patterns on 99 mTc-HMPAO-SPECT, and CSF levels of amyloid-β peptide, total tau protein, and P-tau181P were used together with neuropsychological testing to assess Se (sensitivity) and Sp (specificity) of separate and combined markers. 60 patients reached the endpoint. A definite diagnosis was achieved in 48 patients. CSF biomarkers had a Sp of 71% and a Se of 100% for Alzheimer's disease (AD) diagnosis. Sp increased to 88% and 93% when MRI and MRI + SPECT were combined, at the expense of Se. CSF biomarkers levels also provided clues to frontotemporal (FTD) or vascular dementias (VaD) diagnosis when situated in an intermediate range between normal and pathological values. MRI and SPECT contributed mostly to the diagnosis of VaD (Se 88%, Sp 75%) and FTD (Se 73%, Sp 78%), respectively. Initial neuropsychological testing had a poor diagnostic accuracy, except for a neuropsychiatric inventory score >40 for the diagnosis of FTD (Se 73%, Sp 84%). Independent of the clinical diagnosis, medial temporal lobe atrophy and total-tau were best correlated with cognitive decline at 2 years. In conclusion, CSF biomarkers efficiently predict evolution toward an AD phenotype in CAD. Imaging biomarkers mostly contribute to the differential diagnosis between non-AD dementias. Initial neuropsychological testing was poorly contributive in CAD diagnosis.     

Insulin-like growth factor binding protein-2 interactions with Alzheimer’s disease biomarkers

Plasma levels of insulin-like growth factor binding protein-2 (IGFBP-2) have been associated with Alzheimer’s disease (AD) and brain atrophy. Some evidence suggests a potential synergistic effect of IGFBP-2 and AD neuropathology on neurodegeneration, while other evidence suggests the effect of IGFBP-2 on neurodegeneration is independent of AD neuropathology. Therefore, the current study investigated the interaction between plasma IGFBP-2 and cerebrospinal fluid (CSF) biomarkers of AD neuropathology on hippocampal volume and cognitive function. AD Neuroimaging Initiative data were accessed (n = 354, 75 ± 7 years, 38 % female), including plasma IGFBP-2, CSF total tau, CSF Aβ-42, MRI-quantified hippocampal volume, and neuropsychological performances. Mixed effects regression models evaluated the interaction between IGFBP-2 and AD biomarkers on hippocampal volume and neuropsychological performance, adjusting for age, sex, education, APOE ε4 status, and cognitive diagnosis. A baseline interaction between IGFBP-2 and CSF Aβ-42 was observed in relation to left (t(305) = ?6.37, p = 0.002) and right hippocampal volume (t(305) = ?7.74, p = 0.001). In both cases, higher IGFBP-2 levels were associated with smaller hippocampal volumes but only among amyloid negative individuals. The observed interaction suggests IGFBP-2 drives neurodegeneration through a separate pathway independent of AD neuropathology.     

Quantitative changes in mesial temporal volume, regional cerebral blood flow, and cognition in Alzheimer's disease.

Twenty-six patients with moderately severe Alzheimer's disease (AD) and 16 normal control subjects were studied using either quantitative magnetic resonance imaging (MRI) measures of mesial temporal atrophy (15 patients with AD and 16 normal control subjects) and/or quantitative radioactive iodine 123-N-isopropyl-iodoamphetamine single-photon emission computed tomography (SPECT) assessment of regional cerebral blood flow (20 patients with AD and eight normal control subjects). Nine individuals with AD and eight normal control subjects underwent both structural and functional imaging. On MRI, patients and controls were best discriminated using left amygdala and entorhinal cortex volumes, and on SPECT they were best discriminated by relative left temporoparietal cortex blood flow. Combining these MRI and SPECT measures yielded 100% discrimination. Relative left temporoparietal SPECT regional cerebral blood flow and left superior temporal gyral MRI volume correlated best with severity of cognitive deficit in patients with AD. Mesial temporal MRI atrophy exceeded generalized cerebral shrinkage. Both SPECT and MRI regional changes accorded with areas known to be affected by AD neuropathology.     

The role of neuroimaging in mild cognitive impairment

The main purposes of neuroimaging in Alzheimer's disease (AD) have been moved from diagnosis of advanced AD to diagnosis of very early AD at a prodromal stage of mild cognitive impairment, prediction of conversion from mild cognitive impairment (MCI) to AD, and differential diagnosis from other diseases causing dementia. Structural MRI studies and functional studies using F‐18 fluorodeoxyglucose‐positron emission tomography (FDG‐PET) and brain perfusion single‐photon emission computed tomography (SPECT) are widely used in diagnosis of AD. Outstanding progress in diagnostic accuracy of these neuroimaging modalities has been obtained using statistical analysis on a voxel‐by‐voxel basis after spatial normalization of individual scans to a standardized brain‐volume template instead of visual inspection or a conventional region of interest technique. In a very early stage of AD, this statistical approach revealed gray matter loss in the entorhinal and hippocampal areas and hypometabolism or hypoperfusion in the posterior cingulate cortex and precuneus. These two findings might be related in view of anatomical knowledge that the regions are linked through the circuit of Papez. This statistical approach also offers prediction of conversion from MCI to AD. Presence of hypometabolism or hypoperfusion in parietal association areas and entorhinal atrophy at the MCI stage has been reported to predict rapid conversion to AD.     

Spatial correlation maps of the hippocampus with cerebrospinal fluid biomarkers and cognition in Alzheimer's disease: A longitudinal study

This study is an observational study that takes the existing longitudinal data from Alzheimer''s disease Neuroimaging Initiative to examine the spatial correlation map of hippocampal subfield atrophy with CSF biomarkers and cognitive decline in the course of AD. This study included 421 healthy controls (HC), 557 patients of stable mild cognitive impairment (s‐MCI), 304 Alzheimer''s Disease (AD) patients, and 241 subjects who converted to be AD from MCI (c‐MCI), and 6,525 MRI scans in a period from 2004 to 2019. Our findings revealed that all the hippocampal subfields showed their accelerated atrophy rate from cognitively normal aging to stable MCI and AD. The presubiculum, dentate gyrus, and fimbria showed greater atrophy beyond the whole hippocampus in the HC, s‐MCI, and AD groups and corresponded to a greater decline of memory and attention in the s‐MCI group. Moreover, the higher atrophy rates of the subiculum and CA2/3, CA4 were also associated with a greater decline in attention in the s‐MCI group. Interestingly, patients with c‐MCI showed that the presubiculum atrophy was associated with CSF tau levels and corresponded to the onset age of AD and a decline in attention in patients with c‐MCI. These spatial correlation findings of the hippocampus suggested that the hippocampal subfields may not be equally impacted by normal aging, MCI, and AD, and their atrophy was selectively associated with declines in specific cognitive domains. The presubiculum atrophy was highlighted as a surrogate marker for the AD prognosis along with tau pathology and attention decline.