Mild Cognitive Impairment Due To Alzheimer's Disease Research Articles

Mitophagy biomarkers are changed in the continuum of Alzheimer’s disease

AbstractBackgroundAutophagy is a cellular self “garbage clearance ”system through which cells eliminate and recycle dysfunctional cytoplasmatic components, such as defective organelles and misfolded protein aggregates. Mitophagy is the sub‐type of autophagy that recognizes and degrades damaged or superfluous mitochondria to maintain cellular homeostasis. Emerging evidence demonstrates that autophagy and mitophagy are impaired in Alzheimer’s disease (AD); its upregulation ameliorates Aß pathology and slows down the cognitive decline in animal models of AD, thus representing a potentially treatable target. The change in the mitophagy biomarkers in individuals with AD needs to be clarified. We aimed to explore the changes of mitophagy biomarkers in biomarkers‐defined individuals in various stages of AD and compare them to cognitively unimpaired individuals (CU).MethodWe included 228 biomarker‐defined individuals from the Czech Brain Aging Study:98 AD dementia (ADD), 88 mild cognitive impairment due to AD (MCI‐AD), and 42 CU individuals. They underwent clinical examination, complex neuropsychological assessment, and brain MRI. Commercial ELISA kits were used to measure standard AD biomarkers in CSF (Aß42, Aß40, pTau, tTau), a biomarker of neurodegeneration (neurofilament light chain – NfL), synaptic dysfunction (neurogranin, Ng), and mitophagy biomarkers in CSF (PINK1‐ mitochondrial kinase crucial for mitophagy) and in serum (BNIP3L‐ mitophagy receptor, TFEB‐ transcription factor critical for lysosomal degradation).ResultWe found a significant increase in PINK1 CSF and BNIP3L serum levels in ADD compared to MCI‐AD and CU (ps<.001). TFEB serum levels were decreased in ADD compared to MCI‐AD and CU (ps<.05). Additionally, in ADD, PINK1 correlated with NfL (r = 0.27) and Ng (r = 0.47). In MCI‐AD, there was a correlation between PINK1 and Ng (r = 0.51), but not with NfL. There was no correlation in CU individuals with NfL or Ng.ConclusionWe identified candidate proteins of mitophagy that are changed in various cognitive stages of AD. In the ADD stage, there is an upregulation of the mitophagy inducers, PINK1 and BNIP3L, together with decreased levels of TFEB, a master regulator of lysosomal biogenesis. One of the possible explanations is that these findings reflect impairment in the final stage of autophagy–lysosomal degradation. Further research is needed to clarify its pathophysiological importance in the AD cascade.

Using Virtual Reality to Assess Spatial Cognition in Subjective Cognitive Decline and Mild Cognitive Impairment due to Alzheimer’s Disease

AbstractBackgroundSpatial navigation impairment (SNI) is prevalent in people with Alzheimer’s disease (AD) continuum and may appear in the initial clinical stage. To detect this deficit in people at risk may not only help to prevent getting lost or missing incidents, but also provide a useful clinical feature for diagnosis. Traditional assessments for SNI include questionnaires, paper pencil and maze tests, or video games. Although a real‐world setting is more valid, direct, and accurate, it has many unexpected conditions such as weather, obstacles, or accidents. Thanks to technology, virtual reality (VR) is a new way to assess SNI.MethodWe used PJVR to test spatial navigation ability in cognitively unimpaired (CU), subjective cognitive decline (SCD) and mild cognitive impairment due to AD (MCI‐AD). The PJVR is the VR version (Vive Pro Eye Head‐mounted Display, HTC) of the PJ device, which was developed by Pai and Jan and has been successfully verified its power to discriminate each other among CU, MCI, and mild AD. With a map provided and using joysticks or handles, participants were requested to reach five points in a 660‐meter path on our university campus. Linear deviation in meters in each point was treated as the variable for comparison. A pre‐test training course was given to facilitate the procedure.Result118 subjects signed informed consent and 87 (73.7%) completed the trials, including 18 CU, 41 SCD and 28 MCI‐AD. Fourteen, or 11.9%, of all participants failed the trials due to cybersickness. The averaged linear deviations of the CU, SCD and MCI‐AD were 36.1 (38.2), mean (S.D.), 40.8 (44.4), and 93.7 (46.8) meters respectively (p<0.000). The linear deviation of the PJVR of the participants was correlated with the Questionnaire on Everyday Navigation Abilities (p<0.001), indicating a good real‐world validity.ConclusionAlthough the rate of cybersickness is higher as compared with the reports from Western countries, most of the participants completed the trials. The PJVR is feasible to assess spatial cognition and able to discriminate CU/SCD from MCI‐AD. To simplify PJVR to be practical is important to welcome the era of digital cognitive assessment.

Early detection of mild cognitive impairment due to Alzheimer’s disease using combinations of an online cognitive assessment and blood biomarkers

AbstractBackgroundAccessible measurements to a large screening and early differentiation of mild cognitive impairment due to Alzheimer’s disease (MCI‐AD) from healthy elderly is increasing urgent with the prevalence of Alzheimer’s disease (AD) expanded.Methodan online cognitive assessment (Memtrax) and MoCA were performed, on 99 clinically diagnosed cognitively normal (CON) and 101 MCI‐AD participants. The plasma levels of phosphorylated tau (p‐tau)181 and neurofilament light (NfL) and amyloid beta (Aβ)42/40 were measured using Simoa assay. The relevance between Memtrax and blood biomarkers were conducted by Spearman correlation analysis. Discrimination models were built using assorted machine learning approaches combining Memtrax with blood biomarkers, and model performance was measured using Area Under the Receiver Operating Characteristic Curve (AUC).ResultThe AUC of Memtrax and MoCA in differentiating MCI‐AD from CON was similar. Memtrax has a strong correlation with phosphorylated tau (p‐tau)181 and neurofilament light (NfL), while less related to amyloid beta (Aβ)42/40. Combining Memtrax and blood biomarkers, the AUC of best model reach to 0.975 (95% CI: 0.950‐0.999).ConclusionThe combination of Memtrax and blood biomarkers is promising to the large screening and early detection in MCI‐AD.

Tracking the progression of Alzheimer's disease: Insights from metabolic patterns of SOMI stages

BackgroundSOMI (Stages of Objective Memory Impairment) is a novel classification that identifies six stages of memory decline in Alzheimer's Disease (AD) using the Free and Cued Selective Reminding Test (FCSRT). However, the relationship between SOMI stages and brain metabolism remains unexplored. This study aims to investigate the metabolic correlates of SOMI stages using FDG-PET in Mild Cognitive Impairment due to AD (MCI-AD) and early AD patients. MethodsOne hundred twenty-nine-patients (99 aMCI-AD and 30 AD), and 42 healthy controls (HCs) (MMSE = 29.2 ± .8; age:69.1 ± 8.6 years; education:10.7 ± 3.8 years) who underwent an extensive neuropsychological battery including FCSRT and brain FDG-PET were enrolled. According to their clinical relevance and available sample sizes, SOMI-4 (N = 24 subjects; MMSE score:26.6 ± 2.6: age:75.4 ± 3.2; education:9.9 ± 4.5) and SOMI-5 groups (N = 97; MMSE:25.3 ± 2.6; age:73.9 ± 5.8; education:9.4 ± 4.1) were investigated. ResultsCompared to HCs, SOMI-4 showed hypometabolism in the precuneus, medial temporal gyrus bilaterally, right pecuneus and angular gyrus. SOMI-5 exhibited broader hypometabolism, extending to the left posterior cingulate and medial frontal gyrus bilaterally. The conjunction analysis revealed overlapping areas in the precuneus, medial temporal gyrus bilaterally, and in the right angular gyrus and cuneus. The disjunction analysis identified SOMI-5 specific hypometabolism encompassing left inferior temporal gyrus, uncus and parahippocampal gyrus, and medial frontal gyrus bilaterally (p < .001, p-value (FWE) < .05). DiscussionSOMI-4 relates to posterior hypometabolism, while SOMI-5 to more extensive hypometabolism further encompassing frontal cortices, suggesting SOMI as a biologically relevant classification system of memory decline. ConclusionMemory decline staged with SOMI is associated with hypometabolism spreading in amnesic MCI-AD/AD, suggesting its usefulness as a clinical marker of increasing neurodegeneration.

Differential diagnosis of MCI with Lewy bodies and MCI due to Alzheimer's disease by visual assessment of occipital hypoperfusion on SPECT images.

Predicting progression of mild cognitive impairment (MCI) to Alzheimer's disease (AD) or dementia with Lewy bodies (DLB) is important. We evaluated morphological and functional differences between MCI with Lewy bodies (MCI-LB) and MCI due to AD (MCI-AD), and a method for differentiating between these conditions using brain MRI and brain perfusion SPECT. A continuous series of 101 subjects, who had visited our memory clinic and met the definition of MCI, were enrolled retrospectively. They were consisted of 60 MCI-LB and 41 MCI-AD subjects. Relative cerebral blood flow (rCBF) on SPECT images and relative brain atrophy on MRI images were evaluated. We performed voxel-based analysis and visually inspected brain perfusion SPECT images for regional brain atrophy, occipital hypoperfusion and the cingulate island sign (CIS), for differential diagnosis of MCI-LB and MCI-AD. MRI showed no significant differences in regional atrophy between the MCI-LB and MCI-AD groups. In MCI-LB subjects, occipital rCBF was significantly decreased compared with MCI-AD subjects (p < 0.01, family wise error [FWE]-corrected). Visual inspection of occipital hypoperfusion had sensitivity, specificity, and accuracy values of 100%, 73.2% and 89.1%, respectively, for differentiating MCI-LB and MCI-AD. Occipital hypoperfusion was offered higher diagnostic utility than the CIS. The occipital lobe was the region with significantly decreased rCBF in MCI-LB compared with MCI-AD subjects. Occipital hypoperfusion on brain perfusion SPECT may be a more useful imaging biomarker than the CIS for visually differentiating MCI-LB and MCI-AD.

Odor Discrimination as a Marker of Early Alzheimer's Disease.

Olfactory dysfunction is an early symptom of Alzheimer's disease (AD). However, olfactory tests are rarely performed in clinical practice because their diagnostic efficacy in detecting early AD is unclear. To investigate odor discrimination in patients with early AD and the efficacy of olfactory discrimination tests in differentiating these patients from subjects with normal cognition (CN). Thirty patients each with mild dementia due to AD (MD-AD) and mild cognitive impairment due to AD (MCI-AD) and 30 older subjects with CN were enrolled. All participants underwent cognitive examinations (CDR, MMSE, ADAS-Cog 13, and verbal fluency) and odor discrimination tests (Sniffin' Sticks test, Burghart®, Germany). The MD-AD group achieved significantly worse scores on the olfactory discrimination test than the MCI-AD group, and the MCI-AD group achieved significantly worse results than the CN group (p < 0.05). A cut-off score of≤10 had a diagnostic accuracy of 94.44% (95% CI, 87.51-98.17%) in differentiating patients with MCI-AD/MD-AD from subjects with CN and of 91.67% (95% CI, 81.61-97.24%) in differentiating those with MCI-AD from subjects with CN. Our multinomial logistic regression model with demographic data and ADAS-Cog 13 scores as predictor variables correctly classified 82.2% of the cases (CN, 93.3%; MC-AD, 70%; MD-AD, 83.3%); on adding the olfactory discrimination score to the model, the percentage increased to 92.2% (CN, 96.7%; MCI-AD, 86.7%; MD-AD, 93.3%). Odor discrimination is impaired in cases of early AD and continues to deteriorate as the disease progresses. The olfactory discrimination test showed good diagnostic efficacy in detecting early AD.

Serial Nigrostriatal Dopaminergic Imaging in Mild Cognitive Impairment With Lewy Bodies, Alzheimer Disease, and Age-Matched Controls.

Progressive nigrostriatal pathway degeneration occurs in individuals with dementia with Lewy bodies (LB). Our objective was to investigate whether repeat 123[I]-N-(3-fluoropropyl)-2β-carboxymethoxy-3β-(4-iodophenyl) nortropane (FP-CIT) single photon emission computed tomography (SPECT) can identify progressive dopaminergic loss in mild cognitive impairment (MCI) with Lewy bodies (MCI-LB). Individuals with MCI-LB and MCI due to Alzheimer disease (MCI-AD) underwent comprehensive clinical assessment, 123[I]-FP-CIT SPECT at baseline and annual reviews, and baseline cardiac 123 iodine metaiodobenzylguanidine (I-MIBG). Mixed-effects models were used to investigate changes in 123[I]-FP-CIT specific binding ratio (SBR) in the striatum for each diagnostic group compared with controls. The time interval to the development of a quantitatively abnormal 123[I]-FP-CIT SPECT in the possible and probable MCI-LB groups was determined as the time it took for these groups to reach a striatal uptake 2 SDs below aged-matched controls. Test-retest variation was assessed using baseline and repeat scans in controls. We recruited 20 individuals with MCI-AD, 11 with possible MCI-LB, 25 with probable MCI-LB, and 29 age-matched controls. The mean time between baseline and the final image was 1.6 years (SD = 0.9, range 1.0-4.3). The annual estimated change in SBR was 0.23 for controls (95% CI -0.07 to 0.53), -0.09 (-0.55 to 0.36) for MCI-AD, -0.50 (-1.03 to 0.04) for possible MCI-LB, and -0.48 (-0.89 to -0.06) for probable MCI-LB. The median annual percentage change in SBR in MCI-LB was -5.6% (95% CI -8.2% to -2.9%) and 2.1% (-3.5% to 8.0%) for MCI-AD. The extrapolated time for a normal scan to become abnormal was 6 years. Controls and MCI-AD showed no significant change in dopaminergic binding over time. The mean test-retest variation in controls was 12% (SD 5.5%), which cautions against overinterpretation of small changes on repeat scanning. Progressive dopaminergic loss in the striatum is detectable using 123[I]-FP-CIT SPECT in MCI-LB at a group level. In clinical practice, individual change in striatal 123[I]-FP-CIT uptake seems to be of limited diagnostic value because of high test-retest variation. This study provides Class II evidence that longitudinal declines in striatal uptake measured using 123[I]-FP-CIT SPECT are associated with MCI due to Lewy body disease but not MCI due to Alzheimer disease.

Assessment of COVID-19 lockdown effect on early Alzheimer Disease progression.

Recently, many aspects of daily life have changed due to the COVID-19 pandemic. Patients with Alzheimer Disease (AD) could be more vulnerable to those daily life changes as experts expected. Mainly, the lockdown involved reduced social contact and cognitive stimulation. So, it could affect the AD expression, increasing the patients' disabilities development. The aim of this study is to evaluate the effect of COVID-19 lockdown on cognitive impairment progression in early AD patients. The participants were patients with mild cognitive impairment due to AD (MCI-AD) from the Neurology Unit (La Fe Hospital), who were neuropsychologically evaluated (cognitive impairment, daily activity tests) twice over 2 years. They were classified into a case group (n = 21), evaluated before and after lockdown condition, and a control group (n = 20), evaluated entirely before the lockdown condition. All the participants showed increasing cognitive impairment and functional deterioration over the 2-year period of evaluation (p < 0.05). However, a faster worsening was not observed as a consequence of the COVID-19 pandemic and the lockdown condition. In fact, the statistical significance observed between the two study groups for daily life activities showed that the worsening was even lesser in the group evaluated under the lockdown condition. Medium-term effects of COVID-19 lockdown could not involve an acceleration of the cognitive decline in MCI-AD patients in a 2-year evaluation period. In addition, the least worsening observed for daily living activities in the case group was probably due to the change in routines. Therefore, the common assumption of cognitive worsening of AD progression due to the lockdown in comparison with normal disease progression was not demonstrated in this study, at least for MCI-AD cases. However, more longitudinal studies are required to evaluate long-term effects in these patients.

Plasma biomarkers of neurodegeneration in mild cognitive impairment with Lewy bodies.

Blood biomarkers of Alzheimer's disease (AD) may allow for the early detection of AD pathology in mild cognitive impairment (MCI) due to AD (MCI-AD) and as a co-pathology in MCI with Lewy bodies (MCI-LB). However not all cases of MCI-LB will feature AD pathology. Disease-general biomarkers of neurodegeneration, such as glial fibrillary acidic protein (GFAP) or neurofilament light (NfL), may therefore provide a useful supplement to AD biomarkers. We aimed to compare the relative utility of plasma Aβ42/40, p-tau181, GFAP and NfL in differentiating MCI-AD and MCI-LB from cognitively healthy older adults, and from one another. Plasma samples were analysed for 172 participants (31 healthy controls, 48 MCI-AD, 28 possible MCI-LB and 65 probable MCI-LB) at baseline, and a subset (n = 55) who provided repeated samples after ≥1 year. Samples were analysed with a Simoa 4-plex assay for Aβ42, Aβ40, GFAP and NfL, and incorporated previously-collected p-tau181 from this same cohort. Probable MCI-LB had elevated GFAP (p < 0.001) and NfL (p = 0.012) relative to controls, but not significantly lower Aβ42/40 (p = 0.06). GFAP and p-tau181 were higher in MCI-AD than MCI-LB. GFAP discriminated all MCI subgroups, from controls (AUC of 0.75), but no plasma-based marker effectively differentiated MCI-AD from MCI-LB. NfL correlated with disease severity and increased with MCI progression over time (p = 0.011). Markers of AD and astrocytosis/neurodegeneration are elevated in MCI-LB. GFAP offered similar utility to p-tau181 in distinguishing MCI overall, and its subgroups, from healthy controls.

Features of event-related potentials during retrieval of episodic memory in patients with mild cognitive impairment due to Alzheimer's disease.

To provide a rigorous comparison between patients with mild cognitive impairment due to Alzheimer's disease (MCI-AD) and healthy elderly, as well as to assess the value of electroencephalography (EEG) in terms of early diagnosis, we conducted a neutral image recognition memory task involving individuals with positive biomarkers including β amyloid deposition, pathologic tau or neurodegeneration. The task involving study and test blocks was designed to evaluate participants' recognition memory. Electroencephalogram was recorded synchronously to elicit event-related potentials in patients with MCI-AD and healthy control subjects. We further analyzed differences between groups or conditions in terms of behavioral performance, time domain, and time-frequency domain. The MCI-AD cohort showed a slower response time to old/new images and had low accuracy regarding behavioral performance. The amplitude of the late positive complex for the old/new effects was significantly suppressed in the MCI-AD cohort when compared with that in the HC cohort. The amplitude of the late old/new effects was correlated with the Auditory Verbal Learning Test recognition score in all participants. The time-frequency domain analysis revealed that correct recognition of old items elicited a decrease in beta power, mainly limited to the HC cohort. Moreover, the combination of behavioral (processing speed and accuracy) and electrophysiological (average amplitude and relative power of delta band) measures contributes to classifying patients with MCI-AD from healthy elderly people. Changes of old/new effects, accuracy and response time are sensitive to the impairment of recognition memory in patients with MCI-AD and have moderate value in predicting the incipient stage of AD.

Properties of odor identification testing in screening for early-stage Alzheimer’s disease

Odor identification (OI) is impaired in the early stages of Alzheimer’s disease (AD). However, data regarding the diagnostic properties of OI tests are lacking, preventing their clinical use. We aimed to explore OI and determine the accuracy of OI testing in screening for patients with early AD. In total, 30 participants with mild cognitive impairment due to AD (MCI-AD), 30 with mild dementia due to AD (MD-AD), and 30 cognitively normal elderly participants (CN) were enrolled, and cognitive examination (CDR, MMSE, ADAS-Cog 13, and verbal fluency tests) and assessment of OI (Burghart Sniffin’ Sticks odor identification test) were performed. MCI-AD patients scored significantly worse in OI than CN participants, and MD-AD patients had worse OI scores than MCI-AD patients. The ratio of OI to ADAS-Cog 13 score had good diagnostic accuracy in differentiating AD patients from CN participants and in differentiating MCI-AD patients from CN participants. Substitution of ADAS-Cog 13 score with the ratio of OI to ADAS-Cog 13 score in a multinomial regression model improved the classification accuracy, especially of MCI-AD cases. Our results confirmed that OI is impaired during the prodromal stage of AD. OI testing has a good diagnostic quality and can improve the accuracy of screening for early-stage AD.

Forgetting Rates of Prose Memory in Mild Cognitive Impairment.

Some authors report steeper slopes of forgetting in early Alzheimer's disease (AD), while others do not. Contrasting findings are thought to be due to methodological inconsistencies or variety of testing methods, yet they also emerge when people are assessed on the same testing procedure. We aimed to assess if forgetting slopes of people with mild cognitive impairment due to AD (MCI-AD) are different from age-matched healthy controls (HC) by using a prose paradigm. Twenty-nine people with MCI-AD and twenty-six HC listened to a short prose passage and were asked to freely recall it after delays of 1 h and 24 h. Generalized linear mixed modelling revealed that, compared to HC, people with MCI-AD showed poorer encoding at immediate recall and steeper forgetting up to 1 h in prose memory as assessed by free recall and with repeated testing of the same material. Forgetting rates between groups did not differ from 1 h to 24 h. The differences observed in MCI-AD could be due to a post-encoding deficit. These findings could be accounted either by a differential benefit from retrieval practice, whereby people with MCI-AD benefit less than HC, or by a working memory deficit in people with MCI-AD, which fails to support their memory performance from immediate recall to 1 h.

Structural Cerebral Network Differences in Prodromal Alzheimer’s Disease and Prodromal Dementia with Lewy Bodies

Introduction: Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) have long prodromal phases without dementia. However, the patterns of cerebral network alteration in this early stage of the disease remain to be clarified. Method: Participants were 48 patients with mild cognitive impairment (MCI) due to AD (MCI-AD), 18 patients with MCI with DLB (MCI with Lewy bodies: MCI-LB), and 23 healthy controls who underwent a 1.5-Tesla magnetic resonance imaging scan. Cerebral networks were extracted from individual T1-weighted images based on the intracortical similarity, and we estimated the differences of network metrics among the three diagnostic groups. Results: Whole-brain analyses for degree, betweenness centrality, and clustering coefficient images were performed using SPM8 software. The patients with MCI-LB showed significant reduction of degree in right putamen, compared with healthy subjects. The MCI-AD patients showed significant lower degree in left insula and bilateral posterior cingulate cortices compared with healthy subjects. There were no significant differences in small-world properties and in regional gray matter volume among the three groups. Conclusions: We found the change of degree in the patients with MCI-AD and with MCI-LB, compared with healthy controls. These findings were consistent with the past single-photon emission computed tomography studies focusing on AD and DLB. The disease-related difference in the cerebral neural network might provide an adjunct biomarker for the early detection of AD and DLB.

Odor identification and discrimination as markers of early Alzheimer’s disease

AbstractBackgroundReliable markers are essential in order to achieve accurate diagnosis in the early stages of Alzheimer’s disease (AD). Olfactory impairment has been identified as a possible non‐invasive biomarker of AD. Odor identification tasks are most commonly used for measuring olfactory abilities. However, odor identification is associated to verbal abilities and cultural context. The aim of this study was to determine whether odor discrimination could be a valid marker of early AD.Method65 participants were enrolled in the study. 26 patients with mild cognitive impairment due to AD (MCI‐AD), 26 patients with mild dementia due to AD (MD‐AD) and 13 cognitively normal elderly subjects (CN). All participants underwent cognitive examination (MMSE, CDR, ADAS‐Cog 13, fluency tests) and olfactory function assessment (Burghart Sniffin’ Sticks odor identification and odor discrimination tests).ResultMD‐AD and MCI‐AD subjects performed significantly worse than CN subjects in both odor identification (mean correct responses ± SD was 6.77±1.91; 9.08±2.30; 13.31±1.55 respectively; p&lt;0.001) and odor discrimination (mean correct responses ± SD was 6.27±1.66; 8.19±1.65; 12.92±1.71 respectively; p&lt;0.001) tests. MD‐AD subjects performed significantly worse than MCI‐AD subjects in both odor identification (p&lt;0.05) and odor discrimination (p&lt;0.001) tests.Both odor identification and odor discrimination tests had AUC&gt;0.9 on ROC analysis for differentiating MCI‐AD subjects from CN subjects (AUC 0.938 and 0.982) and for differentiating MD‐AD subjects from CN subjects (AUC 0.99 for both). Neither odor identification, nor odor discrimination test reached AUC&gt;0.8 on ROC analysis for differentiating MCI‐AD from MD‐AD subjects (AUC 0.777 and 0.793).Odor identification differentiated MCI‐AD from CN subjects with sensitivity of 69% and specificity of 100% at cut‐off score of ≤10 correct responses. Odor discrimination differentiated MCI‐AD from CN subjects with sensitivity of 77% and specificity of 100% at cut‐off score of ≤9 correct responses.ConclusionThe study confirmed that tests for olfactory dysfunction can reliably differentiate patients with mild cognitive impairment due to AD from cognitively normal subjects. Both odor identification and discrimination are reliable markers for identification of patients with early Alzheimer’s disease.

Differences in macular vessel density in the superficial plexus across cognitive impairment: the NORFACE cohort

Optical coherence tomography angiography (OCT-A) allows the detection of retinal vessel density (VD) loss, which is a reflection of brain vascular pathology. We aimed to investigate differences in macular VD in the superficial plexus in a large cohort of individuals cognitively unimpaired (CU), with mild cognitive impairment due to Alzheimer´s disease (MCI-AD), MCI due to cerebrovascular pathology (MCI-Va), probable Alzheimer´s disease dementia (ADD) and Vascular Dementia (VaD). Clinical, demographical, ophthalmological and OCT-A data from the Neuro-ophthalmology Research at Fundació ACE (NORFACE) project were analyzed. Differences of macular VD in four quadrants (superior, nasal, inferior and temporal) among the five diagnostic groups were assessed in a multivariate regression model, adjusted by age, sex, education, hypertension, diabetes mellitus, heart disease and stroke. The study cohort comprised 672 participants: 128 CU, 120 MCI-AD, 111 MCI-Va, 257 ADD and 56 VaD. Regression analysis showed a significantly higher VD in the temporal quadrant in MCI-AD compared to CU participants (49.05 ± 4.91 vs 47.27 ± 4.17, p = 0.02, d = 0.40), and a significantly lower VD in the inferior quadrant in MCI-Va compared to CU participants (48.70 ± 6.57 vs 51.27 ± 6.39, p = 0.02, d = 0.40). Individuals with heart disease presented significantly lower VD in the inferior quadrant than those without (p = 0.01). The interaction of sex and diagnosis had no effect in differentiating VD. Mini-Mental State Examination (MMSE) scores were not correlated to VD (all r < 0.16; p > 0.07). In conclusion, our study showed that the MCI-AD and MCI-Va groups had significant differences in macular VD in opposite directions in the temporal and inferior quadrants, respectively, compared to CU participants, suggesting that macular VD might be able to differentiate two pathogenic pathways (AD- and cerebrovascular-related) in early stages of cognitive decline.

Phosphatidylethanolamine Binding Protein1 (PEBP1) in Alzheimer's Disease: ELISA Development and Clinical Validation.

Background: Phosphatidylethanolamine binding protein 1 (PEBP1) is a multifunctional protein, mainly known for its specific binding of phosphatidylethanolamine and the ability to suppress the Raf1-MAPK pathway. Its potential role as an Alzheimer’s disease (AD) biomarker has been proposed in several studies. However, evaluation of its discriminative value in clinical cohorts is missing.Objective:We aimed to develop a new immunoassay for the measurement of PEBP1 in cerebrospinal fluid (CSF) and assess the possible role of this protein as AD biomarker.Methods:We developed a sandwich enzyme-linked immunosorbent assay (ELISA) for detection of PEBP1 in CSF and performed a technical and a clinical validation on two well-characterized cohorts. The first cohort included 14 mild cognitive impairment due to AD (MCI-AD) and 11 other neurological diseases (OND) patients. The second, larger cohort, included 25 MCI-AD, 29 AD dementia (AD-dem), and 21 OND patients.Results:PEBP1 is highly sensitive to pre-analytical conditions, especially to prolonged storage at room temperature or 4°C. Analysis of the first cohort showed a trend of an increase of PEBP1 level in MCI-AD patients versus OND subjects. Analysis of the second cohort did not show significant differences among diagnostic groups. Weak, positive correlation was found between CSF PEBP1 and t-tau, p-tau, and Aβ40 in the AD-dem group.Conclusion:A novel ELISA for the detection of PEBP1 in CSF was developed. Further research is needed to assess the potential of PEBP1 in AD diagnostics. The observed dependence of the PEBP1 signal on operating procedures encourages its potential application as CSF quality control.

Cognitive profile in mild cognitive impairment with Lewy bodies.

This study aimed to elucidate the cognitive profile of patients with mild cognitive impairment with Lewy bodies (MCI-LB) and to compare it to that of patients with mild cognitive impairment due to Alzheimer's disease (MCI-AD). Subjects older than 60 years with probable MCI-LB (n = 60) or MCI-AD (n = 60) were recruited. All patients were tested with Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) to assess their global cognitive profile. The MCI-AD and MCI-LB patients did not differ in total MMSE and MoCA scores. However, some sub-items in MMSE and MoCA were shown to be screening markers for differentiating MCI-LB from MCI-AD. In the visuoconstructive test, the total score and hands subitem score in the clock-drawing test were significantly lower in MCI-LB than in MCI-AD. As for the executive function, the 'animal fluency test', 'repeat digits backward test' and 'take paper by your right hand' in MMSE all showed lower scores in MCI-LB compared with MCI-AD. As for memory, 'velvet' and 'church' in MoCA and 'ball' and 'national flag' in MMSE had lower scores in MCI-AD than in MCI-LB. This study presents the cognitive profile of patients with MCI-LB. In line with the literature on Dementia with Lewy bodies, our results showed lower performance on tests for visuoconstructive and executive function, whereas memory remained relatively spared in the early period.

Assessment of autonomic symptoms may assist with earlyidentification of mild cognitive impairment with Lewybodies.

ObjectivesAutonomic symptoms are a common feature of the synucleinopathies, and may be a distinguishing feature of prodromal Lewy body disease. We aimed to assess whether the cognitive prodrome of dementia with Lewy bodies, mild cognitive impairment (MCI) with Lewy bodies (MCI‐LB), would have more severe reported autonomic symptoms than cognitively healthy older adults, with MCI due to Alzheimer's disease (MCI‐AD) also included for comparison. We also aimed to assess the utility of an autonomic symptom scale in differentiating MCI‐LB from MCI‐AD.MethodsNinety‐three individuals with MCI and 33 healthy controls were assessed with the Composite Autonomic Symptom Score 31‐item scale (COMPASS). Mild cognitive impairment patients also underwent detailed clinical assessment and differential classification of MCI‐AD or MCI‐LB according to current consensus criteria. Differences in overall COMPASS score and individual symptom sub‐scales were assessed, controlling for age.ResultsAge‐adjusted severity of overall autonomic symptomatology was greater in MCI‐LB (Ratio = 2.01, 95% CI: 1.37–2.96), with higher orthostatic intolerance and urinary symptom severity than controls, and greater risk of gastrointestinal and secretomotor symptoms. MCI‐AD did not have significantly higher autonomic symptom severity than controls overall. A cut‐off of 4/5 on the COMPASS was sensitive to MCI‐LB (92%) but not specific to this (42% specificity vs. MCI‐AD and 52% vs. healthy controls).ConclusionsMild cognitive impairment with Lewy bodies had greater autonomic symptom severity than normal ageing and MCI‐AD, but such autonomic symptoms are not a specific finding. The COMPASS‐31 may therefore have value as a sensitive screening test for early‐stage Lewy body disease.

Modelling the Pan-European Economic Burden of Alzheimer's Disease.

Recent advances open the opportunity of altering the course of Alzheimer's disease (AD) through lifestyle-based modifications and novel therapies. Ensuring that society is investing limited budgets in the interventions that have the greatest potential to generate tangible impact will require tools to guide policymakers. To build on previous studies to develop an economic model that estimates the societal burden of AD and evaluates the potential impact of novel interventions in six large European countries. AD progression was modelled using a published Markov structure with a 40-year time horizon to estimate lifetime costs and life years in a cohort aged 65 years and above diagnosed with mild cognitive impairment due to AD (MCI-AD) in 2020. Demographic projections were utilized to estimate the prevalence of MCI-AD up to 2100, total corresponding costs and life years. The model allows a comparison of costs associated with the introduction of a hypothetical new disease-modifying therapy that slows disease progression between MCI-AD and all AD-Dementia stages as well as a 'delayed onset' scenario where disease progression is halted at the MCI-AD stage, potentially occurring, for example, through lifestyle-based modifications. The 2022 present value of total lifetime costs for this cohort moving through all disease stages is ~€1.2T. Approximately 80% of the present value of lifetime costs in our model are driven by informal care and non-medical direct costs. Our model suggests that a 25% and 50% reduction in disease progression compared to natural history could translate into a present value of cost savings of €33.7B and €72.7B. Halting MCI-AD progression for 3 years with no therapeutic effect thereafter resulted in a present value cost savings of €84.7B in savings. Our data further suggest that early intervention via disease-modifying therapies or lifestyle-based modifications in AD could result in cost savings for society. Additionally, our findings reinforce the importance of accounting for the full value of innovative interventions, management and care paradigms, including their potential impact on direct, indirect and intangible costs impacting patients, their care partners and health and social care systems.

A comparative study of 18F‐FDG PET brain metabolism and cognitive performance between normal controls and amnestic Alzheimer’s disease patients

AbstractBackground18F‐fluorodeoxyglucose Positron Emission Tomography (18F‐FDG PET) allows the measurement of brain metabolism in vivo. In neurodegenerative diseases, hypometabolism´s topography patterns usually correlate with certain types of cognitive dysfunction. In the amnestic presentation of Alzheimer’s Disease (AD), the temporoparietal hypometabolism is the typical 18F‐FDG PET signature. However, much less is known about its spatial correlation with other cognitive manifestations typically seen in the clinical setting. Objectives: To compare the distribution of 18F‐FDG PET between Normal Controls (NC), patients with Mild Cognitive impairment due to AD (MCI‐AD), and patients with AD Dementia (ADD) and to analyze each cognitive test as a covariate.MethodCross‐sectional study, including 14 NC (13 PET‐PIB ‐, 1 PET‐PIB +), 25 MCI, and 28 ADD patients, (all PET‐PIB +) matched by age and education. Images were normalized to a template using non‐linear methods. The metabolic differences between the 3 groups were evaluated by a voxel‐wise analysis based on Statistical Parametric Mapping. Statistical models were applied using neuropsychological tests as covariates, and VOIS statistics were generated using the Boogle‐DKT atlas.ResultDifferences were observed between the groups analyzed in middle and inferior temporal, posterior parietal, posterior cingulate, and precuneus cortical regions, among other areas of interest (p &lt;0.005). Some of these areas correlated with a worse performance in verbal episodic memory tests (left temporoparietal regions), visuospatial tests (right parietal regions) and phonological fluency tests (left frontal and temporoparietal regions), among other results (p&lt;0.005).ConclusionIn this study, 18F‐FDG PET voxel‐wise analysis showed metabolic differences between the groups included, following the severity spectrum of each amnestic AD stage considered. Although these differences correlated with some cortical areas usually reported as the “AD metabolic signature”, some cortical regions were associated with cognitive functions that weren´t previously reported, allowing a better understanding of the cortical networks involved in the clinical manifestations of AD.