We aimed to investigate the accuracy of FDG-PET to detect the Alzheimer's disease (AD) brain glucose hypometabolic pattern in 142 patients with amnestic mild cognitive impairment (aMCI) and 109 healthy controls. aMCI patients were followed for at least two years or until conversion to dementia. Images were evaluated by means of visual read by either moderately-skilled or expert readers, and by means of a summary metric of AD-like hypometabolism (PALZ score). Seventy-seven patients converted to AD-dementia after 28.6 ± 19.3 months of follow-up. Expert reading was the most accurate tool to detect these MCI converters from healthy controls (sensitivity 89.6%, specificity 89.0%, accuracy 89.2%) while two moderately-skilled readers were less (p < 0.05) specific (sensitivity 85.7%, specificity 79.8%, accuracy 82.3%) and PALZ score was less (p < 0.001) sensitive (sensitivity 62.3%, specificity 91.7%, accuracy 79.6%). Among the remaining 67 aMCI patients, 50 were confirmed as aMCI after an average of 42.3 months, 12 developed other dementia, and 3 reverted to normalcy. In 30/50 persistent MCI patients, the expert recognized the AD hypometabolic pattern. In 13/50 aMCI, both the expert and PALZ score were negative while in 7/50, only the PALZ score was positive due to sparse hypometabolic clusters mainly in frontal lobes. Visual FDG-PET reads by an expert is the most accurate method but an automated, validated system may be particularly helpful to moderately-skilled readers because of high specificity, and should be mandatory when even a moderately-skilled reader is unavailable.
We investigated the use of Alzheimer's disease (AD) biomarkers in European Alzheimer's Disease Consortium centers and assessed their perceived usefulness for the etiologic diagnosis of mild cognitive impairment (MCI). We surveyed availability, frequency of use, and confidence in diagnostic usefulness of markers of brain amyloidosis (amyloid positron emission tomography [PET], cerebrospinal fluid [CSF] A?42) and neurodegeneration (medial temporal atrophy [MTA] on MR, fluorodeoxyglucose positron emission tomography [FDG-PET], CSF tau). The most frequently used biomarker is visually rated MTA (75% of the 37 responders reported using it "always/frequently") followed by CSF markers (22%), FDG-PET (16%), and amyloid-PET (3%). Only 45% of responders perceive MTA as contributing to diagnostic confidence, where the contribution was rated as "moderate". Seventy-nine percent of responders felt "very/extremely" comfortable delivering a diagnosis of MCI due to AD when both amyloid and neuronal injury biomarkers were abnormal (P < .02 versus any individual biomarker). Responders largely agreed that a combination of amyloidosis and neuronal injury biomarkers was a strongly indicative AD signature.
Large-scale longitudinal neuroimaging studies with diffusion imaging techniques are necessary to test and validate models of white matter neurophysiological processes that change in time, both in healthy and diseased brains. The predictive power of such longitudinal models will always be limited by the reproducibility of repeated measures acquired during different sessions. At present, there is limited quantitative knowledge about the across-session reproducibility of standard diffusion metrics in 3T multi-centric studies on subjects in stable conditions, in particular when using tract based spatial statistics and with elderly people. In this study we implemented a multi-site brain diffusion protocol in 10 clinical 3T MRI sites distributed across 4 countries in Europe (Italy, Germany, France and Greece) using vendor provided sequences from Siemens (Allegra, Trio Tim, Verio, Skyra, Biograph mMR), Philips (Achieva) and GE (HDxt) scanners. We acquired DTI data (2 × 2 × 2 mm(3), b = 700 s/mm(2), 5 b0 and 30 diffusion weighted volumes) of a group of healthy stable elderly subjects (5 subjects per site) in two separate sessions at least a week apart. For each subject and session four scalar diffusion metrics were considered: fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial (AD) diffusivity. The diffusion metrics from multiple subjects and sessions at each site were aligned to their common white matter skeleton using tract-based spatial statistics. The reproducibility at each MRI site was examined by looking at group averages of absolute changes relative to the mean (%) on various parameters: i) reproducibility of the signal-to-noise ratio (SNR) of the b0 images in centrum semiovale, ii) full brain test-retest differences of the diffusion metric maps on the white matter skeleton, iii) reproducibility of the diffusion metrics on atlas-based white matter ROIs on the white matter skeleton. Despite the differences of MRI scanner configurations across sites (vendors, models, RF coils and acquisition sequences) we found good and consistent test-retest reproducibility. White matter b0 SNR reproducibility was on average 7 ± 1% with no significant MRI site effects. Whole brain analysis resulted in no significant test-retest differences at any of the sites with any of the DTI metrics. The atlas-based ROI analysis showed that the mean reproducibility errors largely remained in the 2-4% range for FA and AD and 2-6% for MD and RD, averaged across ROIs. Our results show reproducibility values comparable to those reported in studies using a smaller number of MRI scanners, slightly different DTI protocols and mostly younger populations. We therefore show that the acquisition and analysis protocols used are appropriate for multi-site experimental scenarios.
Late-onset and early-onset Alzheimer's disease (LOAD, EOAD) affect different neural systems and may be separate nosographic entities. The most striking differences are in the medial temporal lobe, severely affected in LOAD and relatively spared in EOAD. We assessed amygdalar morphology and volume in 18 LOAD and 18 EOAD patients and 36 aged-matched controls and explored their relationship with the hippocampal volume. Three-dimensional amygdalar shape was reconstructed with the radial atrophy mapping technique, hippocampal volume was measured using a manual method. Atrophy was greater in LOAD than EOAD: 25% versus 17% in the amygdala and 20% versus 13% in the hippocampus. In the amygdala, LOAD showed significantly greater tissue loss than EOAD in the right dorsal central, lateral, and basolateral nuclei (20%-30% loss, p < 0.03), all known to be connected to limbic regions. In LOAD but not EOAD, greater hippocampal atrophy was associated with amygdalar atrophy in the left dorsal central and medial nuclei (r = 0.6, p < 0.05) also part of the limbic system. These findings support the notion that limbic involvement is a prominent feature of LOAD but not EOAD.
Patients with Alzheimers disease (AD) and schizophrenia display cognitive, behavioural disturbances and morphological abnormalities. Although these latter reflect progressive neurodegeneration in AD, their significance in schizophrenia is still unclear. We explored the patterns of hippocampal and amygdalar atrophy in those patients and their associations with clinical parameters. Structural magnetic resonance imaging was performed in 20 elderly schizophrenia patients, 20 AD and 19 healthy older controls. Hippocampal and amygdalar volumes were obtained by manual segmentation with a standardized protocol and compared among groups. In both schizophrenia and AD patients, left hippocampal and amygdalar volumes were significantly smaller. The hippocampus/amygdala ratio was significantly lower in schizophrenia compared to both AD cases [2.4 bilaterally, 95% C.I. 2.2 to 2.7] and healthy controls bilaterally [2.5, 95% C.I. 2.3 to 2.9 in left and 2.7, 95% C.I. 2.4 to 3.1 in right hemisphere]. In schizophrenia patients, a significant positive correlation was found between age at disease onset and the right hippocampus/amygdala volume ratio (Spearman rho=0.56). Negative symptoms correlated with higher right/left amygdala volume ratio (Spearmans rho=0.43). Our data show that unlike AD, the hippocampus/amygdala ratio is abnormally low and correlates with the age at onset in schizophrenia, being a neurodevelopmental signature of the disease.
Prior studies reported that the hippocampal volume is smaller in Alzheimers disease patients carrying the Apolipoprotein E ?4 allele (APOE4) versus patients who are non-carriers of this allele. This effect however has not been detected consistently, possibly because of the regionally-specific involvement of the hippocampal formation in Alzheimers disease. The aim of this study was to analyze the local effect of APOE4 on hippocampal atrophy in Alzheimers disease patients. Using high-resolution T1-weighted images we investigated 14 patients heterozygous for the ?4 allele (age 72±8 SD years; MMSE 20±4 SD) and 14 patients not carrying the ?4 allele (age 71±10; MMSE 20±5 SD), and 28 age-, sex-, and education-matched controls (age 71±8; MMSE 29±1 SD). The hippocampal formation was outlined with manual tracing and 3D parametric surface models were created for each subject. Radial atrophy was assessed on the whole hippocampal surface using the UCLA mapping technique. E4 carriers and non-carriers did not differ in their level of impairment in global cognition (p=0.91, Mann-Whitney test) or memory (p>0.29). Hippocampal surface analysis showed the typical pattern of CA1 and subicular tissue atrophy in both ?4-carriers and non-carriers compared with controls (e4 carriers: p<0.0002; ?4 non-carriers: p<0.01, permutation test). The left hippocampal volume was significantly smaller in ?4-carriers than non-carriers (p=0.044, Mann-Whitney test), the effect of APOE4 mapping to the subicular/CA1 region (p=0.041, permutation test). Differences were not statistically significant in the right hippocampus (p>0.20, permutation test). These findings show that hippocampal atrophy is greater in APOE4 carriers in regions typically affected by pathology. APOE4 may affect the structural expression of Alzheimers disease.
To explore the regional patterns of white matter (WM) tract damage in (a) patients with probable Alzheimer disease (AD) and (b) patients with amnestic mild cognitive impairment (aMCI) and at least one abnormal biomarker and to investigate whether WM damage is related to gray matter (GM) atrophy.
According to a recent proposal for revised diagnostic criteria for Alzheimer disease, the diagnosis could be made even in the absence of impairment of social function or daily life activities, provided positivity of one or more abnormal biomarkers. The use of the new proposed diagnostic criteria raises ethical issues and needs to be carefully evaluated.
To describe the clinical and neuropsychological features of a large group of cognitively intact persons subjected to brain high-resolution magnetic resonance (MR), to compare them with the general population, and to set norms for medial temporal atrophy and white matter lesions.
Mild alterations in cognitive function are present in normal aging and severe cognitive alterations are a hallmark of Alzheimers disease (AD). Cognitive deficits are prevalent in patients with schizophrenia (SCZ) and worsen with old age. We recently reported that elderly SCZ patients show reduced levels of amyloid-beta (A?)1-42 in cerebrospinal fluid (CSF). To further clarify the role of A? in cognitive decline, we analyzed the whole panel of CSF A? isoforms in elderly SCZ patients as well as in sporadic AD using SELDI TOF MS. The immunoproteomic study revealed, in all analyzed CSF samples, the presence of 15 different A? peptides. In CSF from SCZ, we detected an overall strong reduction of almost all A? species while in sporadic AD A?1-42 was the only peptide reduced. A significant independent association between A?1-40 levels and global cognition was found in SCZ. In addition, in SCZ patients, duration of therapy was positively associated with soluble amyloid precursor protein alpha levels, the total amount of CSF A? and the most abundant A?1-40 isoform. These data suggests a dysmetabolism of amyloid precursor protein in older SCZ patients. Thus, the quite comparable reduction of CSF A?1-42 in AD and in elderly SCZ patients reflects different pathophysiological dynamics in ageing brain.
The aim of this study is to support the use of biomarkers in the diagnosis of mild cognitive impairment (MCI) due to Alzheimers disease (AD) according to the revised NIA-AA diagnostic criteria. We compared clinical features and conversion to AD and other dementias among groups of MCI patients with different abnormal biomarker profiles. In this study, we enrolled 58 patients with MCI, and for each of them AD biomarkers (CSF Abeta42 and tau, temporoparietal hypometabolism on 18F-FDG PET, and hippocampal volume) were collected. Patients were divided into three groups: (i) no abnormal biomarker, (ii) AD biomarker pattern (including three subgroups of early = only abnormal Abeta42, intermediate = abnormal Abeta42 and FDG PET or tau, and late = abnormal Abeta42, FDG PET or tau, and HV), and (iii) any other biomarker combination. MCI patients with AD biomarker pattern had lower behavioural disturbances than patients with any other biomarker combination (p < 0.0005). This group also showed lower performance on verbal and non-verbal memory than the other two groups (p = 0.07 and p = 0.004, respectively). Within the three subgroups with AD biomarker patterns we observed a significant trend toward a higher rate of conversion to dementia (p for trend = 0.006). With regard to dementia conversion, 100 % of patients with an AD biomarker pattern developed AD, but none of the patients with no abnormal biomarker and 27 % of patients with any other biomarker combination (p = 0.002) did so. We also described some clinical cases representative for each of these three groups. The results of this study provide evidence in favour of the use of biomarkers for the diagnosis of MCI due to AD, in line with recently published research criteria.
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