Mild Cognitive Impairment Phase Research Articles

Ketogenic diet and BHB rescue the fall of long-term potentiation in an Alzheimer’s mouse model and stimulates synaptic plasticity pathway enzymes

The Ketogenic Diet (KD) improves memory and longevity in aged C57BL/6 mice. We tested 7 months KD vs. control diet (CD) in the mouse Alzheimer’s Disease (AD) model APP/PS1. KD significantly rescued Long-Term-Potentiation (LTP) to wild-type levels, not by changing Amyloid-β (Aβ) levels. KD’s ‘main actor’ is thought to be Beta-Hydroxy-butyrate (BHB) whose levels rose significantly in KD vs. CD mice, and BHB itself significantly rescued LTP in APP/PS1 hippocampi. KD’s 6 most significant pathways induced in brains by RNAseq all related to Synaptic Plasticity. KD induced significant increases in synaptic plasticity enzymes p-ERK and p-CREB in both sexes, and of brain-derived neurotrophic factor (BDNF) in APP/PS1 females. We suggest KD rescues LTP through BHB’s enhancement of synaptic plasticity. LTP falls in Mild-Cognitive Impairment (MCI) of human AD. KD and BHB, because they are an approved diet and supplement respectively, may be most therapeutically and translationally relevant to the MCI phase of Alzheimer’s Disease.

Visual function changes along the continuum of Alzheimer's disease

Aims/Purpose: The progression of Alzheimer's disease (AD) is manifested by a gradual transition from a preclinical phase, characterized by asymptomatic pathological alterations, to an advanced phase of AD accompanied by cognitive impairment. The aim of this study was to explore visual function along the entire AD continuum.Methods: Each participant underwent a comprehensive visual examination, with only visually healthy individuals being selected for the study. The study comprised the following groups: controls (n = 53), positive family history of AD (FH+) (n = 13), mild cognitive impairment (MCI) (n = 23), mild AD (n = 25), and moderate AD (n = 21). The study analysed the results of visual acuity (VA) and contrast sensitivity (CS).Results: A significant reduction in VA was identified between the control group and the MCI, mild AD and moderate AD groups. CS showed significant changes in all cognitive impairment groups compared to the control group and the FH+ group at spatial frequencies of 12 and 18 cpd. In contrast, significant differences were only observed at spatial frequencies of 3 and 6 cpd between the cognitively impaired groups, starting from moderate AD, with no detectable decrease in CS during the MCI phase. No differences were detected between the control group and the FH+ group. The tests showed a positive correlation with the Mini Mental State Examination score and exhibited a favourable predictive ability in the presence of memory impairment, with higher predictive performance observed in the advance stages of AD.Conclusions: The presence of alterations in VA and CS can be observed as early as the MCI stage in individuals with AD. Recognizing the continuum of AD holds significant significance in early detection, with visual examination offering a straightforward and cost‐effective diagnostic tool for AD. Healthcare professionals can leverage this knowledge to gain a better understanding of the progressive nature of the disease.

Cortical thickness is influenced by bilingual language dominance in typical and pathological cognitive aging

AbstractBackgroundPrior research in clinical and non‐clinical populations demonstrates that speaking more than one language can modify gray matter structure (e.g., DeLuca et al., 2020; Torres et al., 2022). However, existing work has largely classified bilingualism dichotomously, diminishing the ability to establish associations between bilingual factors (e.g., language dominance) and regional cortical thickness (CT).MethodWe examined cross‐sectional differences in CT across a large, ethnically diverse sample of bilingual and monolingual older adults from the Health and Aging Brain Study: Health Disparities cohort (n = 1,605; O’Bryant et al., 2021). Differences in CT between language dominance subgroups across three levels of diagnostic phase (cognitively unimpaired, mild cognitive impairment (MCI), and Alzheimer’s dementia (AD)) were evaluated using linear‐mixed effects models. Participants were characterized as English‐dominant or Spanish‐dominant speakers according to responses on language interview questions and the Short Acculturation Scale for Hispanics (Marin et al., 1987).ResultAssociations between CT and language dominance differed across diagnostic phase (Tukey‐adjusted ps <0.05). In the cognitively unimpaired group, English‐dominant speakers exhibited greater CT than Spanish‐dominant speakers in in regions‐of‐interest (ROIs) related to auditory processing (Heschl’s gyrus), semantic processing (temporal pole), and executive functioning (frontal pole). Spanish‐dominant speakers exhibited greater CT than English‐dominant speakers in two ROIs supporting motor (precentral) and spatial processing (entorhinal). These CT differences were attenuated in the MCI phase. Here, English‐dominant speakers exhibited greater CT than Spanish‐dominant patients in the frontal pole (executive processing). Spanish‐dominant patients did not exhibit greater CT than English‐dominant patients. Notably, this pattern of group differences was reversed in AD patients. Here, Spanish‐dominant patients exhibited greater CT than English‐dominant patients in ROIs in Alzheimer’s disease‐related regions (parahippocampal and entorhinal).ConclusionOur results indicate associations between language dominance and regional CT, with distinct patterns by diagnostic phase. Whereas English‐dominant bilinguals demonstrated greater regional CT relative to Spanish‐dominant bilinguals in the cognitively unimpaired and MCI phase, Spanish‐dominant bilinguals had greater CT in disease‐related regions in the AD phase. The presence of greater CT in Spanish‐dominant bilingual AD patients is suggestive of resistance to pathological progression. Future research examining longitudinal patterns of neural decline in larger samples is needed.

Bilingual neurocognitive resiliency, vulnerability, and Alzheimer's disease biomarker correlates in Latino older adults enrolled in the Health and Aging Brain Study - Health Disparities (HABS-HD).

The effects of bilingualism on neuropsychological test performance in bilinguals with and without cognitive impairment are not well-understood and are relatively limited by small sample sizes of Latinos. Using analysis of covariance (ANCOVA), we explored patterns of cognitive performance and impairment across a large sample of community-dwelling bilingual and monolingual Latino older adults with (n=180) and without (n=643) mild cognitive impairment (MCI) enrolled in HABS-HD. Bilinguals demonstrated cognitive resiliency in the form of significantly better performance on the Trail Making Test and Digit Symbol Substitution Test, observed across the cognitively unimpaired and MCI groups. In contrast, bilinguals demonstrated cognitive vulnerability in the form of significantly poorer performance and higher impairment rates on phonemic fluency in the MCI phase, only. Follow-up analyses revealed less balanced bilinguals demonstrated poorer performance and higher impairment rates on this measure, supported by lower levels of plasma Aβ 42/40. Patterns of cognitive performance and impairment differ as a function of bilingualism. Bilingualism must be considered when evaluating cognitive and biomarker outcomes in Latino older adults. Latino bilinguals perform better on measures of processing speed and coding.Latino bilinguals with MCI demonstrate cognitive vulnerability in verbal fluency.Less balanced bilinguals demonstrate greatest vulnerability anchored by Aβ42/40.

Evaluation of Dietary Intake in Individuals with Mild Cognitive Impairment.

The phase of mild cognitive impairment (MCI) holds significant importance for postponing the onset of dementia. Therefore, MCI has become a central focus in research related to dementia prevention. The purpose of this study was to investigate the dietary intake and dietary patterns of MCI patients in Taiwan. In total, 40 subjects were enrolled in this cross-sectional study that was conducted from July 2019 to September 2021 at the Linkou Chang Gung Memorial Hospital. The results of the clinical dementia rating (CDR) and mini-mental state examination (MMSE) were obtained from medical records. Participants were divided into two groups: a healthy group (MMSE ≥ 26 points, CDR = 0) and an MCI group (MMSE ≥ 26 points, CDR = 0.5). Results indicated that the MCI group had significantly higher copper and lower low-fat meat intake compared to the healthy group. Furthermore, the high MIND (Mediterranean dietary approaches to stop hypertension intervention for neurodegenerative delay) diet score represented a lower risk of MCI. After adjusting for age, gender, diabetes mellitus, hypertension, and calorie intake in the multivariate regression analysis, calcium and fruit intake levels were positively associated with the MMSE, whereas low-fat meat intake was negatively associated with the CDR. In conclusion, the prevalence of MCI demonstrated a close correlation with nutrient intake, including copper and calcium. Furthermore, a MIND diet, particularly one high in n-3 polyunsaturated fatty acids, might be useful for preventing MCI. However, more extensive research with larger populations is needed to confirm this potential.

Neuroimaging modalities in the detection of Alzheimer's disease-associated biomarkers.

Alzheimer's disease (AD) is the most common cause of dementia. Neuropathological changes in AD patients occur up to 10-20 years before the emergence of clinical symptoms. Specific diagnosis and appropriate intervention strategies are crucial during the phase of mild cognitive impairment (MCI) and AD. The detection of biomarkers has emerged as a promising tool for tracking the efficacy of potential therapies, making an early disease diagnosis, and prejudging treatment prognosis. Specifically, multiple neuroimaging modalities, including magnetic resonance imaging (MRI), positron emission tomography, optical imaging, and single photon emission-computed tomography, have provided a few potential biomarkers for clinical application. The MRI modalities described in this review include structural MRI, functional MRI, diffusion tensor imaging, magnetic resonance spectroscopy, and arterial spin labelling. These techniques allow the detection of presymptomatic diagnostic biomarkers in the brains of cognitively normal elderly people and might also be used to monitor AD disease progression after the onset of clinical symptoms. This review highlights potential biomarkers, merits, and demerits of different neuroimaging modalities and their clinical value in MCI and AD patients. Further studies are necessary to explore more biomarkers and overcome the limitations of multiple neuroimaging modalities for inclusion in diagnostic criteria forAD.

From attention-deficit hyperactivity disorder to sporadic Alzheimer's disease-Wnt/mTOR pathways hypothesis.

Alzheimer's disease (AD) is the most common neurodegenerative disorder with the majority of patients classified as sporadic AD (sAD), in which etiopathogenesis remains unresolved. Though sAD is argued to be a polygenic disorder, apolipoprotein E (APOE) ε4, was found three decades ago to pose the strongest genetic risk for sAD. Currently, the only clinically approved disease-modifying drugs for AD are aducanumab (Aduhelm) and lecanemab (Leqembi). All other AD treatment options are purely symptomatic with modest benefits. Similarly, attention-deficit hyperactivity disorder (ADHD), is one of the most common neurodevelopmental mental disorders in children and adolescents, acknowledged to persist in adulthood in over 60% of the patients. Moreover, for ADHD whose etiopathogenesis is not completely understood, a large proportion of patients respond well to treatment (first-line psychostimulants, e.g., methylphenidate/MPH), however, no disease-modifying therapy exists. Interestingly, cognitive impairments, executive, and memory deficits seem to be common in ADHD, but also in early stages of mild cognitive impairment (MCI), and dementia, including sAD. Therefore, one of many hypotheses is that ADHD and sAD might have similar origins or that they intercalate with one another, as shown recently that ADHD may be considered a risk factor for sAD. Intriguingly, several overlaps have been shown between the two disorders, e.g., inflammatory activation, oxidative stress, glucose and insulin pathways, wingless-INT/mammalian target of rapamycin (Wnt/mTOR) signaling, and altered lipid metabolism. Indeed, Wnt/mTOR activities were found to be modified by MPH in several ADHD studies. Wnt/mTOR was also found to play a role in sAD and in animal models of the disorder. Moreover, MPH treatment in the MCI phase was shown to be successful for apathy including some improvement in cognition, according to a recent meta-analysis. In several AD animal models, ADHD-like behavioral phenotypes have been observed indicating a possible interconnection between ADHD and AD. In this concept paper, we will discuss the various evidence in human and animal models supporting the hypothesis in which ADHD might increase the risk for sAD, with common involvement of the Wnt/mTOR-pathway leading to lifespan alteration at the neuronal levels.

The impact of transfer learning on 3D deep learning convolutional neural network segmentation of the hippocampus in mild cognitive impairment and Alzheimer disease subjects.

Research on segmentation of the hippocampus in magnetic resonance images through deep learning convolutional neural networks (CNNs) shows promising results, suggesting that these methods can identify small structural abnormalities of the hippocampus, which are among the earliest and most frequent brain changes associated with Alzheimer disease (AD). However, CNNs typically achieve the highest accuracy on datasets acquired from the same domain as the training dataset. Transfer learning allows domain adaptation through further training on a limited dataset. In this study, we applied transfer learning on a network called spatial warping network segmentation (SWANS), developed and trained in a previous study. We used MR images of patients with clinical diagnoses of mild cognitive impairment (MCI) and AD, segmented by two different raters. By using transfer learning techniques, we developed four new models, using different training methods. Testing was performed using 26% of the original dataset, which was excluded from training as a hold‐out test set. In addition, 10% of the overall training dataset was used as a hold‐out validation set. Results showed that all the new models achieved better hippocampal segmentation quality than the baseline SWANS model (p s < .001), with high similarity to the manual segmentations (mean dice [best model] = 0.878 ± 0.003). The best model was chosen based on visual assessment and volume percentage error (VPE). The increased precision in estimating hippocampal volumes allows the detection of small hippocampal abnormalities already present in the MCI phase (SD = [3.9 ± 0.6]%), which may be crucial for early diagnosis.

Polymorphism Rs2421943 of the Insulin-Degrading Enzyme Gene and the Risk of Late-Onset Alzheimer's Disease.

Insulin-degrading enzyme (IDE) is a widely distributed Zn2+-binding metalloprotease that cleaves multiple short and medium-sized peptides prone to form β-structures. These include insulin and amyloid-β peptides. Accumulation and fibrillation of amyloid-β peptides leading to the formation of amyloid plaques is a characteristic sign of Alzheimer's disease (AD) pathology. The study investigated the rs2421943 single nucleotide polymorphism (SNP) of the IDE gene as a risk factor for MCI (mild cognitive impairment) and AD. Two independent groups of 1670 patients and controls were included. The AD group consisted of 595 patients and 400 controls; the MCI group involved 135 patients and 540 matched controls. PCR and restriction fragment length analysis were used to analyze the rs2421943 polymorphism. Using the miRBase and RNA22 prediction tools in silico indicated that the rs2421943 polymorphism is a potential target for a specific miRNA (hsa-miR-7110-5p). AG and GG genotypes of rs2421943 significantly increased the risk of AD, and the AG genotype increased the risk of MCI. It seems the G allele both increases the risk of AD and accelerates the transition through the MCI phase. In silico study revealed that rs2421943 is inside the sequence binding miRNA hsa-miR-7110-5p. The polymorphism could affect the rate of IDE pre-RNA (heterogeneous nuclear RNA, hnRNA) processing, resulting in slower translation, lower levels of IDE, deficient removal of amyloid-β fragments, and greater risk of and/or accelerated progression of AD. GG and AG genotypes of the single nucleotide polymorphism rs2421943 of insulindegrading enzyme gene increase the risk of AD and MCI.

What Matters to Patients with Alzheimer’s Disease and Their Care Partners? Implications for Understanding the Value of Future Interventions

Alzheimer’s Disease (AD) is the most common cause of dementia. Recent thinking portrays AD as a continuum consisting of three stages: an asymptomatic preclinical period, a mild cognitive impairment phase, and dementia, which can be further classified as mild, moderate or severe. While many studies explore the cognitive and functional aspects of AD, fully understanding AD pathophysiology, as well as the potential value of pharmacological and psycho-social interventions, requires a deeper understanding of patient and care partner priorities, particularly in the early stages where such interventions may have the greatest impact in slowing or delaying progression. Available studies highlight a diverse range of patient and care partner priorities, including impacts on their emotions, moods, and social lives. These priorities have not been systematically incorporated in the clinical and value assessments of potential interventions. We propose approaches to better understand the humanistic impact of AD including conducting additional research into the impacts of interventions from the point of view of patients and care partners, expanding notions of ‘value’ and improving health system capacity for diagnosis.

An enriched environment delays the progression from mild cognitive impairment to Alzheimer's disease in senescence-accelerated mouse prone 8 mice.

A previous study demonstrated that middle-aged (5-6 months of age) senescence-accelerated mouse prone 8 (SAMP8) mice can be used as animal models of mild cognitive impairment (MCI). An enriched environment (EE) can mitigate cognitive decline and decrease the pathological changes associated with various neurodegenerative diseases. In the present study, the learning-memory abilities of SAMP8 mice during the MCI phase (5 months of age) was evaluated and neuropathological changes in the hippocampus were examined after the mice were exposed to an EE for 60 days. In the Morris water maze test, EE-exposed mice demonstrated significantly decreased escape latency and increased time spent in the target quadrant and number of platform crossings compared with control mice. Terminal deoxynucleotidyl transferase dUTP nick end labeling and Nissl staining showed that EE-exposed mice had reduced neuronal apoptosis and increased number of surviving neurons compared with control mice. Golgi staining, transmission electron microscopy, and immunohistochemical staining demonstrated that EE-exposed mice exhibited increased dendritic spine densities among secondary and tertiary apical dendrites; increases in synaptic numerical density, synaptic surface density, and expression of synaptophysin; and reduced deposition of amyloid-β (Aβ) and expression of amyloid-precursor protein (APP) in the hippocampal CA1 region compared with control mice. These results demonstrate that EE exposure effectively decreases neuronal loss and regulates neuronal synaptic plasticity by reducing the expression of APP and the deposition of Aβ in the hippocampal CA1 region, thereby mitigating cognitive decline in SAMP8 mice during the MCI phase and delaying the progression from MCI to Alzheimer's disease.

Evaluation of Memantine in AAV-AD Rat: A Model of Late-Onset Alzheimer's Disease Predementia.

Though our understanding of Alzheimer's disease (AD) remains elusive, it is well known that the disease starts long before the first signs of dementia. This is supported by the large number of symptomatic drug failures in clinical trials and the increased trend to enroll patients at predementia stages with either mild or no cognitive symptoms. However, the design of pre-clinical studies does not follow this attitude, in particular regarding the choice of animal models, often irrelevant to mimic predementia Late Onset Alzheimer's Disease (LOAD). We aimed to pharmacologically validate the AAV-AD rat model to evaluate preventive treatment of AD. We evaluated an N-methyl-D-aspartate receptor antagonist, named memantine, in AAV-AD rats, an age-dependent amyloid rat model which closely mimics Alzheimer's pathology including asymptomatic and prodromal stages. Memantine was used at a clinically relevant dose (20 mg daily oral administration) from 4 (asymptomatic phase) to 10 (mild cognitive impairment phase) months of age. A 6-month treatment with memantine promoted a non-amyloidogenic cleavage of APP followed by a decrease in soluble Aβ42. Consequently, both long-term potentiation and cognitive impairments were prevented. By contrast, the levels of hyperphosphorylated endogenous tau remained unchanged, indicating that a long-term memantine treatment is ineffective to restrain the APP processing-induced tauopathy. Together, our data confirm that relevant models to LOAD, such as the AAV-AD rat, can provide a framework for a better understanding of the disease and accurate assessment of preventive treatments.

Mild cognitive impairment associated with eventual Lewy body disease pathology: Clinical characterization of 75 patients

The clinical characteristics of mild cognitive impairment (MCI) associated with underlying Lewy body disease (LBD) pathology are still being defined. The Mayo Alzheimer’s Disease Research Center database was queried to identify all patients who were diagnosed with MCI from 1996 to 2018, followed prospectively, underwent autopsy, and limbic- or neocortical-predominant LBD was present. The key demographic and clinical features were characterized. Seventy-five patients were identified, of whom 55 (73%) were male, mean education was 15 ± 3 years, baseline MMSE score was 26 ± 2, and all had a CDR score of 0.5. The pathologic findings were neocortical-predominant LBD in 40 and limbic-predominant LBD in 35, with 32 (43%) having coexisting Alzheimer’s disease pathology. The mean age or duration ± SD in years for key features were as follows: onset of cognitive decline 71 ± 9, onset of REM sleep behavior disorder (RBD, n = 45) 63 ± 14, age of MCI diagnosis 73 ± 8, age of dementia diagnosis 75 ± 8, duration from MCI to dementia diagnosis 2 ± 1, age at death 81 ± 8, and duration from dementia diagnosis to death 6 ± 4. At MCI diagnosis, the coexisting features were: RBD 53%, mild parkinsonism 31%, cognitive fluctuations 23%, and visual hallucinations 20%; 19% had none of these present. Of the 70 who developed dementia, 80% met criteria for clinically probable DLB. The absence of many core features in the MCI phase and variable development of these features in the dementia-predominant phenotype of LBD underscores the need for biomarkers which are sensitive and specific to LBD pathology, particularly in the MCI phase.

Correlates of Mild Cognitive Impairment of Community-Dwelling Older Adults in Wuhan, China.

Mild cognitive impairment (MCI) is an early stage of Alzheimer’s disease or other forms of dementia that occurs mainly in older adults. The MCI phase could be considered as an observational period for the secondary prevention of dementia. This study aims to assess potential differences in the risk of MCI among different elderly groups in Wuhan, China, and to further identify the most vulnerable populations using logistic regression models. A total of 622 older adults participated in this study, and the prevalence of MCI was 34.1%. We found that individuals aged 80–84 (odds ratio, OR = 1.908, 95% confidence interval, 95% CI 1.026 to 3.549) or above (OR = 2.529, 95% CI 1.249 to 5.122), and those with two chronic diseases (OR = 1.982, 95% CI 1.153 to 3.407) or more (OR = 2.466, 95% CI 1.419 to 4.286) were more likely to be diagnosed with MCI. Those with high school degrees (OR = 0.451, 95% CI 0.230 to 0.883) or above (OR = 0.318, 95% CI 0.129 to 0.783) and those with a family per-capita monthly income of 3001–4500 yuan (OR = 0.320, 95% CI 0.137 to 0.750) or above (OR = 0.335, 95% CI 0.135 to 0.830) were less likely to experience MCI. The results also showed that those aged 80 or above were more likely to present with cognitive decline and/or reduced activities of daily living (ADL) function, with the odds ratios being 1.874 and 3.782, respectively. Individuals with two, or three or more chronic diseases were more likely to experience cognitive decline and/or reduced ADL function, with odds ratios of 2.423 and 2.631, respectively. Increased risk of suffering from either MCI and/or decline in ADL functioning is strongly positively associated with older age, lower educational levels, poorer family economic status, and multiple chronic diseases. Our findings highlight that the local, regional, and even national specific MCI-related health promotion measures and interventions must target these vulnerable populations.

Frequency and Correlates of Subjective Memory Complaints in Parkinson's Disease with and without Mild Cognitive Impairment: Data from the Parkinson's Disease Cognitive Impairment Study.

Subjective memory complaints (SMC) may represent the preclinical phase of mild cognitive impairment (MCI) due to Alzheimer's disease. Dementia/MCI have been described with a high prevalence in Parkinson's disease (PD), but whether SMC may predict the development of cognitive impairment has been barely explored. To evaluate the frequency and clinical correlates of isolated SMC (PD-SMC) or within the construct of MCI in subjects with PD, 147 PD patients from the PArkinson's disease COgnitive impairment Study (PACOS) were consecutively recruited for the study. This is a multicenter study involving two Movement Disorder Centers in south Italy. All subjects underwent comprehensive neuropsychological evaluation and PD-MCI was diagnosed according to Litvan's criteria. The Memory Assessment Clinics Questionnaire was used to assess SMC. Logistic regression analysis, adjusted for demographics and significant covariates, was used to evaluate clinical differences between groups. Forty-two (28.6%) individuals presented with PD without SMC and/or MCI (PDw), 40 (27,2%) with PD-SMC, 48 (32,6%) PD-SMC-MCI, and 17 (11,6%) PD-MCI without SMC (PD-MCI). When compared to PDw, PD-SMC was significantly associated with anxiety (OR = 3.93, 95% CI = 1.18-13.03), while PD-SMC-MCI related to motor progression (OR = 5.29, 95% CI = 1.12-24.86), and instrumental disability (OR = 6.98, 95% CI = 2.08-23.38). About 60% of patients showed SMC, in isolation or within the MCI frame. The role of SMC in PD seems to have a different etiology depending on the presence/absence of MCI. In particular, PD-SMC would represent a subjective reaction to the disease, while PD-SMC-MCI would depict motor progression and disability.

Multiscale deep neural network based analysis of FDG-PET images for the early diagnosis of Alzheimer’s disease

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases with a commonly seen prodromal mild cognitive impairment (MCI) phase where memory loss is the main complaint progressively worsening with behavior issues and poor self-care. However, not all individuals clinically diagnosed with MCI progress to AD. A fraction of subjects with MCI either progress to non-AD dementia or remain stable at the MCI stage without progressing to dementia. Although a curative treatment of AD is currently unavailable, it is extremely important to correctly identify the individuals in the MCI phase that will go on to develop AD so that they may benefit from a curative treatment when one becomes available in the near future. At the same time, it would be highly desirable to also correctly identify those in the MCI phase that do not have AD pathology so they may be spared from unnecessary pharmocologic interventions that, at best, may provide them no benefit, and at worse, could further harm them with adverse side-effects. Additionally, it may be easier and simpler to identify the cause of the cognitive impairment in these non-AD cases, and hence proper identification of prodromal AD will be of benefit to these individuals as well. Fluorodeoxy glucose positron emission tomography (FDG-PET) captures the metabolic activity of the brain, and this imaging modality has been reported to identify changes related to AD prior to the onset of structural changes. Prior work on designing classifier using FDG-PET imaging has been promising. Since deep-learning has recently emerged as a powerful tool to mine features and use them for accurate labeling of the group membership of given images, we propose a novel deep-learning framework using FDG-PET metabolism imaging to identify subjects at the MCI stage with presymptomatic AD and discriminate them from other subjects with MCI (non-AD / non-progressive). Our multiscale deep neural network obtained 82.51% accuracy of classification just using measures from a single modality (FDG-PET metabolism data) outperforming other comparable FDG-PET classifiers published in the recent literature.

Using Cerebrospinal Fluid Biomarker Testing to Target Treatment to Patients with Mild Cognitive Impairment: A Cost-Effectiveness Analysis.

ObjectiveCerebrospinal fluid (CSF) biomarkers are shown to facilitate a risk identification of patients with mild cognitive impairment (MCI) into different risk levels of progression to Alzheimer’s disease (AD). Knowing a patient’s risk level provides an opportunity for earlier interventions, which could result in potential greater benefits. We assessed the cost effectiveness of the use of CSF biomarkers in MCI patients where the treatment decision was based on patients’ risk level.MethodsWe developed a state-transition model to project lifetime quality-adjusted life-years (QALYs) and costs for a cohort of 65-year-old MCI patients from a US societal perspective. We compared four test-and-treat strategies where the decision to treat was based on a patient’s risk level (low, intermediate, high) of progressing to AD with two strategies without testing, one where no patients were treated during the MCI phase and in the other all patients were treated. We performed deterministic and probabilistic sensitivity analyses to evaluate parameter uncertainty.ResultsTesting and treating low-risk MCI patients was the most cost-effective strategy with an incremental cost-effectiveness ratio (ICER) of US$37,700 per QALY. Our results were most sensitive to the level of treatment effectiveness for patients with mild AD and for MCI patients. Moreover, the ICERs for this strategy at the 2.5th and 97.5th percentiles were US$18,900 and US$50,100 per QALY, respectively.ConclusionBased on the best available evidence regarding the treatment effectiveness for MCI, this study suggests the potential value of performing CSF biomarker testing for early targeted treatments among MCI patients with a narrow range for the ICER.Electronic supplementary materialThe online version of this article (doi:10.1007/s41669-017-0054-z) contains supplementary material, which is available to authorized users.

Early and Mild Phases of Primary Progressive Aphasia: A Case Series.

The early and mild phases of various neurodegenerative diseases, sometimes described as Mild Cognitive Impairment (MCI), has been characterized as the transitional state between normal cognition and dementia. It is described as having cognitive decline not severe enough to cause functional impairment. MCI has been divided into amnestic and non-amnestic subtypes with the amnestic subtype most commonly progressing to AD. The MCI phase of other dementias such as DLB has also been described. There are very few reports summarizing this early phase of Primary Progressive Aphasia. Our aim is to contribute to the clinical characterization of the early and mild phases of clinically suspect PPA in order to better describe the presenting features and neuropsychological profile. This is a cross-sectional case series abstracted from our memory disorders clinic. We retrospectively queried and analyzed the cases of 9 patients with a primary diagnosis of MCI and secondary diagnosis of progressive aphasia. Acquired (non-degenerative) aphasias (e.g. stroke, mass) were excluded. Of the 9 cases, 5 were non-amnestic MCI and 4 were amnestic MCI, all with language as the primary domain. All eMCI cases were non-amnestic. Word finding difficulty was observed in 8 of the 9 cases and sentence repetition impairments in 8 of 8 tested. PPA is a syndrome with an underlying progressive neurodegenerative etiology that results in dementia. PPA, like other neurodegenerative conditions, can transition through an early (i.e. MCI) phase prior to the dementia phase. The clinical description of this early stage of PPA is predominantly characterized by word finding difficulty on observation, sentence repetition impairment on neuropsychological testing, and a diagnosis of MCI or early MCI (eMCI) with language as the primary impaired domain ± an amnestic component.

Comprendre le stade compensatoire de la maladie d'Alzheimer et agir pour promouvoir la cognition et la plasticité cérébrale.

Alzheimer's disease begins with a phase of mild cognitive impairment (MCI), characterized by the presence of minor symptoms that have little or no impact on functional independence. The study of patients with MCI has led to spectacular advances in understanding the prodrome of the disease. It has also produced a typical cognitive profile: an impairment of episodic memory, especially delayed recall and associative memory, deficit in executive functions or working memory and certain semantic problems. Recent studies have also examined compensatory processes that take place during the early phase of the disease. Functional magnetic resonance imagery indicates that the brain is more active in persons with MCI than in normal people. Some researchers have interpreted this hyperactivity as playing a compensatory role. Intervention studies have relied on cognitive training programs to promote adaptation and compensatory plasticity processes. These studies have shown that the memory and well-being of people with MCI could be improved by such programs. They have also revealed changes in the level of cerebral activation among persons with MCI who received this type of intervention. In Summary, studies in neuropsychology and in cognitive neuroscience have greatly contributed to characterizing this critical phase of Alzheimer's disease and offer avenues for intervention that could increase adaptation and improve the quality of life of people suffering from the disease. (PsycINFO Database Record

Reduction of Oxidative/Nitrosative Stress in Brain and its Involvement in the Neuroprotective Effect of n-3 PUFA in Alzheimer's Disease.

Plenty of evidence has shown that an enhanced oxidative or nitrosative stress may play a central role in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD). The suppressive effect of n-3 polyunsaturated fatty acids (n-3 PUFA) against oxidative/nitrosative stressinduced injury in nervous tissues has recently received increasing interest. A number of human experimental studies have concurred to demonstrate that they may exert a substantial preventive role, especially in the very early phase of mild cognitive impairment (MCI) preceding AD. It has been suggested that they may exert an indirect antioxidant/anti-nitrosative role by modulating the expression/ activity of several proteins involved in the modulation of oxidative stress in nervous tissues. In particular, recent data have supported the hypothesis that in the early phase of MCI the light to moderate oxidative stress triggered by not cytotoxic doses of n-3 PUFA can positively regulate the transcriptional activity of nuclear factor erythroid 2-related factor 2 (Nrf2). This may result in the induced expression of heme oxygenase-1 (HO-1) and other antioxidant proteins transcriptionally regulated by Nrf2. Alternatively, the anti-inflammatory and antioxidant/anti-nitrosative effects of n-3 PUFA have been lately related to their ability to blunt microglia persistent activation occurring during chronic inflammation involved in the pathogenesis of neurodegenerative diseases. Evidences have been presented that n-3 PUFA may convert microglia from the macrophage M1 to an M2 phenotype showing lower production of neurotoxicoxidative factors and enhanced phagocytic activity toward Aβ peptide, or even to a further phenotype with neurotrophic/ protective properties.