Predementia Alzheimer's Disease Research Articles

European Projects for Patients with Dementia and Their Caregivers.

As we all know there is no treatment that can stop or delay the progression of dementia. The treatment we use is only symptomatic. EFNS (European Federation of Neurological Societies) recommendations for dementia prevention by Sorbi et al. (2012) concluded that there is no treatment, no lifestyle, which could have an effect on prevention or delay of onset of different forms of dementia until today. The future studies in prevention must recruit younger people, larger sample, and for longer period. The last 10years we have run, in collaboration with organizations in different European countries, many projects in order to support patients with neurodegenerative diseases, mainly patients with dementia and their caregivers. The first project was a 2-year prospective cohort study of antidementia drug non-persistency in mild-to-moderate Alzheimer's disease (AD) in Europe: predictors of discontinuation and switch in the ICTUS (Impact of Cholinergic Treatment USe) study, an FP5 project with 1380 patients. Five studies were published. The second project was DESCRIPA study, an FP5 project to DEvelopment of Screening guidelines and clinical CRIteria for Predementia Alzheimer's disease, with 881 patients with mild cognitive impairment (MCI). LLM (Long Lasting Memories) and VRADA (A virtual reality application for the exercise of dementia and Alzheimer patients) are two projects that include body and cognitive exercise for health for the elderly and patients with mild cognitive impairment. The next is the RECAGE (REspectful Caring for the AGitated Elderly) project (Horizon 2020), a prospective cohort study for coping with behavioral and psychological symptoms of dementia. With six European universities we finished a very interesting FP6 project, the AddNeuroMed one, which gives even now information about the progression of normal elderly MCI and AD patients, in collaboration with other consortia. A very interesting Innovative Medicines Initiative (IMI) project about digital biomarkers was entitled Remote Assessment of Disease and Relapse-Alzheimer's Disease (RADAR project). The main goal of this project was the development and validation of technology-enabled, quantitative and sensitive measures of functional decline in people with early-stage AD. A running project is an Erasmus+ one in the higher education field, "Genetic counseling in European universities: The case of neurodegenerative diseases" (GECONEU project). The target of this study is to develop an online course for university students focusing on genetic counseling, and support people and society to better understand the aims of genetic testing and the usefulness of genetic counseling by involving students in an innovative learning and teaching setting. AD-gaming, BRIDGE, iCONNECT (Intergenerational CONtact between studeNts and people with dEmentia through CreaTive education), E.L.So.M.C.I (English Lessons with the Use of Songs for People with Mild Cognitive Impairment), Games4CoSkills, and De-Sign are all Erasmus+ projects that aim to improve the quality of life of patients with MCI or dementia. Story2remember, Dementia right, ASPAD (Augmentation of the Support of Patients suffering from Alzheimer's Disease and their caregivers), INFOCARE (Supporting Informal Caregivers of People with Dementia), S.IN.CA.L.A (Supporting Informal Carers: A Whole-Family and Life course Approach), and PIA (Peer support workers as an Innovative force in Advocacy in dementia care) are all Erasmus+ projects for training and supporting caregivers of patients with dementia.

Stable cerebrospinal fluid neurogranin and β-site amyloid precursor protein cleaving enzyme 1 levels differentiate predementia Alzheimer's disease patients.

Cerebrospinal fluid (CSF) β-site amyloid precursor protein cleaving enzyme 1 (BACE1), neurogranin and the neurogranin/BACE1 ratio are proposed markers for Alzheimer’s disease. BACE1 is also a drug target. However, CSF levels may differ between early-stage amyloid plaque formation (A) and later stage downstream tau-tangle pathology (T) and neurodegeneration (N) and may be expressed as an A/T/N stage (e.g. A+/T−/N or A+/T+/N+). Whether BACE1 and neurogranin levels are persistent traits or change with disease progression is unknown. The aim of this study was to investigate whether CSF neurogranin and BACE1 concentrations differ between A/T/N stages, whether these change over time and correlate with memory decline. This may have implications for patient selection in future trials. We used CSF markers to determine A/T/N stage using amyloid beta42/40 ratio, p-tau181 and total-tau respectively in predementia Alzheimer’s disease cases (n = 176) [including cases that progressed to dementia (n = 10)] and controls (n = 74) from the Norwegian Dementia Disease Initiation cohort. We selected cases at the presumed early (A+/T−/N−, n = 86) and late stages (A+/T+/N+, n = 90) of the Alzheimer’s disease continuum and controlled with normal markers (A−/T−/N−, n = 74). A subset of subjects in all A/T/N groups underwent repeat CSF sampling at approximately 2-year intervals up to 6 years from baseline. Using linear mixed models, longitudinal measurements of CSF BACE1 and neurogranin levels in A+/T−/N− and A+/T+/N+ as compared to A−/T−/N− healthy controls were performed. Next, we measured changes in CSF BACE1 and neurogranin levels in cases that progressed from A−/T−/N− to A+/T−/N− (n = 12), from A+/T−/N− to A+/T or N+ (n = 12), remained stable A+/T−/N− (n = 26), remained stable A+/T+/N+ (n = 28) compared with controls remaining stable A−/T−/N− (n = 33). Lastly, associations between these markers and memory decline were assessed. Compared with A−/T−/N− healthy controls, neurogranin was unaltered in A+/T−/N− (n.s.) but higher in A+/T+/N+ (P < 0.0001). In contrast, BACE1 was lower in A+/T−/N− (P < 0.05) and higher in A+/T+/N+ (P < 0.0001). The neurogranin/BACE1 ratio was increased in both A+/T−/N− (P < 0.05) and A+/T+/N+ (P < 0.0001) groups as compared to A-/T-/N- healthy controls and was more strongly associated with memory decline (b = −0.29, P = 0.0006) than neurogranin (b = −0.20, P = 0.002) and BACE1 (b = −0.13, P = 0.046). Neurogranin and BACE1 level differences remained stable over time not only within A/T/N groups but also in patients progressing to more pathological A/T/N stages (e.g. progressing from A+/T−/N− to A + T or N+) and in cases progressing to dementia. Our results suggest that neurogranin and BACE1 levels may differentiate pathomechanistic Alzheimer’s disease subgroups, putatively with different options for treatment.

Phenotype-informed polygenic risk scores are associated with worse outcome in individuals at risk of Alzheimer's disease.

IntroductionPatients with predementia Alzheimer's disease (AD) and at‐risk subjects are targets for promising disease‐modifying treatments, and improved polygenic risk scores (PRSs) could improve early‐stage case selection.MethodsPhenotype‐informed PRSs were developed by selecting AD‐associated variants conditional on relevant inflammatory or cardiovascular traits. The primary outcome was longitudinal changes in measures of AD pathology, namely development of pathological amyloid deposition, medial temporal lobe atrophy, and cognitive decline in a prospective cohort study including 394 adults without AD dementia.ResultsHigh‐risk groups defined by phenotype‐informed AD PRSs had significantly steeper volume decline in medial temporal cortices, and the high‐risk group defined by the cardiovascular‐informed AD PRS had significantly increased hazard ratio of pathological amyloid deposition, compared to low‐risk groups.DiscussionAD PRSs informed by inflammatory disorders or cardiovascular risk factors and diseases are associated with development of AD pathology markers and may improve identification of subjects at risk for progression of AD.

Evolution of the diagnostic frontiers of Alzheimer's disease and new therapeutic possibilities

Over the past three decades, the definition and diagnostic boundaries of Alzheimer's disease (AD) have been repeatedly revised due to significant progress in understanding of the pathogenesis of neurodegeneration associated with Alzheimer's disease and development of high-tech diagnostic methods. The current approach to diagnosing AD is based on the discovery of biomarkers that reflect the two main neuropathological processes involved in the development of primary neurodegeneration underlying AD-abnormal amyloidogenesis and neuronal degeneration. The currently available diagnostic tools are limited to the detection of cerebrospinal biomarkers and/or assessment of the abnormal amyloid and tau protein burden in the brain via amyloid and tau positron emission tomography ligands. Practical implementation (mostly in the research field) of the biological model of AD diagnosis has led to a significant expansion of its diagnostic boundaries with the inclusion of predementia AD stages: asymptomatic and symptomatic, the latter is clinically corresponding to amnestic mild cognitive impairment (aMCI-amnestic mild cognitive impairment). On the one hand, this approach significantly expands the possibilities to study and use preventive technologies aiming to avert or delay the progression of predementia cognitive impairment to dementia but, on the other, it is associated with a number of negative implications from both the clinical and ethical points of view. A significant limitation of purely biological diagnosis of AD based on biomarker levels is due to the low prognostic value of biomarkers, which can cause diagnostic confusion in certain circumstances. Moreover, since the future evolution of the asymptomatic stage is not yet clear and there are still no reliable ways to prevent the cognitive and behavioral symptoms associated with AD, disclosure of stressful information about this "terrifying" diagnosis to patients can cause irreversible damage by triggering depressive disorder, which is a risk factor of AD itself. The current knowledge about AD prognosis in amyloid-positive cognitively unimpaired patients is insufficient. The most adequate approach to early AD diagnostics appears to be the clinical and biological model, as recommended by the International Working Group (IWG2021), which requires a combination of the clinical AD phenotype and the detection of biomarkers specific to this disease. The article discusses the potential directions for the development of biological diagnostic methods, including those based on the so-called peripheral (plasma) biomarker technologies and promising directions for the development of biological methods of secondary AD prevention.

EEG slowing in predementia Alzheimer's disease is compatible with neuronal hyperactivity: A multiscale computational modeling study.

Evidence from animal models of Alzheimer's disease (AD) for neuronal hyperactivity and inhibitory dysfunction is accumulating, but the exact mechanism by which these microscale abnormalities lead to large-scale brain dysfunction and cognitive impairment in AD remains unclear. This study investigated empirically informed pathophysiological mechanisms of neuronal hyperactivity in a computational neurophysiological brain model and compared its output to EEG data of predementia AD patients. EEG-like oscillations were simulated by a computational brain network model of 78 neural masses, each representing regional activity of a large population of interconnected excitatory and inhibitory neurons, coupled according to human DTI-derived structural topology. Several scenarios of amyloid-β mediated neuronal hyperactivity were investigated, including excitatory hyperexcitability and inhibitory neuronal dysfunction. The model offered a direct readout of neuronal activity by showing excitatory neuron pulse density. Consequently, we performed spectral analysis and analyzed absolute power and relative power in relevant frequency bands and peak frequency on the model output of each simulated AD scenario as well as for resting state EEG of predementia AD patients with positive amyloid biomarkers (n = 196) and elderly controls (n = 180). Similarity in outcome measure changes between the modelled output of each scenario and human EEG resulted in a scenario compatibility score (range 0-6). Predementia AD patients showed increased relative theta power and decreased relative higher alpha power. The modeled scenarios involving 'inhibitory neuron hypoexcitability' and 'excessive neuronal excitation' were most compatible with the observed EEG changes in AD (score of 5), providing support for their presumed role. Other scenarios produced improbable physiologically parameter change combinations. Of the two best compatible scenarios, inhibitory hypoexcitability was the only scenario that led to neuronal hyperactivity in the model. We found that neuronal hyperactivity scenarios (i.e. increased pulse density) is compatible with large-scale oscillatory slowing of predementia AD patients. This study provides support for amyloid-driven neuronal disinhibition due to inhibitory hypoexcitability as most likely pathophysiological mechanism to explain oscillatory slowing in predementia AD.

Cerebrospinal fluid markers for synaptic function and Alzheimer type changes in late life depression

To explore markers for synaptic function and Alzheimer disease (AD) pathology in late life depression (LLD), predementia AD and normal controls (NC). A cross-sectional study to compare cerebrospinal fluid (CSF) levels of neurogranin (Ng), Beta-site amyloid-precursor-protein cleaving enzyme1 (BACE1), Ng/BACE1 ratio and Amyloid-β 42/40 ratio, phosphorylated-tau and total-tau in LLD with (LLD AD) or without (LLD NoAD) AD pathology, predementia AD and normal controls (NC). We included 145 participants (NC = 41; predementia AD = 66 and LLD = 38). LLD comprised LLD AD (n = 16), LLD NoAD (n = 19), LLD with non-AD typical changes (n = 3, excluded). LLD AD (pADJ < 0.05) and predementia AD (pADJ < 0.0001) showed significantly higher Ng than NC. BACE1 and Ng/BACE1 ratio were altered similarly. Compared to LLD NoAD, LLD AD showed significantly higher Ng (pADJ < 0.001), BACE1 (pADJ < 0.05) and Ng/BACE1 ratio (pADJ < 0.01). All groups had significantly lower Aβ 42/40 ratio than NC (predementia AD and LLD AD, p < 0.0001; LLD NoAD, p < 0.05). Both LLD groups performed similarly on tests of memory and executive function, but significantly poorer than NC. Synaptic function in LLD depended on AD pathology. LLD showed an association to Amyloid dysmetabolism. The LLD groups performed poorer cognitively than NC. LLD AD may be conceptualized as “predementia AD with depression”.

US, EU, and Japanese Regulatory Guidelines for Development of Drugs for Treatment of Alzheimer's Disease: Implications for Global Drug Development.

Drug development guidelines from regulatory authorities provide important information to sponsors on requirements for clinical evidence needed to support approval of new drugs. In the field of Alzheimer’s disease (AD), recently published guidelines are available from EU, US, and Japanese regulatory authorities. In this review, these three guidelines are compared and discussed with emphasis on the recommendations provided for demonstration of efficacy in pivotal clinical trials conducted in predementia stages of AD. Similarities and differences are highlighted, and impact for global drug development is discussed in the context of the new International Conference on Harmonization E17 guideline on multiregional clinical trials. The AD field is characterized by significant challenges as, to date, no drug approval precedence exists in predementia AD despite numerous and ambitious efforts to slow the progression of the disease by pharmacologic intervention. Despite these uncertainties regulatory authorities across regions have blazed a trail for proactive multistakeholder collaboration, involvement, and continuous dialogue, setting a positive example on how to foster a supportive environment for development of new and meaningful treatments for patients with AD globally.

Differentiation of mild cognitive impairment using an entorhinal cortex-based test of virtual reality navigation.

The entorhinal cortex is one of the first regions to exhibit neurodegeneration in Alzheimer's disease, and as such identification of entorhinal cortex dysfunction may aid detection of the disease in its earliest stages. Extensive evidence demonstrates that the entorhinal cortex is critically implicated in navigation underpinned by the firing of spatially modulated neurons. This study tested the hypothesis that entorhinal-based navigation is impaired in pre-dementia Alzheimer's disease. Forty-five patients with mild cognitive impairment (26 with CSF Alzheimer's disease biomarker data: 12 biomarker-positive and 14 biomarker-negative) and 41 healthy control participants undertook an immersive virtual reality path integration test, as a measure of entorhinal-based navigation. Behavioural performance was correlated with MRI measures of entorhinal cortex volume, and the classification accuracy of the path integration task was compared with a battery of cognitive tests considered sensitive and specific for early Alzheimer's disease. Biomarker-positive patients exhibited larger errors in the navigation task than biomarker-negative patients, whose performance did not significantly differ from controls participants. Path-integration performance correlated with Alzheimer's disease molecular pathology, with levels of CSF amyloid-β and total tau contributing independently to distance error. Path integration errors were negatively correlated with the volumes of the total entorhinal cortex and of its posteromedial subdivision. The path integration task demonstrated higher diagnostic sensitivity and specificity for differentiating biomarker positive versus negative patients (area under the curve = 0.90) than was achieved by the best of the cognitive tests (area under the curve = 0.57). This study demonstrates that an entorhinal cortex-based virtual reality navigation task can differentiate patients with mild cognitive impairment at low and high risk of developing dementia, with classification accuracy superior to reference cognitive tests considered to be highly sensitive to early Alzheimer's disease. This study provides evidence that navigation tasks may aid early diagnosis of Alzheimer's disease, and the basis of this in animal cellular and behavioural studies provides the opportunity to answer the unmet need for translatable outcome measures for comparing treatment effect across preclinical and clinical trial phases of future anti-Alzheimer's drugs.

The role of hippocampus in the retrieval of autobiographical memories in patients with amnestic Mild Cognitive Impairment due to Alzheimer's disease.

The role of the hippocampus and neocortical areas in the retrieval of past memories in pre-dementia Alzheimer's disease (AD) patients was investigated. The aim was to assess whether the hippocampus has a temporary role in memory trace formation, according to the Cortical Reallocation Theory (CRT), or whether it continuously updates and enriches memories, according to the Multiple Trace Theory. According to the former theory, hippocampal damage should affect more recent memories, whereas the association cortex is expected to affect memories of the entire lifespan. In the second case, damage to either the hippocampus or the association cortices should affect memories of the entire lifespan. Seventeen patients with amnestic Mild Cognitive Impairment due to AD were submitted to autobiographical (i.e., episodic and semantic personal) memory assessment. Patients underwent MRI for the acquisition of T1-weighted brain volumes. Voxel-based morphometry was used to assess correlations between grey matter (GM) volumes and autobiographical memory. Correlation analyses revealed a strict association between GM volumes in the hippocampus and patients' ability to retrieve the most recent but not the oldest autobiographical memories in both aspects, episodic and semantic. Moreover, patients' GM volumes in the pre-frontal and temporal polar areas were associated with recollection of episodic and semantic events, respectively. Finally, GM volumes in the precuneus and occipital cortex were associated with retrieval of the most recent episodic events. These findings indicate that the hippocampus has a specific time-dependent role; thus, they support the CRT.

The End of the Beginning of the Alzheimer's Disease Nightmare: A Devil's Advocate's View.

Although there have been so many failures in Alzheimer's disease (AD) modifying trials, there are still many compounds in the pipeline and the hope still remains that the entrance of disease-modifying treatment (DMT) for AD will positively and dramatically change the whole situation of AD treatment. However, if DMT does enter the market, it will be the beginning of a great number of challenges and problems. The current infrastructure for diagnostics of early (pre-dementia) AD does not have the capacity to meet the demands and expectations of the population. Neither is there capacity for treatment monitoring and follow-ups. If screening is considered, there will be a great risk for false positive cases and a great number of people who will have to undergo diagnostics. There will be high costs for diagnostics and treatment initially, while potential benefits will occur much later in other sectors than where the payers for treatment are. Although there are great hopes that prevention of cardiovascular risk factors and changes in lifestyle might impact the risk for dementia, there is still no consensus that this is the case. Finally, the relevance of different AD paradigms such as amyloid and tau is still a matter of discussion, particularly regarding the oldest old.

Gray matter networks and clinical progression in subjects with predementia Alzheimer's disease

We studied whether gray matter network parameters are associated with rate of clinical progression in nondemented subjects who have abnormal amyloid markers in the cerebrospinal fluid (CSF), that is, predementia Alzheimer's disease. Nondemented subjects (62 with subjective cognitive decline; 160 with mild cognitive impairment (MCI); age = 68 ± 8 years; Mini–Mental State Examination (MMSE) = 28 ± 2.4) were selected from the Amsterdam Dementia Cohort when they had abnormal amyloid in CSF (<640 pg/mL). Networks were extracted from gray matter structural magnetic resonance imaging (MRI), and 9 parameters were calculated. Cox proportional hazards models were used to test associations between each connectivity predictor and rate of progression to MCI or dementia. After a median time of 2.2 years, 122 (55%) subjects showed clinical progression. Lower network parameter values were associated with increased risk for progression, with the strongest hazard ratio of 0.29 for clustering (95% confidence interval = 0.12–0.70; p < 0.01). Results remained after correcting for tau, hippocampal volume, and MMSE scores. Our results suggest that at predementia stages, gray matter network parameters may have use to identify subjects who will show fast clinical progression.

Genetic Risk as a Marker of Amyloid-β and Tau Burden in Cerebrospinal Fluid.

Background: The search for a biomarker of Alzheimer’s disease (AD) pathology (amyloid-β (Aβ) and tau) is ongoing, with the best markers currently being measurements of Aβ and tau in cerebrospinal fluid (CSF) and via positron emission tomography (PET) scanning. These methods are relatively invasive, costly, and often have high screening failure rates. Consequently, research is aiming to elucidate blood biomarkers of Aβ and tau.Objective: This study aims to investigate a case/control polygenic risk score (PGRS) as a marker of tau and investigate blood markers of a combined Aβ and tau outcome for the first time. A sub-study also considers plasma tau as markers of Aβ and tau pathology in CSF.Methods: We used data from the EDAR*, DESCRIPA**, and Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohorts in a logistic regression analysis to investigate blood markers of Aβ and tau in CSF. In particular, we investigated the extent to which a case/control PGRS is predictive of CSF tau, CSF amyloid, and a combined amyloid and tau outcome. The predictive ability of models was compared to that of age, gender, and APOE genotype (‘basic model’).Results: In EDAR and DESCRIPA test data, inclusion of a case/control PGRS was no more predictive of Aβ, and a combined Aβ and tau endpoint than the basic models (accuracies of 66.0%, and 73.3% respectively). The tau model saw a small increase in accuracy compared to basic models (59.6%). ADNI 2 test data also showed a slight increase in accuracy for the Aβ model when compared to the basic models (61.4%).Conclusion: We see some evidence that a case/control PGRS is marginally more predictive of Aβ and tau pathology than the basic models. The search for predictive factors of Aβ and tau pathologies, above and beyond demographic information, is still ongoing. Better understanding of AD risk alleles, development of more sensitive assays, and studies of larger sample size are three avenues that may provide such factors. However, the clinical utility of possible predictors of brain Aβ and tau pathologies must also be investigated.*‘Beta amyloid oligomers in the early diagnosis of AD and as marker for treatment response’**‘Development of screening guidelines and criteria for pre-dementia Alzheimer’s disease’

Reduced Regional Cortical Thickness Rate of Change in Donepezil-Treated Subjects With Suspected Prodromal Alzheimer's Disease.

Cortical thinning, previously identified during prodromal stages of Alzheimer's disease (AD), is a "candidate" biomarker implemented in AD clinical therapy trials. We investigated the effect of donepezil treatment on cortical thickness in mild cognitively impaired subjects with the amnestic syndrome of the hippocampal type, a prodromal at-risk group for progression to AD dementia. Data were from a longitudinal analysis of a community-based multicenter suspected prodromal AD cohort diagnosed by the Free and Cued Selective Reminding Test (81 donepezil vs 92 placebo) enrolled in a double-blind, randomized, placebo-controlled parallel group design using donepezil (10 mg/day). The study started in November 2006 and concluded in August 2010. All subjects underwent 2 brain structural magnetic resonance imaging (MRI) scans, at baseline and at the end of the trial. Structural MRI images had been processed using the automated pipeline for longitudinal segmentation and surface reconstruction implemented in FreeSurfer. The primary outcome measure of this post hoc study was the annualized percentage change (APC) of cortical thickness. The donepezil group exhibited reduced APC cortical thinning compared to placebo in the rostral anterior cingulate (right: P = .048; left: P = .032), the orbitofrontal (right: P = .012; left: P < .048), and the right inferior frontal (P = .022) cortices and in the right insula (P = .010). These results were not statistically significant after Bonferroni correction likely due to insufficient power for cortical thickness measurements in the study group powered for the predefined hippocampus outcome. Our findings support the hypothesis that cortical thickness is a reliable candidate surrogate outcome in early predementia AD trials. In addition, donepezil treatment may have an impact on cortical structure/morphology in areas innervated by the medial and lateral cholinergic pathways. ClinicalTrials.gov identifier: NCT00403520.

The 4 Mountains Test: A Short Test of Spatial Memory with High Sensitivity for the Diagnosis of Pre-dementia Alzheimer's Disease

This protocol describes the administration of the 4 Mountains Test (4MT), a short test of spatial memory, in which memory for the topographical layout of four mountains within a computer-generated landscape is tested using a delayed match-to-sample paradigm. Allocentric spatial memory is assessed by altering the viewpoint, colors and textures between the initially presented and target images. Allocentric spatial memory is a key function of the hippocampus, one of the earliest brain regions to be affected in Alzheimer's disease (AD) and impairment of hippocampal function predates the onset of dementia. It was hypothesized that performance on the 4MT would aid the diagnosis of predementia AD, which manifests clinically as Mild Cognitive Impairment (MCI). The 4MT was applied to patients with MCI, stratified further based on cerebrospinal fluid (CSF) AD biomarker status (10 MCI biomarker positive, 9 MCI biomarker negative), and with mild AD dementia, as well as healthy controls. Comparator tests included tests of episodic memory and attention widely accepted as sensitive measures of early AD. Behavioral data were correlated with quantitative MRI measures of the hippocampus, precuneus and posterior cingulate gyrus. 4MT scores were significantly different between the two MCI groups (p = 0.001), with a test score of ≤8/15 associated with 100% sensitivity and 78% specificity for the classification of MCI with positive AD biomarkers, i.e., predementia AD. 4MT test scores correlated with hippocampal volume (r = 0.42) and cortical thickness of the precuneus (r = 0.55). In conclusion, the 4MT is effective in identifying the early stages of AD. The short duration, easy application and scoring, and favorable psychometric properties of the 4MT fulfil the need for a simple but accurate diagnostic test for predementia AD.

The 4 Mountains Test: A Short Test of Spatial Memory with High Sensitivity for the Diagnosis of Pre-dementia Alzheimer's Disease.

This protocol describes the administration of the 4 Mountains Test (4MT), a short test of spatial memory, in which memory for the topographical layout of four mountains within a computer-generated landscape is tested using a delayed match-to-sample paradigm. Allocentric spatial memory is assessed by altering the viewpoint, colors and textures between the initially presented and target images.Allocentric spatial memory is a key function of the hippocampus, one of the earliest brain regions to be affected in Alzheimer's disease (AD) and impairment of hippocampal function predates the onset of dementia. It was hypothesized that performance on the 4MT would aid the diagnosis of predementia AD, which manifests clinically as Mild Cognitive Impairment (MCI).The 4MT was applied to patients with MCI, stratified further based on cerebrospinal fluid (CSF) AD biomarker status (10 MCI biomarker positive, 9 MCI biomarker negative), and with mild AD dementia, as well as healthy controls. Comparator tests included tests of episodic memory and attention widely accepted as sensitive measures of early AD. Behavioral data were correlated with quantitative MRI measures of the hippocampus, precuneus and posterior cingulate gyrus.4MT scores were significantly different between the two MCI groups (p = 0.001), with a test score of ≤8/15 associated with 100% sensitivity and 78% specificity for the classification of MCI with positive AD biomarkers, i.e., predementia AD. 4MT test scores correlated with hippocampal volume (r = 0.42) and cortical thickness of the precuneus (r = 0.55).In conclusion, the 4MT is effective in identifying the early stages of AD. The short duration, easy application and scoring, and favorable psychometric properties of the 4MT fulfil the need for a simple but accurate diagnostic test for predementia AD.

Recommended cognitive outcomes in preclinical Alzheimer's disease: Consensus statement from the European Prevention of Alzheimer's Dementia project

The Horizon 2020/IMI European Prevention of Alzheimer's Dementia (EPAD) project will undertake large-scale proof-of-concept trials in predementia Alzheimer's disease (AD). Within EPAD, the monitoring of cognitive trajectories in the preclinical period will constitute a central outcome measure; however, there are currently no clear guidelines as to how this should be achieved as most measures have been developed for the period around dementia diagnosis. The EPAD Scientific Advisory Group for Clinical and Cognitive Outcomes identified appropriate cognitive measures based on a literature search covering both cognitive correlates of preclinical brain changes from imaging studies and cognitive changes observed over time in nondementia population cohorts developing incident dementia. These measures were evaluated according to the following criteria: validity, coherence with biomarker changes, psychometric properties, cross-cultural suitability, availability of alternative forms, and normative data limited practice effects. The resulting consensus statement provides recommendations for both future drug trials and research into preclinical Alzheimer's disease.

Hippocampal Subfield Volumetry and 3D Surface Mapping in Subjective Cognitive Decline.

Subjective cognitive decline (SCD) may be the first clinical sign of Alzheimer's disease (AD). SCD individuals with normal cognition may already have significant hippocampal atrophy, a well-known feature of AD. To test the hypothesis that SCD, compared to healthy individuals without SCD, have a pattern of hippocampal subfield atrophy similar to that measured in the AD pathology. 17 SCD, 21 AD, and 40 matched controls underwent a standard T1-weighted MRI and a dedicated high-resolution MRI proton-density hippocampal sequence. For each participant, three hippocampal regions-of-interest were manually delineated on the proton-density hippocampal sequence corresponding to the CA1, subiculum, and other (including CA2-3-4 and dentate gyrus) subfields. Total intracranial volume (TIV)-normalized subfield volumes were compared between-group. Voxelwise group comparisons assessed from the standard T1 MRI were also projected on 3D hippocampal surface views. Both patient groups showed significant TIV-normalized volume decrease in hippocampus global volume and in CA1 and subiculum subfields as well as in the other subfield in AD compared to controls. Significant differences were observed between SCD and AD in hippocampus global TIV-normalized volume. Atrophy maps on hippocampal surface showed major involvement of the lateral part (CA1) in both SCD and AD, with larger overlap of other regions in AD. The findings indicate topographically similar hippocampal subfield changes in SCD individuals as those found in AD. This further highlights the relevance of SCD recruited from a memory clinic in assessing pre-dementia AD stages.

Identifying clinically relevant milestone decline in predementia Alzheimer's disease

Identifying clinically relevant milestone decline in predementia Alzheimer's disease

Predicting Prodromal Alzheimer's Disease in Subjects with Mild Cognitive Impairment Using Machine Learning Classification of Multimodal Multicenter Diffusion-Tensor and Magnetic Resonance Imaging Data.

Alzheimer's disease (AD) patients show early changes in white matter (WM) structural integrity. We studied the use of diffusion tensor imaging (DTI) in assessing WM alterations in the predementia stage of mild cognitive impairment (MCI). We applied a Support Vector Machine (SVM) classifier to DTI and volumetric magnetic resonance imaging data from 35 amyloid-β42 negative MCI subjects (MCI-Aβ42-), 35 positive MCI subjects (MCI-Aβ42+), and 25 healthy controls (HC) retrieved from the European DTI Study on Dementia. The SVM was applied to DTI-derived fractional anisotropy, mean diffusivity (MD), and mode of anisotropy (MO) maps. For comparison, we studied classification based on gray matter (GM) and WM volume. We obtained accuracies of up to 68% for MO and 63% for GM volume when it came to distinguishing between MCI-Aβ42- and MCI-Aβ42+. When it came to separating MCI-Aβ42+ from HC we achieved an accuracy of up to 77% for MD and a significantly lower accuracy of 68% for GM volume. The accuracy of multimodal classification was not higher than the accuracy of the best single modality. Our results suggest that DTI data provide better prediction accuracy than GM volume in predementia AD.

Cognitive/Clinical Endpoints for Pre-Dementia AD Trials.

With the aging of the world's population, the prevalence of Alzheimer's disease (AD) is rising. Yet it remains the only leading cause of death for which there is no disease-modifying treatment available, despite substantial academic and industry efforts. Disappointing clinical trials over the last several years have led to a growing consensus on the need to intervene early in the disease process, before clinical symptoms begin (1). Built on the hypothetical model of disease progression proposed by Jack et al (2, 3), which has since been supported by empirical data (4), the dominant paradigm today posits that the pathophysiologic processes underlying AD begin long before symptoms (5). However drug development at this stage is complicated by the difficulty of assessing a therapeutic benefit in subjects who are, by definition, clinically normal.