Predementia Stages Of Alzheimer's Disease Research Articles

Alzheimer's disease genetic pathways impact cerebrospinal fluid biomarkers and imaging endophenotypes in non-demented individuals.

Unraveling how Alzheimer's disease (AD) genetic risk is related to neuropathological heterogeneity, and whether this occurs through specific biological pathways, is a key step toward precision medicine. We computed pathway-specific genetic risk scores (GRSs) in non-demented individuals and investigated how AD risk variants predict cerebrospinal fluid (CSF) and imaging biomarkers reflecting AD pathology, cardiovascular, white matter integrity, and brain connectivity. CSF amyloidbeta and phosphorylated tau were related to most GRSs. Inflammatory pathways were associated with cerebrovascular disease, whereas quantitative measures of white matter lesion and microstructure integrity were predicted by clearance and migration pathways. Functional connectivity alterations were related to genetic variants involved in signal transduction and synaptic communication. This study reveals distinct genetic risk profiles in association with specific pathophysiological aspects in predementia stages of AD, unraveling the biological substrates of the heterogeneity of AD-associated endophenotypes and promoting a step forward in disease understanding and development of personalized therapies. Polygenic risk for Alzheimer's disease encompasses six biological pathways that can be quantified with pathway-specific genetic risk scores, and differentially relate to cerebrospinal fluid and imaging biomarkers. Inflammatory pathways are mostly related to cerebrovascular burden. White matter health is associated with pathways of clearance and membrane integrity, whereas functional connectivity measures are related to signal transduction and synaptic communication pathways.

Towards a future where Alzheimer's disease pathology is stopped before the onset of dementia.

Alzheimer's disease (AD) is a major healthcare challenge with no curative treatment at present. To address this challenge, we need a paradigm shift, where we focus on pre-dementia stages of AD. In this Perspective, we outline a strategy to move towards a future with personalized medicine for AD by preparing for and investing in effective and patient-orchestrated diagnosis, prediction and prevention of the dementia stage. While focusing on AD, this Perspective also discusses studies that do not specify the cause of dementia. Future personalized prevention strategies encompass multiple components, including tailored combinations of disease-modifying interventions and lifestyle. By empowering the public and patients to be more actively engaged in the management of their health and disease and by developing improved strategies for diagnosis, prediction and prevention, we can pave the way for a future with personalized medicine, in which AD pathology is stopped to prevent or delay the onset of dementia.

Choroid plexus volume is associated with levels of CSF proteins predominantly expressed by the choroid plexus in non‐demented individuals with AD pathophysiology.

AbstractBackgroundThe choroid plexus (CP) is a structure located inside the brain ventricles and is responsible for the production of cerebrospinal fluid (CSF), transport of proteins across the epithelium to the CSF and clearance of proteins from the CSF. The CP undergoes changes with aging, which are exacerbated in Alzheimer's disease (AD) and could alter CP functioning. Nonetheless, the relation between CP functioning and AD pathophysiology is still unclear. Here, we investigated the association of CP volume with levels of CSF proteins predominantly expressed by the CP and amyloid positivity in non‐demented individuals.MethodWe included 235 individuals with normal cognition (NC) or mild cognitive impairment (MCI) from the European EMIF‐AD MBD study (49% women, mean age 67.9 (SD 7.9) years). Based on CSF Aβ1‐42 (A, data‐driven cut‐offs) and p‐tau (T, center‐specific cut‐offs), individuals were classified as cognitively normal with normal A and T (controls, n=54). Based on CSF Aβ1‐42, individuals with NC or MCI were classified as amyloid‐positive (CN A+, n=61; MCI A+, n=67). CSF proteomic data were centrally generated using TMT mass spectrometry and 5 CSF proteins with predominant expression in the CP were selected based on the Protein Atlas, Harmonizome and literature (TTR, MFRP, SLC5A5, FOLR1, SOD3). CP and hippocampal volumes on MRI were quantified using FreeSurfer. We used non‐parametric (Spearman) partial correlations corrected for age, gender and total intracranial volume (TIV).ResultLower Aβ42 levels were associated with higher CP volume in MCI (Figure 1). Higher levels of CP predominant expressed proteins were generally associated with increased CP volume in persons with amyloid positivity, in both preclinical and prodromal AD (Table 1). Lower Aβ42 levels were associated with lower hippocampal volume in MCI (Figure 2). Lower hippocampal volumes were associated with higher CP volumes in MCI (Figure 3). Nonetheless, hippocampal volume and the levels of CP predominant expressed proteins were generally not correlated (Table 2).ConclusionOur findings suggest that CP volume is associated with levels of proteins predominantly expressed by the CP in predementia stages of AD. This would suggest CP dysfunction in early AD. This is important for future research and AD treatment development.

Why a clinical trial is as good as its outcome measure: A framework for the selection and use of cognitive outcome measures for clinical trials of Alzheimer's disease.

A crucial aspect of any clinical trial is using the right outcome measure to assess treatment efficacy. Compared to the rapidly evolved understanding and measurement of pathophysiology in preclinical and early symptomatic stages of Alzheimer's disease (AD), relatively less progress has been made in the evolution of clinical outcome assessments (COAs) for those stages. The current paper aims to provide a benchmark for the design and evaluation of COAs for use in early AD trials. We discuss lessons learned on capturing cognitive changes in predementia stages of AD, including challenges when validating novel COAs for those early stages and necessary evidence for their implementation in clinical trials. Moving forward, we propose a multi-step framework to advance the use of more effective COAs to assess clinically meaningful changes in early AD, which will hopefully contribute to the much-needed consensus around more appropriate outcome measures to assess clinical efficacy of putative treatments. HIGHLIGHTS: We discuss lessons learned on capturing cognitive changes in predementia stages of AD. We propose a framework for the design and evaluation of performance based cognitive tests for use in early AD trials. We provide recommendations to facilitate the implementation of more effective cognitive outcome measures in AD trials.

Cerebrospinal fluid growth-associated protein 43 levels in patients with progressive and stable mild cognitive impairment.

Cerebrospinal fluid (CSF) growth-associated protein 43 (GAP-43) is prominently elevated in Alzheimer's disease (AD) dementia patients in comparison to normal controls. CSF GAP-43 levels in mild cognitive impairment (MCI) individuals who have different clinical trajectories need to be studied. We examined 137 cognitively normal (CN) controls, 218 stable MCI patients (sMCI), 99 progressive MCI (pMCI) patients, and 120 AD dementia patients. Associations between the CSF GAP-43 levels and the four diagnosis groups were evaluated with multiple-variable linear regression. The relationships between CSF GAP-43 and core CSF biomarkers were assessed by Spearman correlations. Cox regression analysis was performed to assess the values of GAP-43 in predicting MCI conversion. We examined associations between baseline CSF GAP-43 levels and longitudinal cognitive function, hippocampal volumes, and brain glucose metabolism using linear mixed-effects models. CSF GAP-43 was elevated in the pMCI and AD groups in comparison to the CN group and in the pMCI and AD groups in comparison to the sMCI group. CSF GAP-43 significantly predicted conversion from MCI to AD. CSF GAP-43 was a significant predictor of cognitive decline, hippocampal atrophy, and brain hypometabolism over time. Furthermore, elevated CSF GAP-43 levels were associated with accelerated deterioration in cognition and neurodegeneration. CSF GAP-43 is increased in the predementia stage of AD, and it may enhance the neurodegenerative process. Future efforts on pharmacological interventions targeting synaptic dysfunction could be promising in AD treatment.

New potential biomarkers of Alzheimer's disease: markers of endothelial dysfunction and neuroinflammation.

Alzheimer's disease (AD) is the most common cause of dementia in the elderly. The aim of the work wasObjective: to determine the relationship between laboratory biomarkers in blood plasma and cerebrospinal fluid (CSF) in patients with AD and indicators of neuropsychological testing.Patients and methods. 52 patients with AD were examined, in which the concentration of 90 potential biomarkers were measured in blood plasma and CSF. Neuropsychological assessment included the Mini-Mental State Exam (MMSE), Frontal Assessment Battery (FAB), Montreal Cognitive Assessment (MoCA), and etc.Results and discussion. Correlations of different strength between the values of biomarkers in blood plasma and CSF and the results of neuropsychological assessment were revealed. A correlation was found between the soluble cell adhesion molecule (sICAM-1) in blood plasma and the largest number of neuropsychological tests sensitive to dementia stages (MoCA, MMSE, FAB) in patients with AD at the dementia stage. A correlation was found between the concentration of growth/differentiation factor 15 and interferon γ in blood plasma and FAB scores in patients with AD. The levels of granulocyte colony-stimulating factor (G-CSF) in CSF were associated with the dementia stage in AD, and the interleukin-1 receptor antagonist (IL-1RA) levels, on the contrary, with stages preceding the development of dementia in AD.Conclusion. sICAM-1 level in blood plasma, which is a marker of endothelial dysfunction, may be an indicator of the severity of the vascular neurodegenerative process in AD at the dementia stage. G-CSF in the CSF is associated with the dementia stage in AD, and IL-1RA – with the pre-dementia stage of AD, which determines the prospect of their further study as diagnostic markers.

Trajectory of Unawareness of Memory Decline in Individuals With Autosomal Dominant Alzheimer Disease

Recent studies have suggested that unawareness, or anosognosia, of memory decline is present in predementia stages of Alzheimer disease (AD) and may serve as an early symptomatic indicator of AD. To investigate the evolution of anosognosia of memory decline in individuals who carry the PSEN1 E280A variant for autosomal dominant AD compared with family members who do not carry the variant. This cohort study investigated a total of 2379 members of a Colombian kindred with autosomal dominant AD who were part of the Alzheimer's Prevention Initiative Registry. Assessments were completed at the University of Antioquia, Colombia, with data collected between January 1, 2000, and July 31, 2019. Awareness of memory function was operationalized using the discrepancy between self-report and study partner report on a memory complaint scale. Linear mixed effects models were used to assess memory self-awareness over age separately in variant carriers and noncarriers. This study included 396 variant carriers (mean [SD] age, 32.7 [11.9] years; 200 [50.5%] female), of whom 59 (14.9%) were cognitively impaired, and 1983 cognitively unimpaired noncarriers (mean [SD] age, 33.5 [12.5] years; 1129 [56.9%] female). The variant carriers demonstrated increased awareness until the mean (SD) age of 35.0 (2.0) years and had anosognosia at approximately 43 years of age, approximately 6 years before their estimated median age of dementia onset (49 years; 95% CI, 49-51 years). Cognitively unimpaired noncarriers reported more complaints than their study partners aged 20 and 60 years (10.1 points, P < .001). On the awareness index, a decrease with age (mean [SE] estimate, -0.04 [0.02] discrepant-points per years; t = -2.2; P = .03) in the noncarriers and in the variant carriers (mean [SE] estimate, -0.21 [0.04] discrepant-points per years; t = -5.1; P < .001) was observed. In this cohort study, increased participant complaints were observed in both groups, suggesting that increased awareness of memory function was common and nonspecific to AD in this cohort. In variant carriers, awareness of memory function decreased in the predementia stages, reaching anosognosia close to the age of mild cognitive impairment onset, providing support for the usefulness of awareness of memory decline.

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.

Cognitive reserve and clinical progression in Alzheimer disease: A paradoxical relationship.

ObjectiveTo investigate the relationship between cognitive reserve (CR) and clinical progression across the Alzheimer disease (AD) spectrum.MethodsWe selected 839 β-amyloid (Aβ)–positive participants with normal cognition (NC, n = 175), mild cognitive impairment (MCI, n = 437), or AD dementia (n = 227) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). CR was quantified using standardized residuals (W scores) from a (covariate-adjusted) linear regression with global cognition (13-item Alzheimer's Disease Assessment Scale–cognitive subscale) as an independent variable of interest, and either gray matter volumes or white matter hyperintensity volume as dependent variables. These W scores, reflecting whether an individual's degree of cerebral damage is lower or higher than clinically expected, were tested as predictors of diagnostic conversion (i.e., NC to MCI/AD dementia, or MCI to AD dementia) and longitudinal changes in memory (ADNI-MEM) and executive functions (ADNI-EF).ResultsThe median follow-up period was 24 months (interquartile range 6–42). Corrected for age, sex, APOE4 status, and baseline cerebral damage, higher gray matter volume-based W scores (i.e., greater CR) were associated with a lower diagnostic conversion risk (hazard ratio [HR] 0.22, p < 0.001) and slower decline in memory (β = 0.48, p < 0.001) and executive function (β = 0.67, p < 0.001). Stratified by disease stage, we found similar results for NC (diagnostic conversion: HR 0.30, p = 0.038; ADNI-MEM: β = 0.52, p = 0.028; ADNI-EF: β = 0.42, p = 0.077) and MCI (diagnostic conversion: HR 0.21, p < 0.001; ADNI-MEM: β = 0.43, p = 0.003; ADNI-EF: β = 0.59, p < 0.001), but opposite findings (i.e., more rapid decline) for AD dementia (ADNI-MEM: β = −0.91, p = 0.002; ADNI-EF: β = −0.77, p = 0.081).ConclusionsAmong Aβ-positive individuals, greater CR related to attenuated clinical progression in predementia stages of AD, but accelerated cognitive decline after the onset of dementia.

Amyloid Network Topology Characterizes the Progression of Alzheimer's Disease During the Predementia Stages.

There is increasing evidence showing that the accumulation of the amyloid-β (Aβ) peptide into extracellular plaques is a central event in Alzheimer's disease (AD). These abnormalities can be detected as lowered levels of Aβ42 in the cerebrospinal fluid (CSF) and are followed by increased amyloid burden on positron emission tomography (PET) several years before the onset of dementia. The aim of this study was to assess amyloid network topology in nondemented individuals with early stage Aβ accumulation, defined as abnormal CSF Aβ42 levels and normal Florbetapir PET (CSF+/PET−), and more advanced Aβ accumulation, defined as both abnormal CSF Aβ42 and Florbetapir PET (CSF+/PET+). The amyloid networks were built using correlations in the mean 18F-florbetapir PET values between 72 brain regions and analyzed using graph theory analyses. Our findings showed an association between early amyloid stages and increased covariance as well as shorter paths between several brain areas that overlapped with the default-mode network (DMN). Moreover, we found that individuals with more advanced amyloid accumulation showed more widespread changes in brain regions both within and outside the DMN. These findings suggest that amyloid network topology could potentially be used to assess disease progression in the predementia stages of AD.

Apolipoprotein A1 in Cerebrospinal Fluid and Plasma and Progression to Alzheimer's Disease in Non-Demented Elderly.

HDL-cholesterol transporter Apolipoprotein A1 (ApoA1) holds neuroprotective properties, such as inhibition of amyloid-β aggregation. Low plasma ApoA1 concentrations are associated with Alzheimer's disease (AD). Little is known about ApoA1 levels in the pre-dementia stages of AD. To investigate associations between cerebrospinal fluid (CSF) and plasma ApoA1 levels and clinical progression toward AD in non-demented elderly. From the Amsterdam Dementia Cohort, we included 429 non-demented elderly with subjective cognitive decline (SCD; n = 206, 61±9 years, Mini-Mental State Exam (MMSE) 28±2) and mild cognitive impairment (MCI; n = 223, 67±8 years, MMSE 27±2), with a mean follow-up of 2.5±1.6 years. We used Cox proportional hazard models to investigate relations between CSF and plasma ApoA1 concentrations and clinical progression, defined as progression to MCI or AD for SCD, and progression to AD for MCI. Analyses were adjusted for age, gender, MMSE, and plasma cholesterol levels. Analyses were stratified for diagnosis and APOEɛ4 carriership. 117 patients (27%) showed clinical progression. One standard deviation increase of CSF ApoA1 was associated with a 30% increased risk of clinical progression (hazard ratio (HR) (95% CI) = 1.3(1.0-1.6)). The effect appeared to be attributable to the APOEɛ4 carriers with SCD (HR 3.3(1.0-10.9)). Lower plasma ApoA1 levels were associated with an increased risk of clinical progression in APOEɛ4 carriers with SCD (HR 5.0(1.3-18.9)). Higher CSF and lower plasma ApoA1 levels were associated with an increased risk of clinical progression in APOEɛ4 carriers with SCD; suggesting that ApoA1 may be involved in the earliest stages of AD.

Abnormal organization of white matter networks in patients with subjective cognitive decline and mild cognitive impairment

Network analysis has been widely used in studying Alzheimer's disease (AD). However, how the white matter network changes in cognitive impaired patients with subjective cognitive decline (SCD) (a symptom emerging during early stage of AD) and amnestic mild cognitive impairment (aMCI) (a pre-dementia stage of AD) is still unclear. Here, structural networks were constructed respectively based on FA and FN for 36 normal controls, 21 SCD patients, and 33 aMCI patients by diffusion tensor imaging and graph theory. Significantly lower efficiency was found in aMCI patients than normal controls (NC). Though not significant, the values in those with SCD were intermediate between aMCI and NC. In addition, our results showed significantly altered betweenness centrality located in right precuneus, calcarine, putamen, and left anterior cingulate in aMCI patients. Furthermore, association was found between network metrics and cognitive impairment. Our study suggests that the structural network properties might be preserved in SCD stage and disrupted in aMCI stage, which may provide novel insights into pathological mechanisms of AD.

Oxidative stress-mediated activation of extracellular signal-regulated kinase contributes to mild cognitive impairment-related mitochondrial dysfunction

Mild cognitive impairment (MCI) occurs during the predementia stage of Alzheimer disease (AD) and is characterized by a decline in cognitive abilities that frequently represents a transition between normal cognition and AD dementia. Its pathogenesis is not well understood. Here, we demonstrate the direct consequences and potential mechanisms of oxidative stress and mitochondrial dynamic and functional defects in MCI-derived mitochondria. Using a cytoplasmic hybrid (cybrid) cell model in which mitochondria from MCI or age-matched non-MCI subjects were incorporated into a human neuronal cell line depleted of endogenous mitochondrial DNA, we evaluated the mitochondrial dynamics and functions, as well as the role of oxidative stress in the resultant cybrid lines. We demonstrated that increased expression levels of mitofusin 2 (Mfn2) are markedly induced by oxidative stress in MCI-derived mitochondria along with aberrant mitochondrial functions. Inhibition of oxidative stress rescues MCI-impaired mitochondrial fusion/fission balance as shown by the suppression of Mfn2 expression, attenuation of abnormal mitochondrial morphology and distribution, and improvement in mitochondrial function. Furthermore, blockade of MCI-related stress-mediated activation of extracellular signal-regulated kinase (ERK) signaling not only attenuates aberrant mitochondrial morphology and function but also restores mitochondrial fission and fusion balance, in particular inhibition of overexpressed Mfn2. Our results provide new insights into the role of the oxidative stress–ERK–Mfn2 signal axis in MCI-related mitochondrial abnormalities, indicating that the MCI phase may be targetable for the development of new therapeutic approaches that improve mitochondrial function in age-related neurodegeneration.

Advances in the prevention of Alzheimer's disease and dementia.

Definitions and diagnostic criteria for all medical conditions are regularly subjected to reviews and revisions as knowledge advances. In the field of Alzheimer's disease (AD) research, it has taken almost three decades for diagnostic nomenclature to undergo major re-examination. The shift towards presymptomatic and pre-dementia stages of AD has brought prevention and treatment trials much closer to each other than before. Here we discuss: (i) the impact of diagnostic reliability on the possibilities for developing preventive strategies for AD; (ii) the scientific evidence to support moving from observation to action; (iii) ongoing intervention studies; and (iv) the methodological issues and prospects for balancing strategies for high-risk individuals with those for broad population-based prevention. The associations between neuropathology and cognition are still not entirely clear. In addition, the risk factors for AD dementia and the neuropathological hallmarks of AD may not necessarily be the same. Cognitive impairment has a clearer clinical significance and should therefore remain the main focus of prevention. Risk/protective factors for dementia/AD need to be studied from a life-course perspective. New approaches in prevention trials include enrichment strategies based on genetic risk factors or beta-amyloid biomarkers (at least four ongoing pharmacological trials), and multidomain interventions simultaneously targeting various vascular and lifestyle-related risk factors (at least three ongoing trials). Experience from prevention programmes in other chronic diseases can provide additional methodological improvements. Building infrastructures for international collaborations is necessary for managing the worldwide public health problem of AD and dementia. The International Database on Aging and Dementia (IDAD) and the European Dementia Prevention Initiative (EDPI) are examples of ongoing international efforts aiming to improve the methodology of preventive studies and provide the basis for larger intervention trials.

Imaging biomarkers for amyloid: a new generation of probes and what lies ahead

Since the original 1984 criteria for Alzheimer's disease (AD), put forth by a work group jointly established by the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the Alzheimer's Disease and Related Disorders Association (ADRDA) (McKhannet al., 1984), important advances have occurred in our ability to detect AD pathophysiology, with the incorporation of biomarkers – defined as anatomic, biochemical, or physiologic parameters that providein vivoevidence of AD neuropathology (Cummings, 2011) – that can improve the certainty of AD diagnosis. Use of imaging biomarkers such as positron emission tomography (PET) with amyloid ligands, particularly in asymptomatic and pre-dementia stages of AD, however, has been the subject of debate (Duboiset al., 2013), with arguments both for and against the biomarker driven diagnosis of AD.

Cerebral Blood Flow is an Earlier Indicator of Perfusion Abnormalities than Cerebral Blood Volume in Alzheimer's Disease

The purpose of this study was to elucidate whether cerebral blood flow (CBF) can better characterize perfusion abnormalities in predementia stages of Alzheimer's disease (AD) than cerebral blood volume (CBV) and whether cortical atrophy is more associated with decreased CBV or with decreased CBF. We compared measurements of CBV, CBF, and mean cortical thickness obtained from magnetic resonance images in a group of healthy controls, patients with mild cognitive impairment (MCI) who converted to AD after 2 years of clinical follow-up (MCI-c), and patients with mild AD. A significant decrease in perfusion was detected in the parietal lobes of the MCI-c patients with CBF parametric maps but not with CBV maps. In the MCI-c group, a negative correlation between CBF values and cortical thickness in the right parahippocampal gyrus suggests an increase in CBF that depends on cortical atrophy in predementia stages of AD. Our study also suggests that CBF deficits appear before CBV deficits in the progression of AD, as CBV abnormalities were only detected at the AD stage, whereas CBF changes were already detected in the MCI stage. These results confirm the hypothesis that CBF is a more sensitive parameter than CBV for perfusion abnormalities in MCI-c patients.

Basal forebrain atrophy and cortical amyloid deposition in nondemented elderly subjects

BackgroundBoth neurodegeneration of the cholinergic basal forebrain (BF) and deposition of β-amyloid are early events in the course of Alzheimer's disease (AD). Associations between increased amyloid pathology and cholinergic atrophy have been described in autopsy studies. MethodsWe used structural MRI and AV45-PET amyloid imaging data of 225 cognitively normal or mildly impaired elderly subjects from the Alzheimer's Disease Neuroimaging Initiative to assess in vivo associations between BF atrophy and cortical amyloid deposition. Associations were examined using region-of-interest (ROI) and voxel-based approaches with reference to cytoarchitectonic mappings of the cholinergic BF nuclei. ResultsROI- and voxel-based approaches yielded complementary evidence for an association between BF volume and cortical amyloid deposition in presymptomatic and predementia stages of AD, irrespective of age, gender, and APOE genotype. ConclusionsThe observed correlations between BF atrophy and cortical amyloid load likely reflect associations between cholinergic degeneration and amyloid pathology as reported in neuropathologic examination studies.

Rationale for use of the Clinical Dementia Rating Sum of Boxes as a primary outcome measure for Alzheimer’s disease clinical trials

BackgroundWe used the database of the Alzheimer's Disease Neuroimaging Initiative (ADNI) to explore the psychometric properties of the Clinical Dementia Rating Sum of Boxes (CDR-SB) to consider its utility as an outcome measure for clinical trials in early and mild, as well as later, stages of Alzheimer's disease (AD). MethodsWe assessed internal consistency, structural validity, convergent validity, and 2-year internal and external responsiveness of the CDR-SB using data from 382 subjects with early or mild AD at entry into the ADNI study. ResultsThe CDR-SB assesses both cognitive and functional domains of AD disability. Mean scores declined nearly linearly; CDR-SB cognitive and functional subsums contributed equally to total scores at both very mild (early) and mild stages of the disease. ConclusionsThe CDR-SB has psychometric properties that make it attractive as a primary outcome measure that comprehensively assesses both cognitive and functional disability in AD patients. It may prove particularly useful for studies in early, predementia stages of AD.

Cortical excitability in very mild Alzheimer’s disease: a long-term follow-up study

Measurement of motor cortex excitability using paired-pulse transcranial magnetic stimulation (pTMS) has been proposed for the early diagnosis of Alzheimer's disease (AD) and could also be useful for monitoring treatment response and disease progression. However, studies conducted at the pre-dementia stage of AD are scarce, very few long-term data are available, and correlations between cortical excitability and cognitive performance have not been addressed. Eleven patients with mild cognitive impairment (MCI) that converted to AD-related dementia and 12 elderly control subjects were selected for this study. Cognitive assessments and pTMS were conducted at baseline in the two groups and also after 4 and 21 months of treatment with donepezil in the AD group. Non-parametric statistics were used to compare cortical excitability between the two study groups at baseline and to analyse disease course in the AD group. Correlation analysis was performed to investigate associations between cortical excitability and cognitive performance. Short-latency intracortical inhibition (SICI) and intracortical facilitation were reduced in AD patients. However, there was high inter-individual variability, and statistical significance was only attained at a 2-ms interstimulus interval (ISI). A trend towards recovery of 2-ms SICI was observed after treatment with donepezil. Baseline cortical excitability at 300 ms was associated with better cognitive performance in AD patients. Although the present results do not support a role for pTMS in the early diagnosis of late-onset AD, a potential role in prediction of treatment response and understanding of disease mechanisms emerged.

Effects of medial temporal lobe degeneration on brain perfusion in amnestic MCI of AD type: deafferentation and functional compensation?

Cortical atrophy is correlated with the progression of neuropathological lesions within the medial temporal lobes (MTL) in Alzheimer's disease (AD). Our aim was to determine which local and remote functional changes result from MTL volume loss at the predementia stage. We studied the relationship between entorhinal and hippocampal MR volumes and whole-brain SPECT perfusion via a voxel-based correlative analysis in 19 patients with amnestic mild cognitive impairment with a memory profile suggestive of early AD. Right MTL volumes were positively correlated with remote posterior perfusion of the posterior cingulate cortex, and negatively correlated with remote anterior perfusion of the right medial and dorsolateral prefrontal cortex. There was no local correlation between volumes and perfusion within the MTL. These findings provide further insight into functional changes that result from MTL volume loss during the predementia stage of AD. The positive correlation between MTL volumes and posterior cingulate perfusion may reflect the deafferentation of a temporocingulate network due to mediotemporal degeneration. The paradoxical negative correlation between MTL volumes and prefrontal perfusion may result from recruitment of an alternative anterior temporofrontal network. It remains to be investigated how the "net sum" of this perfusion modulation affects memory and other cognitive domains through a possible compensatory perspective.