Evaluation of in vivo staging of amyloid deposition in cognitively unimpaired elderly aged 78-94.

Amyloid-beta (Aß) deposition is common in cognitively unimpaired (CU) elderly >85 years. This study investigated amyloid distribution and evaluated three published in vivo amyloid-PET staging schemes from a cognitively unimpaired (CU) cohort aged 84.9 ± 4.3 years (n = 75). SUV-based principal component analysis (PCA) was applied to 18F-flutemetamol PET data to determine an unbiased regional covariance pattern of tracer uptake across grey matter regions. PET staging schemes were applied to the data and compared to the PCA output. Concentration of p-tau181 was measured in blood plasma. The PCA revealed three distinct components accounting for 91.2% of total SUV variance. PC1 driven by the large common variance of uptake in neocortical and striatal regions was significantly positively correlated with global SUVRs, APOE4 status and p-tau181 concentration. PC2 represented mainly non-specific uptake in typical amyloid-PET reference regions, and PC3 the occipital lobe. Application of the staging schemes demonstrated that the majority of the CU cohort (up to 93%) were classified as having pathological amount and distribution of Aß. Good correspondence existed between binary (+/-) classification and later amyloid stages, however, substantial differences existed between schemes for low stages with 8-17% of individuals being unstageable, i.e., not following the sequential progression of Aß deposition. In spite of the difference in staging outcomes there was broad spatial overlap between earlier stages and PC1, most prominently in default mode network regions. This study critically evaluated the utility of in vivo amyloid staging from a single PET scan in CU elderly and found that early amyloid stages could not be consistently classified. The majority of the cohort had pathological Aß, thus, it remains an open topic what constitutes abnormal brain Aß in the oldest-old and what is the best method to determine that.

Amyloid-ß and APOE genotype predict memory decline in cognitively unimpaired older individuals independently of Alzheimer's disease polygenic risk score.

BACKGROUND: What combination of risk factors for Alzheimer's disease (AD) are most predictive of cognitive decline in cognitively unimpaired individuals remains largely unclear. We studied associations between APOE genotype, AD-Polygenic Risk Scores (AD-PRS), amyloid-ß pathology and decline in cognitive functioning over time in a large sample of cognitively unimpaired older individuals. METHODS: We included 276 cognitively unimpaired older individuals (75 ± 10 years, 63% female) from the EMIF-AD PreclinAD cohort. An AD-PRS was calculated including 83 genome-wide significant variants. The APOE gene was not included in the PRS and was analyzed separately. Baseline amyloid-ß status was assessed by visual read of [18F]flutemetamol-PET standardized uptake value images. At baseline and follow-up (2.0 ± 0.4 years), the cognitive domains of memory, attention, executive function, and language were measured. We used generalized estimating equations corrected for age, sex and center to examine associations between APOE genotype and AD-PRS with amyloid-ß status. Linear mixed models corrected for age, sex, center and education were used to examine associations between APOE genotype, AD-PRS and amyloid-ß status, and their interaction on changes in cognitive functioning over time. RESULTS: Fifty-two participants (19%) had abnormal amyloid-ß, and 84 participants (31%) carried at least one APOE ε4 allele. APOE genotype and AD-PRS were both associated with abnormal amyloid-ß status. Increasingly more risk-full APOE genotype, a high AD-PRS and an abnormal amyloid-ß status were associated with steeper decline in memory functioning in separate models (all p ≤ 0.02). A model including 4-way interaction term (APOE×AD-PRS×amyloid-ß×time) was not significant. When modelled together, both APOE genotype and AD-PRS predicted steeper decline in memory functioning (APOE ß(SE)=-0.05(0.02); AD-PRS ß(SE)=-0.04(0.01)). Additionally, when modelled together, both amyloid-ß status and AD-PRS predicted a steeper decline in memory functioning (amyloid-ß ß(SE)=-0.07(0.04); AD-PRS ß(SE)=-0.04(0.01)). Modelling both APOE genotype and amyloid-ß status, we observed an interaction, in which APOE genotype was related to steeper decline in memory and language functioning in amyloid-ß abnormal individuals only (ß(SE)=-0.13(0.06); ß(SE)=-0.22(0.07), respectively). CONCLUSION: Our results suggest that APOE genotype is related to steeper decline in memory and language functioning in individuals with abnormal amyloid-ß only. Furthermore, independent of amyloid-ß status other genetic risk variants contribute to memory decline in initially cognitively unimpaired older individuals.

[18F]Florbetapir positron emission tomography: identification of muscle amyloid in inclusion body myositis and differentiation from polymyositis.

OBJECTIVES: With the tools available currently, confirming the diagnosis of inclusion body myositis (IBM) can be difficult. Many patients are initially misdiagnosed with polymyositis (PM). In this observational study at a UK adult neuromuscular centre, we investigated whether amyloid positron emission tomography could differentiate between IBM and PM. METHODS: Ten patients with IBM and six with PM underwent clinical review, [18F]florbetapir positron emission tomography and MRI of skeletal musculature. Differences in [18F]florbetapir standardised uptake value ratios in skeletal muscle regions of interest were evaluated. Relationships between [18F]florbetapir standardised uptake value ratios and measures of disease severity (clinical and by MRI of skeletal muscle) were assessed. RESULTS: [18F]florbetapir standardised uptake value ratios were significantly higher in those with IBM compared with PM for all assessed regions (total-[18F]florbetapir standardised uptake value ratio 1.45 (1.28 to 2.05) vs 1.01 (0.80 to 1.22), p=0.005). For total-[18F]florbetapir standardised uptake value ratios≥1.28, sensitivity and specificity for IBM was 80% and 100%, respectively. CONCLUSIONS: [18F]florbetapir amyloid positron emission tomography differentiates IBM from PM. Successful development could facilitate accurate diagnosis, inclusion in clinical trials and help avoid unnecessary exposure to potentially harmful treatments.

Dual-phase [18F]florbetapir in frontotemporal dementia.

PURPOSE: The PET tracer [18F]florbetapir is a specific fibrillar amyloid-beta (Aß) biomarker. During the late scan phase (> 40 min), it provides pathological information about Aß status. Early scan phase (0-10 min) can provide FDG-'like' information. The current investigation tested the feasibility of using florbetapir as a dual-phase biomarker in behavioural variant frontotemporal dementia (bvFTD). METHODS: Eight bvFTD patients underwent [18F]florbetapir and [18]FDG-PET scans. Additionally, ten healthy controls and ten AD patients underwent florbetapir-PET only. PET data were acquired dynamically for 60-min post-injection. The bvFTD PET data were used to define an optimal time window, representing blood flow-related pseudo-metabolism ('pseudo-FDG'), of florbetapir data that maximally correlated with the corresponding real FDG SUVR (40-60 min) in a composite neocortical FTD region. RESULTS: A 2 to 5-min time window post-injection of the florbetapir-PET data provided the largest correlation (Pearson's r = 0.79, p = 0.02) to the FDG data. The pseudo-FDG images demonstrated strong internal consistency with actual FDG data and were also visually consistent with the bvFTD patients' hypometabolic profiles. The ability to identify bvFTD from blind visual rating of pseudo-FDG images was consistent with previous reports using FDG data (sensitivity = 75%, specificity = 85%). CONCLUSIONS: This investigation demonstrates that early phase florbetapir uptake shows a reduction of frontal lobe perfusion in bvFTD, similar to metabolic findings with FDG. Thus, dynamic florbetapir scans can serve as a dual-phase biomarker in dementia patients to distinguish FTD from AD and cognitively normal elderly, removing the need for a separate FDG-PET scan in challenging dementia cases.

Diagnostic utility of 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) in asymptomatic subjects at increased risk for Alzheimer's disease.

PURPOSE: To assess the clinical utility of 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) for detection of early signs of neurodegeneration in conditions of increased risk for Alzheimer's disease (AD) as defined by: subjective cognitive decline (SCD), evidence of cerebral amyloid-pathology, apolipoprotein E (APOE) ε4-positive genotype, or autosomal dominant forms of AD (ADAD) in asymptomatic stages. METHODS: A comprehensive literature search was conducted using the PICO model to extract evidence from relevant studies. An expert panel then voted using the Delphi method on three different diagnostic scenarios. RESULTS: The level of empirical study evidence for the use of FDG-PET to detect meaningful early signs of neurodegeneration was considered to be poor for ADAD and lacking for SCD and asymptomatic persons at risk, based on APOE ε4-positive genotype or cerebral amyloid pathology. Consequently, and consistent with current diagnostic criteria, panelists decided not to recommend routine clinical use of FDG-PET in these situations and to currently mainly reserve it for research purposes. CONCLUSION: Currently, there is limited evidence on which to base recommendations regarding the clinical routine use of FDG-PET to detect diagnostically meaningful early signs of neurodegeneration in asymptomatic subjects with ADAD, with APOE ε4-positive genotype, or with cerebral amyloid pathology, and in subjects with SCD. Future prospective studies are warranted and in part already ongoing, aiming to assess the added value of FDG-PET in this context beyond research applications.

Functional neuroanatomical associations of working memory in early-onset Alzheimer's disease.

OBJECTIVE: To characterize metabolic correlates of working memory impairment in clinically defined subtypes of early-onset Alzheimer's disease. BACKGROUND: Established models of working memory suggest a key role for frontal lobe function, yet the association in Alzheimer's disease between working memory impairment and visuospatial and language symptoms suggests that temporoparietal neocortical dysfunction may be responsible. METHODS: Twenty-four patients with predominantly early-onset Alzheimer's disease were clinically classified into groups with predominantly amnestic, multidomain or visual deficits. Patients underwent neuropsychological evaluation focused on the domains of episodic and working memory, T1-weighted magnetic resonance imaging and brain fluorodeoxyglucose positron emission tomography. Fluorodeoxyglucose positron emission tomography data were analysed by using a region-of-interest approach. RESULTS: Patients with multidomain and visual presentations performed more poorly on tests of working memory compared with amnestic Alzheimer's disease. Working memory performance correlated with glucose metabolism in left-sided temporoparietal, but not frontal neocortex. Carriers of the apolipoprotein E4 gene showed poorer episodic memory and better working memory performance compared with noncarriers. CONCLUSIONS: Our findings support the hypothesis that working memory changes in early-onset Alzheimer's disease are related to temporoparietal rather than frontal hypometabolism and show dissociation from episodic memory performance. They further support the concept of subtypes of Alzheimer's disease with distinct cognitive profiles due to prominent neocortical dysfunction early in the disease course. Copyright © 2017 John Wiley & Sons, Ltd.

Resilience to cognitive impairment in the oldest-old: design of the EMIF-AD 90+ study.

BACKGROUND: The oldest-old (subjects aged 90 years and older) population represents the fastest growing segment of society and shows a high dementia prevalence rate of up to 40%. Only a few studies have investigated protective factors for cognitive impairment in the oldest-old. The EMIF-AD 90+ Study aims to identify factors associated with resilience to cognitive impairment in the oldest-old. In this paper we reviewed previous studies on cognitive resilience in the oldest-old and described the design of the EMIF-AD 90+ Study. METHODS: The EMIF-AD 90+ Study aimed to enroll 80 cognitively normal subjects and 40 subjects with cognitive impairment aged 90 years or older. Cognitive impairment was operationalized as amnestic mild cognitive impairment (aMCI), or possible or probable Alzheimer's Disease (AD). The study was part of the European Medical Information Framework for AD (EMIF-AD) and was conducted at the Amsterdam University Medical Centers (UMC) and at the University of Manchester. We will test whether cognitive resilience is associated with cognitive reserve, vascular comorbidities, mood, sleep, sensory system capacity, physical performance and capacity, genetic risk factors, hallmarks of ageing, and markers of neurodegeneration. Markers of neurodegeneration included an amyloid positron emission tomography, amyloid ß and tau in cerebrospinal fluid/blood and neurophysiological measures. DISCUSSION: The EMIF-AD 90+ Study will extend our knowledge on resilience to cognitive impairment in the oldest-old by extensive phenotyping of the subjects and the measurement of a wide range of potential protective factors, hallmarks of aging and markers of neurodegeneration. TRIAL REGISTRATION: Nederlands Trial Register NTR5867 . Registered 20 May 2016.

An evidence-based algorithm for the utility of FDG-PET for diagnosing Alzheimer's disease according to presence of medial temporal lobe atrophy.

BACKGROUND: Imaging biomarkers for Alzheimer's disease include medial temporal lobe atrophy (MTLA) depicted on computed tomography (CT) or magnetic resonance imaging (MRI) and patterns of reduced metabolism on fluorodeoxyglucose positron emission tomography (FDG-PET). AIMS: To investigate whether MTLA on head CT predicts the diagnostic usefulness of an additional FDG-PET scan. METHOD: Participants had a clinical diagnosis of Alzheimer's disease (n = 37) or dementia with Lewy bodies (DLB; n = 30) or were similarly aged controls (n = 30). We visually rated MTLA on coronally reconstructed CT scans and, separately and blind to CT ratings, abnormal appearances on FDG-PET scans. RESULTS: Using a pre-defined cut-off of MTLA ⩾5 on the Scheltens (0-8) scale, 0/30 controls, 6/30 DLB and 23/30 Alzheimer's disease had marked MTLA. FDG-PET performed well for diagnosing Alzheimer's disease v DLB in the low-MTLA group (sensitivity/specificity of 71%/79%), but in the high-MTLA group diagnostic performance of FDG-PET was not better than chance. CONCLUSIONS: In the presence of a high degree of MTLA, the most likely diagnosis is Alzheimer's disease, and an FDG-PET scan will probably not provide significant diagnostic information. However, in cases without MTLA, if the diagnosis is unclear, an FDG-PET scan may provide additional clinically useful diagnostic information.

Amyloid imaging for dementia in clinical practice.

In vivo imaging of brain amyloid using positron emission tomography (PET) scanning is widely used in research studies of dementia, with three amyloid PET ligands being licenced for clinical use. The main clinical use of PET is to help confirm or exclude the likely diagnosis of Alzheimer's disease in challenging cases, where diagnostic uncertainty remains after current clinical and investigative work up. Whilst diagnostically valuable in such select cases, much wider clinical adoption, especially for very early disease, will be limited by both cost and the lack of a currently effective disease-modifying treatment that requires such early case identification. The use of amyloid imaging to appropriately stratify subjects for prognostic studies and therapeutic trials should increase the efficiency and potentially shorten the time of such studies, and its use combined with other biomarkers and genetics will likely lead to new ways of defining and classifying the dementias.

Alzheimer Disease Biomarkers as Outcome Measures for Clinical Trials in MCI.

BACKGROUND: The aim of this study was to compare the performance and power of the best-established diagnostic biological markers as outcome measures for clinical trials in patients with mild cognitive impairment (MCI). METHODS: Magnetic resonance imaging, F-18 fluorodeoxyglucose positron emission tomography markers, and Alzheimer's Disease Assessment Scale-cognitive subscale were compared in terms of effect size and statistical power over different follow-up periods in 2 MCI groups, selected from Alzheimer's Disease Neuroimaging Initiative data set based on cerebrospinal fluid (abnormal cerebrospinal fluid Aß1-42 concentration-ABETA+) or magnetic resonance imaging evidence of Alzheimer disease (positivity to hippocampal atrophy-HIPPO+). Biomarkers progression was modeled through mixed effect models. Scaled slope was chosen as measure of effect size. Biomarkers power was estimated using simulation algorithms. RESULTS: Seventy-four ABETA+ and 51 HIPPO+ MCI patients were included in the study. Imaging biomarkers of neurodegeneration, especially MR measurements, showed highest performance. For all biomarkers and both MCI groups, power increased with increasing follow-up time, irrespective of biomarker assessment frequency. CONCLUSION: These findings provide information about biomarker enrichment and outcome measurements that could be employed to reduce MCI patient samples and treatment duration in future clinical trials.

Imaging epigenetic regulation by histone deacetylases in the brain using PET/MRI with ¹8F-FAHA.

Epigenetic modifications mediated by histone deacetylases (HDACs) play important roles in the mechanisms of different neurologic diseases and HDAC inhibitors (HDACIs) have shown promise in therapy. However, pharmacodynamic profiles of many HDACIs in the brain remain largely unknown due to the lack of validated methods for noninvasive imaging of HDAC expression-activity. In this study, dynamic PET/CT imaging was performed in 4 rhesus macaques using [(18)F]FAHA, a novel HDAC substrate, and [(18)F]fluoroacetate, the major radio-metabolite of [(18)F]FAHA, and fused with corresponding MR images of the brain. Quantification of [(18)F]FAHA accumulation in the brain was performed using a customized dual-tracer pharmacokinetic model. Immunohistochemical analyses of brain tissue revealed the heterogeneity of expression of individual HDACs in different brain structures and cell types and confirmed that PET/CT/MRI with [(18)F]FAHA reflects the level of expression-activity of HDAC class IIa enzymes. Furthermore, PET/CT/MRI with [(18)F]FAHA enabled non-invasive, quantitative assessment of pharmacodynamics of HDAC inhibitor SAHA in the brain.

[¹¹C]-(R)PK11195 tracer kinetics in the brain of glioma patients and a comparison of two referencing approaches.

PURPOSE: Translocator protein (TSPO) is a biomarker of neuroinflammation that can be imaged by PET using [¹¹C]-(R)PK11195. We sought to characterize the [¹¹C]-(R)PK11195 kinetics in gliomas of different histotypes and grades, and to compare two reference tissue input functions (supervised cluster analysis versus cerebellar grey matter) for the estimation of [¹¹C]-(R)PK11195 binding in gliomas and surrounding brain structures. METHODS: Twenty-three glioma patients and ten age-matched controls underwent structural MRI and dynamic [¹¹C]-(R)PK11195 PET scans. Tissue time-activity curves (TACs) were extracted from tumour regions as well as grey matter (GM) and white matter (WM) of the brains. Parametric maps of binding potential (BPND) were generated with the simplified reference tissue model using the two input functions, and were compared with each other. TSPO expression was assessed in tumour tissue sections by immunohistochemistry. RESULTS: Three types of regional kinetics were observed in individual tumour TACs: GM-like kinetics (n=6, clearance of the tracer similar to that in cerebellar GM), WM-like kinetics (n=8, clearance of the tracer similar to that in cerebral WM) and a form of mixed kinetics (n=9, intermediate rate of clearance). Such kinetic patterns differed between low-grade astrocytomas (WM-like kinetics) and oligodendrogliomas (GM-like and mixed kinetics), but were independent of tumour grade. There was good agreement between parametric maps of BPND derived from the two input functions in all controls and 10 of 23 glioma patients. In 13 of the 23 patients, BPND values derived from the supervised cluster input were systematically smaller than those using the cerebellar input. Immunohistochemistry confirmed that TSPO expression increased with tumour grade. CONCLUSION: The three types of [¹¹C]-(R)PK11195 kinetics in gliomas are determined in part by tracer delivery, and indicated that kinetic analysis is a valuable tool in the study of gliomas with the potential for in vivo discrimination between low-grade astrocytomas and oligodendrogliomas. Supervised cluster and cerebellar input functions produced consistent BPND estimates in approximately half of the gliomas investigated, but had a systematic difference in the remainder. The cerebellar input is preferred based on theoretical and practical considerations.

A European multicentre PET study of fibrillar amyloid in Alzheimer's disease.

PURPOSE: Amyloid PET tracers have been developed for in vivo detection of brain fibrillar amyloid deposition in Alzheimer's disease (AD). To serve as an early biomarker in AD the amyloid PET tracers need to be analysed in multicentre clinical studies. METHODS: In this study 238 [(11)C]Pittsburgh compound-B (PIB) datasets from five different European centres were pooled. Of these 238 datasets, 18 were excluded, leaving [(11)C]PIB datasets from 97 patients with clinically diagnosed AD (mean age 69 ± 8 years), 72 patients with mild cognitive impairment (MCI; mean age 67.5 ± 8 years) and 51 healthy controls (mean age 67.4 ± 6 years) available for analysis. Of the MCI patients, 64 were longitudinally followed for 28 ± 15 months. Most participants (175 out of 220) were also tested for apolipoprotein E (ApoE) genotype. RESULTS: [(11)C]PIB retention in the neocortical and subcortical brain regions was significantly higher in AD patients than in age-matched controls. Intermediate [(11)C]PIB retention was observed in MCI patients, with a bimodal distribution (64 % MCI PIB-positive and 36 % MCI PIB-negative), which was significantly different the pattern in both the AD patients and controls. Higher [(11)C]PIB retention was observed in MCI ApoE ε4 carriers compared to non-ApoE ε4 carriers (p < 0.005). Of the MCI PIB-positive patients, 67 % had converted to AD at follow-up while none of the MCI PIB-negative patients converted. CONCLUSION: This study demonstrated the robustness of [(11)C]PIB PET as a marker of neocortical fibrillar amyloid deposition in brain when assessed in a multicentre setting. MCI PIB-positive patients showed more severe memory impairment than MCI PIB-negative patients and progressed to AD at an estimated rate of 25 % per year. None of the MCI PIB-negative patients converted to AD, and thus PIB negativity had a 100 % negative predictive value for progression to AD. This supports the notion that PIB-positive scans in MCI patients are an indicator of prodromal AD.

Diagnostic accuracy of markers for prodromal Alzheimer's disease in independent clinical series.

OBJECTIVE: To capitalize on data from different clinical series to compare sensitivity and specificity of individual biomarkers for predicting mild cognitive impairment (MCI) progression to Alzheimer's disease (AD). METHODS: Medial temporal atrophy, cortical hypometabolism, and cerebrospinal fluid biomarkers were assessed in 18 patients with mild cognitive impairment (MCI) with prodromal AD (pAD; conversion time, 26 ± 12 months) and 18 stable MCI (sMCI) patients from the Translational Outpatient Memory Clinic cohort, as well as in 24 pAD patients (conversion time, 36 ± 12 months) and 33 sMCI patients from the Alzheimer's Disease Neuroimaging Initiative cohort. Medial temporal atrophy was measured by manual, semi-automated, and automated hippocampal volumetry; cortical hypometabolism was measured using several indices of AD-related hypometabolism pattern; and cerebrospinal fluid markers were amyloid ß (Aß)42 and total tau protein concentrations. For each biomarker, sensitivity for pAD, specificity for sMCI, and diagnostic accuracy were computed. RESULTS: Sensitivity to predict MCI conversion to AD in the Alzheimer's Disease Neuroimaging Initiative and Translational Outpatient Memory Clinic cohorts was 79% and 94% based on Aß42, 46% and 28% based on hippocampal volumes, 33% to 66% and 56% to 78% based on different hypometabolism indices, and 46% and 61% based on total tau levels, respectively. Specificity to exclude sMCI was 27% and 50% based on Aß42, 76% and 94% based on hippocampal volumes, 58% to 67% and 55% to 83% based on different hypometabolism indices, and 61% and 83% based on total tau levels, respectively. CONCLUSIONS: Current findings suggest that Aß42 concentrations and hippocampal volumes may be used in combination to best identify pAD.

Structural and metabolic correlates of neuropsychological profiles in multiple system atrophy and Parkinson's disease.

BACKGROUND: Despite increased recognition of cognitive impairment in Multiple System Atrophy (MSA), its neuroanatomical correlates are not well defined. We aimed to explore cognitive profiles in MSA with predominant parkinsonism (MSA-P) and Parkinson's disease (PD) and their relationship to frontostriatal structural and metabolic changes. METHODS: Detailed clinical and neuropsychological evaluation was performed together with diffusion tensor imaging (DTI) and [18F]-fluoro-deoxyglucose positron emission tomography ([18F]-FDG-PET) in patients with MSA-P (n = 11) and PD (n = 11). We compared clinical and neuropsychological data to healthy controls (n = 9) and correlated neuropsychological data with imaging findings in MSA-P and PD. RESULTS: Patients with MSA-P showed deficits in executive function (Trail Making Test B-A) and scored higher in measures of depression and anxiety compared to those with PD and healthy controls. Widespread frontostriatal white matter tract reduction in fractional anisotropy was seen in MSA-P and PD compared to an imaging control group. Stroop Test interference performance correlated with [18F]-FDG uptake in the bilateral dorsolateral prefrontal cortex (DLPFC) and with white matter integrity between the striatum and left inferior frontal gyrus (IFG) in PD. Trail Making Test performance correlated with corticostriatal white matter integrity along tracts from the bilateral IFG in MSA-P and from the right DLPFC in both groups. CONCLUSION: Executive dysfunction was more prominent in patients with MSA-P compared to PD. DLPFC metabolism and frontostriatal white matter integrity seem to be a driver of executive function in PD, whereas alterations in corticostriatal white matter integrity may contribute more to executive dysfunction in MSA-P.

Staging of the cognitive decline in Alzheimer's disease: insights from a detailed neuropsychological investigation of mild cognitive impairment and mild Alzheimer's disease.

OBJECTIVE: The decline of episodic memory in Alzheimer's disease (AD) is well established, but the exact appearance and staging of deficits in other cognitive domains is sometimes contentious. The current investigation attempted to elucidate the appearance of additional cognitive deficits in the non-episodic domains and to understand these deficits with respect to the known pathological staging of AD. METHODS: A cross-sectional investigation compared cognitively normal age-matched controls with patients with mild AD and mild cognitive impairment (MCI) using a detailed neuropsychological assessment. RESULTS: The systematic investigation of cognitive performance across the major cognitive domains demonstrates that the appearance of additional cognitive deficits in MCI and AD can be predicted, with impaired semantic cognition performance pre-empting the appearance of attention/executive dysfunction and visuospatial deficits in the majority of patients with MCI. CONCLUSIONS: This progressive pattern of cognitive deficits fits with the known pathological staging of AD, and the data further highlight the relative rarity of pure amnestic MCI. These results indicate that any neuropsychological test battery used to assess patients with MCI should include language and semantic memory tests in addition to typical episodic memory tests, as changes within this domain might be a sensitive indication of incipient AD.

Imaging Clinical Subtypes and Associated Brain Networks in Alzheimer's Disease.

Alzheimer's disease (AD) does not present uniform symptoms or a uniform rate of progression in all cases. The classification of subtypes can be based on clinical symptoms or patterns of pathological brain alterations. Imaging techniques may allow for the identification of AD subtypes and their differentiation from other neurodegenerative diseases already at an early stage. In this review, the strengths and weaknesses of current clinical imaging methods are described. These include positron emission tomography (PET) to image cerebral glucose metabolism and pathological amyloid or tau deposits. Magnetic resonance imaging (MRI) is more widely available than PET. It provides information on structural or functional changes in brain networks and their relation to AD subtypes. Amyloid PET provides a very early marker of AD but does not distinguish between AD subtypes. Regional patterns of pathology related to AD subtypes are observed with tau and glucose PET, and eventually as atrophy patterns on MRI. Structural and functional network changes occur early in AD but have not yet provided diagnostic specificity.