Mild Cognitive Impairment Stage Research Articles

Tau protein spreads through functionally connected neurons in Alzheimer's disease: a combined MEG/PET study.

Recent studies on Alzheimer's disease (AD) suggest that tau proteins spread through the brain following neuronal connections. Several mechanisms could be involved in this process: spreading between brain regions that interact strongly (functional connectivity); through the pattern of anatomical connections (structural connectivity); or simple diffusion. Using magnetoencephalography (MEG), we investigated which spreading pathways influence tau protein spreading by modelling the tau propagation process using an epidemic spreading model. We compared the modelled tau depositions with 18F-flortaucipir PET binding potentials at several stages of the AD continuum. In this cross-sectional study, we analysed source-reconstructed MEG data and dynamic 100-min 18F-flortaucipir PET from 57 subjects positive for amyloid-β pathology [preclinical AD (n = 16), mild cognitive impairment (MCI) due to AD (n = 16) and AD dementia (n = 25)]. Cognitively healthy subjects without amyloid-β pathology were included as controls (n = 25). Tau propagation was modelled as an epidemic process (susceptible-infected model) on MEG-based functional networks [in alpha (8-13 Hz) and beta (13-30 Hz) bands], a structural or diffusion network, starting from the middle and inferior temporal lobe. The group-level network of the control group was used as input for the model to predict tau deposition in three stages of the AD continuum. To assess performance, model output was compared to the group-specific tau deposition patterns as measured with 18F-flortaucipir PET. We repeated the analysis by using networks of the preceding disease stage and/or using regions with most observed tau deposition during the preceding stage as seeds. In the preclinical AD stage, the functional networks predicted most of the modelled tau-PET binding potential, with best correlations between model and tau-PET [corrected amplitude envelope correlation (AEC-c) alpha C = 0.584; AEC-c beta C = 0.569], followed by the structural network (C = 0.451) and simple diffusion (C = 0.451). Prediction accuracy declined for the MCI and AD dementia stages, although the correlation between modelled tau and tau-PET binding remained highest for the functional networks (C = 0.384; C = 0.376). Replacing the control-network with the network from the preceding disease stage and/or alternative seeds improved prediction accuracy in MCI but not in the dementia stage. These results suggest that in addition to structural connections, functional connections play an important role in tau spread, and highlight that neuronal dynamics play a key role in promoting this pathological process. Aberrant neuronal communication patterns should be taken into account when identifying targets for future therapy. Our results also suggest that this process is more important in earlier disease stages (preclinical AD/MCI); possibly, in later stages, other processes may be influential.

The correlation between changes in gray matter microstructure and cerebral blood flow in Alzheimer's disease.

To investigate the relationship between changes in cerebral blood flow (CBF) and gray matter (GM) microstructure in Alzheimer's disease (AD) and mild cognitive impairment (MCI). A recruited cohort of 23 AD patients, 40 MCI patients, and 37 normal controls (NCs) underwent diffusional kurtosis imaging (DKI) for microstructure evaluation and pseudo-continuous arterial spin labeling (pCASL) for CBF assessment. We investigated the differences in diffusion- and perfusion-related parameters across the three groups, including CBF, mean diffusivity (MD), mean kurtosis (MK), and fractional anisotropy (FA). These quantitative parameters were compared using volume-based analyses for the deep GM and surface-based analyses for the cortical GM. The correlation between CBF, diffusion parameters, and cognitive scores was assessed using Spearman coefficients, respectively. The diagnostic performance of different parameters was investigated with k-nearest neighbor (KNN) analysis, using fivefold cross-validation to generate the mean accuracy (mAcc), mean precision (mPre), and mean area under the curve (mAuc). In the cortical GM, CBF reduction primarily occurred in the parietal and temporal lobes. Microstructural abnormalities were predominantly noted in the parietal, temporal, and frontal lobes. In the deep GM, more regions showed DKI and CBF parametric changes at the MCI stage. MD showed most of the significant abnormalities among all the DKI metrics. The MD, FA, MK, and CBF values of many GM regions were significantly correlated with cognitive scores. In the whole sample, the MD, FA, and MK were associated with CBF in most evaluated regions, with lower CBF values associated with higher MD, lower FA, or lower MK values in the left occipital lobe, left frontal lobe, and right parietal lobe. CBF values performed best (mAuc = 0.876) for distinguishing the MCI from the NC group. Last, MD values performed best (mAuc = 0.939) for distinguishing the AD from the NC group. Gray matter microstructure and CBF are closely related in AD. Increased MD, decreased FA, and MK are accompanied by decreased blood perfusion throughout the AD course. Furthermore, CBF values are valuable for the predictive diagnosis of MCI and AD. GM microstructural changes are promising as novel neuroimaging biomarkers of AD.

Plasma neuregulin 1 as a synaptic biomarker in Alzheimer’s disease

AbstractBackgroundSynaptic dysfunction is an early core feature of Alzheimer’s disease (AD), closely associated with cognitive symptoms. Neuregulin 1 (NRG1) is a growth and differentiation factor with a key role in the development and maintenance of synaptic transmission. Previous reports have shown that changes in cerebrospinal fluid (CSF) NRG1 concentration are associated with cognitive status and biomarker evidence of AD pathology. Plasma biomarkers reflecting synaptic impairment would be of great clinical interest. Our oubjective was to measure plasma NRG1 concentration in AD patients in comparison with other neurodegenerative disorders and neurological controls (NC) and to study its association with cerebrospinal fluid (CSF) core AD and synaptic biomarkers.MethodThis retrospective study enrolled 127 participants including patients with AD at mild cognitive impairment stage (AD‐MCI, n = 27) and at dementia stage (n = 35), non‐AD dementia (n = 26, Aβ‐negative), non‐AD MCI (n = 19) and neurological controls (n = 20). Plasma and CSF NRG1, as well as CSF core AD biomarkers (Aβ 42/Aβ 40 ratio, phospho‐tau and total tau), were measured using ELISA. CSF synaptic markers were measured using ELISA for GAP‐43 and neurogranin and through immunoprecipitation mass spectrometry for SNAP‐25.ResultPlasma NRG1 concentration was higher in AD‐MCI and AD dementia patients compared with neurological controls (respectively P = 0.005 and P<0.001). Plasma NRG1 differentiated AD MCI patients from neurological controls with an area under the curve of 88.3%, and AD dementia patients from NC with an area under the curve of 87.3%. Plasma NRG1 correlated with CSF NRG1 (β = 0.372, P = 0.0056, adjusted on age and sex). Plasma NRG1 was associated with AD CSF core biomarkers in the whole cohort and in Aβ‐positive patients (β = ‐0.197‐ 0.423). Plasma NRG1 correlated with CSF GAP‐43, neurogranin and SNAP‐25 (β = 0.278‐0.355). Plasma NRG1 concentration correlated inversely with MMSE in the whole cohort and in Aβ‐positive patients (all, β = ‐0.188, P = 0.038; Aβ+: β = ‐0.255, P = 0.038).ConclusionPlasma NRG1 concentration is increased in AD patients and correlates with CSF core AD and synaptic biomarkers, and cognitive status. Thus, plasma NRG1 is a promising non‐invasive biomarker to monitor synaptic impairment in AD.

Neuropsychiatric symptoms in mild cognitive impairment and Alzheimer’s disease: Relation with disease stage, sex, and daily function impairment

AbstractBackgroundTo reveal the relations between neuropsychiatric symptoms (NPS), stages of cognitive impairment, sex, and daily function impairment in patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD).Method1,154 patients with MCI and AD were enrolled from 2014 to 2021 from the Memory Clinic, The First Affiliated Hospital of Chongqing Medical University. Mini‐mental State Examination (MMSE) was used to assess the cognitive function, and Clinical dementia rating scale (CDR) was used to evaluate the disease severity of patients. NPS and function of patients’ daily life were evaluated by Neuropsychiatric Inventory (NPI) and activities of daily living (ADL) respectively.ResultPsychosis symptoms displayed the highest prevalence in MCI (43.3%) and mild AD stage (62.2%), while in moderate and severe AD, behavior symptoms showed its dominance (86.7% and 96.4%, respectively). Delusion, apathy, AMB and sleep disturbance were the discriminant symptoms across the spectrum of cognitive decline (all P <0.05). Depression was more prominent in female (26.1% vs. 14.9% in MCI; 40.2% vs. 21.0% in AD, all P< 0.05) while male patients presented higher prevalence in apathy (27.0% vs. 18.6% in MCI; 54.1% vs. 42.8% in AD, all P< 0.05). Physical self‐maintenance was negatively impacted by apathy and sleep disturbance at mild AD stage, while instrumental activity of daily living was significantly influenced by aberrant motor behavior in MCI and mild AD (all P< 0.05).ConclusionThe prevalence of NPS is correlated with sex, the stage of cognitive impairment and daily living function. Revealing their relations can allow he development of better prevention and treatment strategies for patients with cognitive impairment.

Regional cerebral atrophy correlates with amyloid accumulation in preclinical Alzheimer’s disease

AbstractBackgroundThis study was aimed to evaluate the regional hierarchical brain atrophy among the preclinical to mild cognitive impairment (MCI) stages of Alzheimer’s disease associated with amyloid deposition using [18F]flutemetamol positron emission tomography and volumetric magnetic resonance imaging.MethodThis was a prospective, single‐cohort study of volunteers who were living independently in Itabashi‐ku (Tokyo, Japan). One hundred thirty‐six participants (female/male = 96/40, mean age/standard deviation = 79.2/4.0 years) were recruited. Two subjects, one with meningeal thickening and another with sequelae in the brain, and 17 visually amyloid‐negative MCI subjects who possibly had neurodegenerative disease other than Alzheimer’s disease were excluded from the further analysis. We applied voxel‐based regression slope analysis between composite voxel of interest values calculated with Cortex ID Suite (GE Healthcare) on [18F]flutemetamol positron emission tomography and volumetric magnetic resonance images in three groups: 70 amyloid‐negative cognitively normal (CN) participants, 29 amyloid‐positive cognitively normal (PreC) participants, and 18 amyloid‐positive MCI (MCI+) participants. Statistical Parametric Mapping 12 software was used for analysis.ResultEven in the cognitively normal stage, the PreC group showed a larger slope of atrophy in the basal forebrain and middle frontal gyri than the CN group. In the MCI+ group, the slopes were larger in the lateral and medial parietal lobes, uncus, and right lateral temporal areas.ConclusionThe speed of amyloid‐related atrophy in the basal forebrain and middle frontal gyri was quick even in the preclinical stage of Alzheimer’s disease. As no significant slope changes were observed among the three groups in the medial temporal area, except for the uncus, the well‐known medial temporal atrophy in early Alzheimer’s disease might not be related to the accumulation of amyloid.

Association of Telomere Length with Cognitive Impairment.

Telomere attrition is attributed to Alzheimer's disease (AD), major depressive disorder, stress levels, physical inactivity, short sleep duration, and reduced educational abilities. In this article, we tried to assess the association between the telomere length in peripheral blood leukocytes and level of cognitive impairment and its dependence on age and sex.Healthy subjects and patients with amnestic mild cognitive impairment (aMCI) and different AD stages were recruited in the study. All patients were assessed by the same standard diagnostic procedure, including neurological examination-Mini-Mental State Examination (MMSE). Blood samples from 66 subjects (18 men and 48 women, mean age 71.2 ± 0.56years) were collected for DNA extraction from peripheral mononuclear cells (PBMC). Relative telomere length (RTL) was measured by monochrome multiplex polymerase chain reaction.The data obtained in the study indicate that RTL in PBMCs has a statistically significant association with MMSE score (p < 0.02). Moreover, the sex-specific difference was observed for the association between telomere length and various parameters of MMSE. Also, it has been found that a decrease in RTL by one unit is associated with an increase in the odds to get AD at a ratio of 2.54 (95% CI, 1.25 to 5.17).The results obtained in this research are in coherence with other studies that telomere length may be a valuable biomarker of cognitive decline. However, the potential need for longitudinal studies of telomere length, in order to estimate the influence of hereditary and environmental factors, remains.

Amyloid accumulation in the medial temporal area starts in the mild cognitive impairment stage of Alzheimer’s disease in [18F]flutemetamol positron emission tomography

AbstractBackgroundThis study was aimed to evaluate the hierarchical accumulation of amyloid in the Alzheimer’s brain according to clinical stage using [18F]flutemetamol positron emission tomography.MethodThis was a prospective, single‐cohort study of volunteers who lived independently in Itabashi‐ku (Tokyo, Japan). One hundred thirty‐six participants (female/male = 96/40, mean age/standard deviation = 79.2/4.0 years) were recruited. Two subjects, one with meningeal thickening and another with sequelae in the brain, and 17 visually amyloid‐negative MCI subjects who possibly had neurodegenerative disease other than Alzheimer’s disease were excluded from the further analysis. We applied voxel‐based regression slope analysis using composite voxel of interest values calculated with Cortex ID Suite (GE Healthcare) and [18F]flutemetamol positron emission tomography images in three groups: 70 amyloid‐negative cognitively normal (CN) participants, 29 amyloid‐positive cognitively normal (PreC) participants, and 18 amyloid‐positive MCI (MCI+) participants. Statistical Parametric Mapping 12 software was used for analysis.ResultCompared with the CN group, the PreC group showed accelerated amyloid accumulation in a wide area, except for the medial temporal lobe, paracentral sulcus, and medial occipital lobe. In amyloid‐positive subjects, amyloid accumulation was quicker in the paracentral sulcus, occipital cortex, and left medial temporal lobe in the MCI+ group than in the PreC group. Additional voxel of interest analyses were applied to the statistically significant areas. In the right posterior cingulate area, there was no significant difference between the PreC and MCI+ groups; however, the PreC and MCI+ groups showed a significantly quicker amyloid accumulation than the CN group. In contrast, in the left medial temporal area, the increase of amyloid accumulation was greater only in the MCI+ group compared to the PreC and CN groups.ConclusionIn amyloid‐positive subjects, amyloid accumulation in the left medial temporal lobe did not increase in the preclinical stage. In the medial temporal and occipital lobes, which are relatively spared from amyloid accumulation, it is considered to start late in the MCI stage and not in the preclinical stage. Further study of volume and other biomarkers is requreid to evaluate the regional pathophysiological variability of AD.

Gut microbiome dysbiosis in Alzheimer's disease and mild cognitive impairment: A systematic review and meta-analysis.

Alzheimer's disease (AD) is a neurodegenerative disorder that causes gradual memory loss. AD and its prodromal stage of mild cognitive impairment (MCI) are marked by significant gut microbiome perturbations, also known as gut dysbiosis. However, the direction and extent of gut dysbiosis have not been elucidated. Therefore, we performed a meta-analysis and systematic review of 16S gut microbiome studies to gain insights into gut dysbiosis in AD and MCI. We searched MEDLINE, Scopus, EMBASE, EBSCO, and Cochrane for AD gut microbiome studies published between Jan 1, 2010 and Mar 31, 2022. This study has two outcomes: primary and secondary. The primary outcomes explored the changes in α-diversity and relative abundance of microbial taxa, which were analyzed using a variance-weighted random-effects model. The secondary outcomes focused on qualitatively summarized β-diversity ordination and linear discriminant analysis effect sizes. The risk of bias was assessed using a methodology appropriate for the included case-control studies. The geographic cohorts' heterogeneity was examined using subgroup meta-analyses if sufficient studies reported the outcome. The study protocol has been registered with PROSPERO (CRD42022328141). Seventeen studies with 679 AD and MCI patients and 632 controls were identified and analyzed. The cohort is 61.9% female with a mean age of 71.3±6.9 years. The meta-analysis shows an overall decrease in species richness in the AD gut microbiome. However, the phylum Bacteroides is consistently higher in US cohorts (standardised mean difference [SMD] 0.75, 95% confidence interval [CI] 0.37 to 1.13, p < 0.01) and lower in Chinese cohorts (SMD -0.79, 95% CI -1.32 to -0.25, p < 0.01). Moreover, the Phascolarctobacterium genus is shown to increase significantly, but only during the MCI stage. Notwithstanding possible confounding from polypharmacy, our findings show the relevance of diet and lifestyle in AD pathophysiology. Our study presents evidence for region-specific changes in abundance of Bacteroides, a major constituent of the microbiome. Moreover, the increase in Phascolarctobacterium and the decrease in Bacteroides in MCI subjects shows that gut microbiome dysbiosis is initiated in the prodromal stage. Therefore, studies of the gut microbiome can facilitate early diagnosis and intervention in Alzheimer's disease and perhaps other neurodegenerative disorders.

Multi-modal cross-attention network for Alzheimer’s disease diagnosis with multi-modality data

Alzheimer’s disease (AD) is a neurodegenerative disorder, the most common cause of dementia, so the accurate diagnosis of AD and its prodromal stage mild cognitive impairment (MCI) is significant. Recent studies have demonstrated that multiple neuroimaging and biological measures contain complementary information for diagnosis. Many existing multi-modal models based on deep learning simply concatenate each modality’s features despite substantial differences in representation spaces. In this paper, we propose a novel multi-modal cross-attention AD diagnosis (MCAD) framework to learn the interaction between modalities for better playing their complementary roles for AD diagnosis with multi-modal data including structural magnetic resonance imaging (sMRI), fluorodeoxyglucose-positron emission tomography (FDG-PET) and cerebrospinal fluid (CSF) biomarkers. Specifically, the imaging and non-imaging representations are learned by the image encoder based on cascaded dilated convolutions and CSF encoder, respectively. Then, a multi-modal interaction module is introduced, which takes advantage of cross-modal attention to integrate imaging and non-imaging information and reinforce relationships between these modalities. Moreover, an extensive objective function is designed to reduce the discrepancy between modalities for effectively fusing the features of multi-modal data, which could further improve the diagnosis performance. We evaluate the effectiveness of our proposed method on the ADNI dataset, and the extensive experiments demonstrate that our MCAD achieves superior performance for multiple AD-related classification tasks, compared to several competing methods. Also, we investigate the importance of cross-attention and the contribution of each modality to the diagnostics performance. The experimental results demonstrate that combining multi-modality data via cross-attention is helpful for accurate AD diagnosis.

β-Amyloid Load on PET Along the Continuum of Dementia With Lewy Bodies.

β-Amyloid (Aβ) plaques can co-occur with Lewy-related pathology in patients with dementia with Lewy bodies (DLB), but Aβ load at prodromal stages of DLB still needs to be elucidated. We investigated Aβ load on PET throughout the DLB continuum, from an early prodromal stage of isolated REM sleep behavior disorder (iRBD) to a stage of mild cognitive impairment with Lewy bodies (MCI-LB), and finally DLB. We performed a cross-sectional study in patients with a diagnosis of iRBD, MCI-LB, or DLB from the Mayo Clinic Alzheimer Disease Research Center. Aβ levels were measured by Pittsburgh compound B (PiB) PET, and global cortical standardized uptake value ratio (SUVR) was calculated. Global cortical PiB SUVR values from each clinical group were compared with each other and with those of cognitively unimpaired (CU) individuals (n = 100) balanced on age and sex using analysis of covariance. We used multiple linear regression testing for interaction to study the influences of sex and APOE ε4 status on PiB SUVR along the DLB continuum. Of the 162 patients, 16 had iRBD, 64 had MCI-LB, and 82 had DLB. Compared with CU individuals, global cortical PiB SUVR was higher in those with DLB (p < 0.001) and MCI-LB (p = 0.012). The DLB group included the highest proportion of Aβ-positive patients (60%), followed by MCI-LB (41%), iRBD (25%), and finally CU (19%). Global cortical PiB SUVR was higher in APOE ε4 carriers compared with that in APOE ε4 noncarriers in MCI-LB (p < 0.001) and DLB groups (p = 0.049). Women had higher PiB SUVR with older age compared with men across the DLB continuum (β estimate = 0.014, p = 0.02). In this cross-sectional study, levels of Aβ load was higher further along the DLB continuum. Whereas Aβ levels were comparable with those in CU individuals in iRBD, a significant elevation in Aβ levels was observed in the predementia stage of MCI-LB and in DLB. Specifically, APOE ε4 carriers had higher Aβ levels than APOE ε4 noncarriers, and women tended to have higher Aβ levels than men as they got older. These findings have important implications in targeting patients within the DLB continuum for clinical trials of disease-modifying therapies.

CSF Synaptic Biomarkers in AT(N)-Based Subgroups of Lewy Body Disease.

Patients with Lewy body disease (LBD) often show a co-occurring Alzheimer disease (AD) pathology. CSF biomarkers allow the detection in vivo of AD-related pathologic hallmarks included in the amyloid-tau-neurodegeneration (AT(N)) classification system. Here, we aimed to investigate whether CSF biomarkers of synaptic and neuroaxonal damage are correlated with the presence of AD copathology in LBD and can be useful to differentiate patients with LBD with different AT(N) profiles. We retrospectively measured CSF levels of AD core biomarkers (Aβ42/40 ratio, phosphorylated tau protein, and total tau protein) and of synaptic (β-synuclein, α-synuclein, synaptosomal-associated protein 25 [SNAP-25], and neurogranin) and neuroaxonal proteins (neurofilament light chain [NfL]) in 28 cognitively unimpaired participants with nondegenerative neurologic conditions and 161 participants with a diagnosis of either LBD or AD (at both mild cognitive impairment, AD-MCI, and dementia stages, AD-dem). We compared CSF biomarker levels in clinical and AT(N)-based subgroups. CSF β-synuclein, α-synuclein, SNAP-25, neurogranin, and NfL levels did not differ between LBD (n = 101, age 67.2 ± 7.8 years, 27.7% females) and controls (age 64.8 ± 8.6 years, 39.3% females) and were increased in AD (AD-MCI: n = 30, AD-dem: n = 30, age 72.3 ± 6.0 years, 63.3% females) compared with both groups (p < 0.001 for all comparisons). In LBD, we found increased levels of synaptic and neuroaxonal degeneration biomarkers in patients with A+T+ (LBD/A+T+) than with A-T- profiles (LBD/A-T-) (p < 0.01 for all), and β-synuclein showed the highest discriminative accuracy between the 2 groups (area under the curve 0.938, 95% CI 0.884-0.991). CSF β-synuclein (p = 0.0021), α-synuclein (p = 0.0099), and SNAP-25 concentrations (p = 0.013) were also higher in LBD/A+T+ than in LBD/A+T- cases, which had synaptic biomarker levels within the normal range. CSF α-synuclein was significantly decreased only in patients with LBD with T- profiles compared with controls (p = 0.0448). Moreover, LBD/A+T+ and AD cases did not differ in any biomarker level. LBD/A+T+ and AD cases showed significantly increased CSF levels of synaptic and neuroaxonal biomarkers compared with LBD/A-T- and control subjects. Patients with LBD and AT(N)-based AD copathology showed, thus, a distinct signature of synaptic dysfunction from other LBD cases. This study provides Class II evidence that CSF levels of β-synuclein, α-synuclein, SNAP-25, neurogranin, and NfL are higher in patients with AD than in patients with LBD.

Ultra-Early Screening of Cognitive Decline Due to Alzheimer's Pathology.

Alzheimer's pathology can be assessed and defined via Aβ and tau biomarkers. The preclinical period of Alzheimer's disease is long and lasts several decades. Although effective therapies to block pathological processes of Alzheimer's disease are still lacking, downward trends in the incidence and prevalence of dementia have occurred in developed countries. Accumulating findings support that education, cognitive training, physical exercise/activities, and a healthy lifestyle can protect cognitive function and promote healthy aging. Many studies focus on detecting mild cognitive impairment (MCI) and take a variety of interventions in this stage to protect cognitive function. However, when Alzheimer's pathology advances to the stage of MCI, interventions may not be successful in blocking the development of the pathological process. MCI individuals reverting to normal cognitive function exhibited a high probability to progress to dementia. Therefore, it is necessary to take effective measures before the MCI stage. Compared with MCI, an earlier stage, transitional cognitive decline, may be a better time window in which effective interventions are adopted for at-risk individuals. Detecting this stage in large populations relies on rapid screening of cognitive function; given that many cognitive tests focus on MCI detection, new tools need to be developed.

Validation of the European Cross-Cultural Neuropsychological Test Battery (CNTB) for the assessment of mild cognitive impairment due to Alzheimer's disease and Parkinson's disease.

The Cross-Cultural Neuropsychological Test Battery (CNTB) is a novel test battery specifically designed to reduce the impact of multiculturality in cognitive assessment. We aimed to validate the CNTB in Spaniards in patients with Alzheimer's disease (AD), including patients at mild cognitive impairment (MCI) and mild dementia stages, and Parkinson's disease with MCI (PD-MCI). Thirty patients with AD-MCI, 30 with AD-dementia (AD-D), and 30 with PD-MCI were recruited. Each clinical group was compared against a healthy control group (HC) with no differences in sex, age, or years of education. Intergroup comparisons, ROC analysis, and cut-off scores were calculated. AD-MCI scored lower than HC in those subtests associated with episodic memory and verbal fluency. AD-D also showed lower scores in executive functions and visuospatial tests. Effect sizes for all the subtests were large. PD-MCI showed lower performance than HC in memory and executive functions, particularly on error scores, with large effect sizes. Comparing AD-MCI and PD-MCI, AD-MCI had lower memory scores, while PD-MCI showed the worst performance in executive functions. CNTB showed appropriate convergent validity with standardized neuropsychological tests measuring the same cognitive domains. We obtained similar cut-off scores to previous studies performed in other populations. The CNTB showed appropriate diagnostic properties in AD and PD, including those stages with mild cognitive impairment. This supports the utility of the CNTB for the early detection of cognitive impairment in AD and PD.

Neuropharmacology of Lecanemab-irmb: A new drug granted in the treatment of Alzheimer's disease

United state food and drug administration approved on 6 January 2023, Lecanemab-irmb via the accelerated approval pathway for the treatment of Alzheimer’s disease. Researchers evaluated Lecanemab-irmb’s efficacy in a double-blind, placebo-controlled, parallel-group, dose-finding study of 856 patients with Alzheimer’s disease. Treatment was initiated in patients with mild cognitive impairment or mild dementia stage of disease and confirmed the presence of amyloid beta pathology. Patients receiving the treatment had significant dose and time-dependent reduction of amyloid beta plaque, with patients receiving the approved dose of lecanemab, 10 milligram/kilogram every two weeks, having a statistically significant reduction in brain amyloid plaque from baseline to Week 79 compared to the placebo arm, which had no reduction of amyloid beta plaque. These results support the accelerated approval of Lecanemab-irmb, which is based on the observed reduction of amyloid beta plaque, a marker of Alzheimer’s disease. The amyloid beta plaque was quantified using positron emission tomography (PET) imaging to estimate the brain levels of amyloid beta plaque in a composite of brain regions expected to be widely affected by Alzheimer’s disease pathology compared to a brain region expected to be spared of such pathology.

Automatic and manual segmentation of the piriform cortex: Method development and validation in patients with temporal lobe epilepsy and Alzheimer's disease

The piriform cortex (PC) is located at the junction of the temporal and frontal lobes. It is involved physiologically in olfaction as well as memory and plays an important role in epilepsy. Its study at scale is held back by the absence of automatic segmentation methods on MRI. We devised a manual segmentation protocol for PC volumes, integrated those manually derived images into the Hammers Atlas Database (n= 30) and used an extensively validated method (multi-atlas propagation with enhanced registration, MAPER) for automatic PC segmentation. We applied automated PC volumetry to patients with unilateral temporal lobe epilepsy with hippocampal sclerosis (TLE; n= 174 including n= 58 controls) and to the Alzheimer's Disease Neuroimaging Initiative cohort (ADNI; n= 151, of whom with mild cognitive impairment (MCI), n= 71; Alzheimer's disease (AD), n= 33; controls, n= 47). In controls, mean PC volume was 485 mm3 on the right and 461 mm3 on the left. Automatic and manual segmentations overlapped with a Jaccard coefficient (intersection/union) of ~0.5 and a mean absolute volume difference of ~22 mm3 in healthy controls, ~0.40/ ~28 mm3 in patients with TLE, and ~ 0.34/~29 mm3 in patients with AD. In patients with TLE, PC atrophy lateralised to the side of hippocampal sclerosis (p< .001). In patients with MCI and AD, PC volumes were lower than those of controls bilaterally (p< .001). Overall, we have validated automatic PC volumetry in healthy controls and two types of pathology. The novel finding of early atrophy of PC at the stage of MCI possibly adds a novel biomarker. PC volumetry can now be applied at scale.

Effectiveness of Lifestyle Medicine on Cognitive Functions in Mild Cognitive Impairments and Dementia: A Systematic Review on Randomized Controlled Trials.

Mild cognitive impairment (MCI) and dementia are associated with lifestyle risk factors, making lifestyle medicine a potentially viable intervention for people with MCI and dementia. The present study aims to examine the effectiveness of lifestyle medicine on cognitive functions among people with MCI and dementia, by performing a systematic review and meta-analysis on randomized controlled trials (RCT). A systematic literature search was conducted to extract RCTs adopting lifestyle interventions of diet, exercise, and stress management or emotional well-being. Results showed that 65 studies were eligible. Exercise was the most promising lifestyle intervention that improved various cognitive functions among people with MCI and dementia, and was more effective in MCI than in dementia. Interventions on stress management or emotional well-being did not show a significant effect on people with MCI, and the evidence for people with dementia was insufficient to conclude. Similarly, due to the lack of RCTs on a healthy dietary pattern, the effectiveness of diet interventions was not examined. In conclusion, the exercise component of lifestyle medicine can be an effective and clinically significant intervention for protecting people with MCI and dementia against cognitive declines, especially when served as an early intervention at the stage of MCI.

Metabolic syndrome biomarkers relate to rate of cognitive decline in MCI and dementia stages of Alzheimer’s disease

BackgroundThe relationship between biomarkers of metabolic syndrome and insulin resistance, plasma triglyceride/HDL cholesterol (TG/HDL-C) ratio, on the rate of cognitive decline in mild cognitive impairment (MCI) and dementia stages of Alzheimer’s disease (AD) is unknown. The role of peripheral and cerebrospinal fluid (CSF) levels of Apolipoprotein A1 (ApoA1), a key functional component of HDL, on cognitive decline also remains unclear among them. Here we evaluate baseline plasma TG/HDL-C ratio and CSF and plasma ApoA1 levels and their relation with cognitive decline in the MCI and Dementia stages of AD.Patients and methodsA retrospective longitudinal study (156 participants; 106 MCI, 50 AD dementia) from the Alzheimer’s Disease Neuroimaging Initiative, with an average of 4.0 (SD 2.8) years follow-up. Baseline plasma TG/HDL-C, plasma, and CSF ApoA1 and their relationship to inflammation and blood–brain barrier (BBB) biomarkers and longitudinal cognitive outcomes were evaluated. Multivariable linear mixed effect models were used to assess the effect of baseline analytes with longitudinal changes in Mini-Mental State Exam (MMSE), Clinical Dementia Rating–Sum of Boxes (CDR-SB), and Logical Memory delayed recall (LM) score after controlling for well-known covariates.ResultsA total of 156 participants included 98 women, 63%; mean age was 74.9 (SD 7.3) years. At baseline, MCI and dementia groups did not differ significantly in TG/HDL-C (Wilcoxon W statistic = 0.39, p = 0.39) and CSF ApoA1 levels (W = 3642, p = 0.29), but the dementia group had higher plasma ApoA1 than the MCI group (W = 4615, p = 0.01). Higher TG/HDL-C ratio was associated with faster decline in CDR-SB among MCI and dementia groups. Higher plasma ApoA1 was associated with faster decline in MMSE and LM among MCI, while in contrast higher CSF ApoA1 levels related to slower cognitive decline in MMSE among MCI. CSF and plasma ApoA1 also show opposite directional correlations with biomarkers of BBB integrity. CSF but not plasma levels of ApoA1 positively correlated to inflammation analytes in the AGE-RAGE signaling pathway in diabetic complications (KEGG ID:KO04933).ConclusionsBiomarkers of metabolic syndrome relate to rate of cognitive decline among MCI and dementia individuals. Elevated plasma TG/HDL-C ratio and plasma ApoA1 are associated with worse cognitive outcomes in MCI and dementia participants. CSF ApoA1 and plasma ApoA1 likely have different roles in AD progression in MCI stage.

Accumulation of network redundancy marks the early stage of Alzheimer's disease.

Brain wiring redundancy counteracts aging-related cognitive decline by reserving additional communication channels as a neuroprotective mechanism. Such a mechanism plays a potentially important role in maintaining cognitive function during the early stages of neurodegenerative disorders such as Alzheimer's disease (AD). AD is characterized by severe cognitive decline and involves a long prodromal stage of mild cognitive impairment (MCI). Since MCI subjects are at high risk of converting to AD, identifying MCI individuals is essential for early intervention. To delineate the redundancy profile during AD progression and enable better MCI diagnosis, we define a metric that reflects redundant disjoint connections between brain regions and extract redundancy features in three high-order brain networks-medial frontal, frontoparietal, and default mode networks-based on dynamic functional connectivity (dFC) captured by resting-state functional magnetic resonance imaging (rs-fMRI). We show that redundancy increases significantly from normal control (NC) to MCI individuals and decreases slightly from MCI to AD individuals. We further demonstrate that statistical features of redundancy are highly discriminative and yield state-of-the-art accuracy of up to 96.8 ± 1.0% in support vector machine (SVM) classification between NC and MCI individuals. This study provides evidence supporting the notion that redundancy serves as a crucial neuroprotective mechanism in MCI.

Pixel-Level Fusion Approach with Vision Transformer for Early Detection of Alzheimer’s Disease

Alzheimer’s disease (AD) has become a serious hazard to human health in recent years, and proper screening and diagnosis of AD remain a challenge. Multimodal neuroimaging input can help identify AD in the early mild cognitive impairment (EMCI) and late mild cognitive impairment (LMCI) stages from normal cognitive development using magnetic resonance imaging (MRI) and positron emission tomography (PET). MRI provides useful information on brain structural abnormalities, while PET data provide the difference between physiological and pathological changes in brain anatomy. The precision of diagnosing AD can increase when these data are combined. However, they are heterogeneous and appropriate, and an adequate number of features are required for AD classification. This paper proposed a multimodal fusion-based approach that uses a mathematical technique called discrete wavelet transform (DWT) to analyse the data, and the optimisation of this technique is achieved through transfer learning using a pre-trained neural network called VGG16. The final fused image is reconstructed using inverse discrete wavelet transform (IDWT). The fused images are classified using a pre-trained vision transformer. The evaluation of the benchmark Alzheimer’s disease neuroimaging initiative (ADNI) dataset shows an accuracy of 81.25% for AD/EMCI and AD/LMCI in MRI test data, as well as 93.75% for AD/EMCI and AD/LMCI in PET test data. The proposed model performed better than existing studies when tested on PET data with an accuracy of 93.75%.

Structural and functional differences in the brains of patients with MCI with and without depressive symptoms and their relations with Alzheimer's disease: an MRI study.

The mild cognitive impairment (MCI) stage among elderly individuals is very complex, and the level of diagnostic accuracy is far from ideal. Some studies have tried to improve the 'MCI due to Alzheimer's disease (AD)' classification by further stratifying these patients into subgroups. Depression-related symptoms may play an important role in helping to better define the MCI stage in elderly individuals. In this work, we explored functional and structural differences in the brains of patients with nondepressed MCI (nDMCI) and patients with MCI with depressive symptoms (DMCI), and we examined how these groups relate to AD atrophy patterns and cognitive functioning. Sixty-five participants underwent MRI exams and were divided into four groups: cognitively normal, nDMCI, DMCI, and AD. We compared the regional brain volumes, cortical thickness, and white matter microstructure measures using diffusion tensor imaging among groups. Additionally, we evaluated changes in functional connectivity using fMRI data. In comparison to the nDMCI group, the DMCI patients had more pronounced atrophy in the hippocampus and amygdala. Additionally, DMCI patients had asymmetric damage in the limbic-frontal white matter connection. Furthermore, two medial posterior regions, the isthmus of cingulate gyrus and especially the lingual gyrus, had high importance in the structural and functional differentiation between the two groups. It is possible to differentiate nDMCI from DMCI patients using MRI techniques, which may contribute to a better characterization of subtypes of the MCI stage.