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The first National Research Summit on Care, Services, and Supports for Persons with Dementia and Their Caregivers was held on October 16-17, 2017, at the National Institutes of Health. In this paper, participants from the Summit Session on Research on Care Needs and Supportive Approaches for Persons with Dementia summarize the state of the science, identify gaps in knowledge, and offer recommendations to improve science and practice in long-term care. Recommendations cover 4 areas focused on persons living with dementia: (1) symptoms (behavioral and psychological symptoms of dementia, function, cognition, and sleep); (2) dementia care settings (physical and social environments, home, and residential care); (3) living with dementia (living well with dementia, living alone with dementia, and living with dementia and intellectual and developmental disabilities); and (4) technology as a cross-cutting theme. The participants identify 10 of the most pressing research issues based on the findings from their collective papers. Final Summit recommendations included those presented by session participants and will be used to advise federal agencies and other organizations that fund research.

Sensory functions of organs of the head and neck allow humans to interact with the environment and establish social bonds. With aging, smell, taste, vision, and hearing decline. Evidence suggests that accelerated impairment in sensory abilities can reflect a shift from healthy to pathological aging, including the development of Alzheimer's disease (AD) and other neurological disorders. While the drivers of early sensory alteration in AD are not elucidated, insults such as trauma and infections can affect sensory function. Herein, we review the involvement of the major head and neck sensory systems in AD, with emphasis on microbes exploiting sensory pathways to enter the brain (the "gateway" hypothesis) and the potential feedback loop by which sensory function may be impacted by central nervous system infection. We emphasize detection of sensory changes as first-line surveillance in senior adults to identify and remove potential insults, like microbial infections, that could precipitate brain pathology. [ABSTRACT FROM AUTHOR]

INTRODUCTION: This study derived composite scores for two novel cognitive measures, the No Practice Effect (NPE) battery and the Miami Computerized Functional Skills Assessment and Training system for use in early‐stage Alzheimer's disease (AD) clinical trials. Their psychometric properties and associations with AD risk markers were compared to those of well‐established measures. METHODS: For 291 older adults with healthy cognition or early mild cognitive impairment, Exploratory factor analyses were used to identify the factor structure of the NPE. Factor and total scores were examined for their psychometric properties and associations with AD risk biomarkers. RESULTS: Composite scores from the novel cognitive and functional measures demonstrated better psychometric properties (distribution and test‐retest reliability) and stronger associations with AD‐related demographic, genetic, and brain risk markers than well‐established measures, DISCUSSION: These novel measures have potential for use as primary cognitive and functional outcomes in early‐stage AD clinical trials. Highlights: Well‐established cognitive tests may not accurately detect subtle cognitive changes.No Practice Effect (NPE) and Computerized Functional Skills Assessment and Training are novel measures designed to have improved psychometric properties.NPE had Executive Function, Cognitive Control/Speed, and Episodic Memory domains.Novel measures had better psychometric properties compared to established measures.Significant associations with Alzheimer's disease biomarkers were found with novel measures. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The effects of sleep–wake behavior on perceived fatigability and cognitive abilities when performing daily activities have not been investigated across levels of cognitive reserve (CR). METHODS: CR Index Questionnaire (CRIq) data were collected and subjected to moderated mediation analysis. RESULTS: In amnestic mild cognitive impairment (aMCI; n = 41), CR moderated sleep‐related impairments (SRIs), and fatigability at low CR (CRIq < 105.8, p = 0.004) and mean CR (CRIq = 126.9, p = 0.03) but not high CR (CRIq > 145.9, p = 0.65) levels. SRI affected cognitive abilities mediated by fatigability at low CR (p < 0.001) and mean CR (p = 0.003) levels. In healthy controls (n = 13), SRI in fatigability did not alter cognitive abilities across CR levels; controls had higher leisure scores than patients with aMCI (p = 0.003, effect size = 0.93). DISCUSSION: SRI can amplify impaired cognitive abilities through exacerbation of fatigability in patients with aMCI with below‐mean CR. Therefore, improving sleep–wake regulation and leisure activities may protect against fatigability and cognitive decline. Highlights: Clinical fatigue and fatigability cannot be alleviated by rest.Clinical fatigability disrupts daily activities during preclinical Alzheimer's.High cognitive reserve mitigates sleep–wake disturbance effects.High cognitive reserve attenuates clinical fatigability effects on daily functioning.Untreated obstructive sleep apnea potentiates Alzheimer's pathology in the brain. [ABSTRACT FROM AUTHOR]

Background: Histopathologic studies of Alzheimer's disease (AD) suggest that extracellular amyloid-β (Aβ) plaques promote the spread of neurofibrillary tau tangles. However, these two proteinopathies initiate in spatially distinct brain regions, so how they interact during AD progression is unclear. Objective: In this study, we utilized Aβ and tau positron emission tomography (PET) scans from 572 older subjects (476 healthy controls (HC), 14 with mild cognitive impairment (MCI), 82 with mild AD), at varying stages of the disease, to investigate to what degree tau is associated with cortical Aβ deposition. Methods: Using multiple linear regression models and a pseudo-longitudinal ordering technique, we investigated remote tau-Aβ associations in four pathologic phases of AD progression based on tau spread: 1) no-tau, 2) pre-acceleration, 3) acceleration, and 4) post-acceleration. Results: No significant tau-Aβ association was detected in the no-tau phase. In the pre-acceleration phase, the earliest stage of tau deposition, associations emerged between regional tau in medial temporal lobe (MTL) (i.e., entorhinal cortex, parahippocampal gyrus) and cortical Aβ in lateral temporal lobe regions. The strongest tau-Aβ associations were found in the acceleration phase, in which tau in MTL regions was strongly associated with cortical Aβ (i.e., temporal and frontal lobes regions). Strikingly, in the post-acceleration phase, including 96% of symptomatic subjects, tau-Aβ associations were no longer significant. Conclusions: The results indicate that associations between tau and Aβ are stage-dependent, which could have important implications for understanding the interplay between these two proteinopathies during the progressive stages of AD. [ABSTRACT FROM AUTHOR]

Recent evidence indicates that sensory and motor changes may precede the cognitive symptoms of Alzheimer's disease (AD) by several years and may signify increased risk of developing AD. Traditionally, sensory and motor dysfunctions in aging and AD have been studied separately. To ascertain the evidence supporting the relationship between age-related changes in sensory and motor systems and the development of AD and to facilitate communication between several disciplines, the National Institute on Aging held an exploratory workshop titled "Sensory and Motor Dysfunctions in Aging and AD." The scientific sessions of the workshop focused on age-related and neuropathologic changes in the olfactory, visual, auditory, and motor systems, followed by extensive discussion and hypothesis generation related to the possible links among sensory, cognitive, and motor domains in aging and AD. Based on the data presented and discussed at this workshop, it is clear that sensory and motor regions of the central nervous system are affected by AD pathology and that interventions targeting amelioration of sensory-motor deficits in AD may enhance patient function as AD progresses.

Background: There is ample evidence in animal models that lithium increases Brain‐Derived Neurotrophic Factor (BDNF) with supporting evidence in human studies. Little is known, however, about the effects of lithium on BDNF in Alzheimer's Dementia (AD). In one study of patients with Mild Cognitive Impairment, serum BDNF increased after treatment with lithium. These patients also showed mild improvement in cognitive function. Objectives: To evaluate low‐dose lithium treatment of agitation in Alzheimer's disease (AD). Method: We measured levels of BDNF in patients treated with lithium prior to and after a 12‐week randomized placebo‐controlled trial. Results: BDNF levels did not change significantly and were not associated with improvement in overall neuropsychiatric symptoms or in cognitive function. Conclusions: More research is needed to understand the potential effects of lithium on BDNF in AD including whether its use might be dependent on the stage of cognitive decline and dementia. Key points: Lithium is known to increase Brain‐Derived Neurotrophic Factor (BDNF) levels.BDNF has neuroprotective properties.Decreased levels of BDNF have been found in the brains of people with AD.Little is known about the association between the effects of Lithium on BDNF in patients with AD. [ABSTRACT FROM AUTHOR]

Background: The positron emission tomography (PET) radiotracer [18F]MK‐6240 exhibits high specificity for neurofibrillary tangles (NFTs) of tau protein in Alzheimer's disease (AD), high sensitivity to medial temporal and neocortical NFTs, and low within‐brain background. Objectives were to develop and validate a reproducible, clinically relevant visual read method supporting [18F]MK‐6240 use to identify and stage AD subjects versus non‐AD and controls. Methods: Five expert readers used their own methods to assess 30 scans of mixed diagnosis (47% cognitively normal, 23% mild cognitive impairment, 20% AD, 10% traumatic brain injury) and provided input regarding regional and global positivity, features influencing assessment, confidence, practicality, and clinical relevance. Inter‐reader agreement and concordance with quantitative values were evaluated to confirm that regions could be read reliably. Guided by input regarding clinical applicability and practicality, read classifications were defined. The readers read the scans using the new classifications, establishing by majority agreement a gold standard read for those scans. Two naïve readers were trained and read the 30‐scan set, providing initial validation. Inter‐rater agreement was further tested by two trained independent readers in 131 scans. One of these readers used the same method to read a full, diverse database of 1842 scans; relationships between read classification, clinical diagnosis, and amyloid status as available were assessed. Results: Four visual read classifications were determined: no uptake, medial temporal lobe (MTL) only, MTL and neocortical uptake, and uptake outside MTL. Inter‐rater kappas were 1.0 for the naïve readers gold standard scans read and 0.98 for the independent readers 131‐scan read. All scans in the full database could be classified; classification frequencies were concordant with NFT histopathology literature. Discussion: This four‐class [18F]MK‐6240 visual read method captures the presence of medial temporal signal, neocortical expansion associated with disease progression, and atypical distributions that may reflect different phenotypes. The method demonstrates excellent trainability, reproducibility, and clinical relevance supporting clinical use. Highlights: A visual read method has been developed for [18F]MK‐6240 tau positron emission tomography.The method is readily trainable and reproducible, with inter‐rater kappas of 0.98.The read method has been applied to a diverse set of 1842 [18F]MK‐6240 scans.All scans from a spectrum of disease states and acquisitions could be classified.Read classifications are consistent with histopathological neurofibrillary tangle staging literature. [ABSTRACT FROM AUTHOR]

Background: Mild cognitive impairment (MCI) represents a high risk group for Alzheimer's disease (AD). Computerized Cognitive Games Training (CCT) is an investigational strategy to improve targeted functions in MCI through the modulation of cognitive networks.Objective: The goal of this study was to examine the effect of CCT versus a non-targeted active brain exercise on functional cognitive networks.Methods: 107 patients with MCI were randomized to CCT or web-based crossword puzzles. Resting-state functional MRI (fMRI) was obtained at baseline and 18 months to evaluate differences in fMRI measured within- and between-network functional connectivity (FC) of the default mode network (DMN) and other large-scale brain networks: the executive control, salience, and sensorimotor networks.Results: There were no differences between crosswords and games in the primary FC outcome. However, secondary analyses suggest differential effects on between-network connectivity involving the DMN and SLN, and within-network connectivity of the DMN in subjects with late MCI. Paradoxically, in both cases, there was a decrease in FC for games and an increase for the crosswords control (p < 0.05), accompanied by lesser cognitive decline in the crosswords group.Conclusion: Results do not support a differential impact on within-network DMN FC between games and crossword puzzle interventions. However, crossword puzzles might nonspecifically engage multiple specialized cognitive networks at a low level, resulting in cognitively beneficial remodeling between the DMN and other networks, and within the DMN in subjects at higher risk of dementia. [ABSTRACT FROM AUTHOR]

In this review, we comprehensively, qualitatively, and critically synthesized several features of APOE-e2, a known APOE protective variant, including its associations with longevity, cognition, and neuroimaging, and neuropathology, all in humans. If e2's protective effects--and their limits--could be elucidated, it could offer therapeutic windows for Alzheimer's disease (AD) prevention or amelioration. Literature examining e2 within the years 1994-2021 were considered for this review. Studies on human subjects were selectively reviewed and were excluded if observation of e2 was not specified. Effects of e2 were compared with e3 and e4, separately and as a combined non-e2 group. Our examination of existing literature indicated that the most robust protective role of e2 is in longevity and AD neuropathologies, but e2's effect on cognition and other AD imaging markers (brain structure, function, and metabolism) were inconsistent, thus inconclusive. Notably, e2 was associated with greater risk of non-AD proteinopathies and a disadvantageous cerebrovascular profile. We identified multiple methodological shortcomings of the literature on brain function and cognition that could have contributed to inconsistent and potentially misleading findings. We make careful interpretations of existing findings and provide directions for research strategies that could effectively examine the independent and unbiased effect of e2 on AD risk. [ABSTRACT FROM AUTHOR]

Background: The association between sleep and Alzheimer's disease (AD) biomarkers are well-established, but little is known about how they interact to change the course of AD.Objective: To determine the potential interaction between sleep disturbance and Aβ, tau, and APOE4 on brain atrophy and cognitive decline.Methods: Sample included 351 participants (mean age 72.01 ± 6.67, 50.4%female) who were followed for approximately 5 years as part of the Alzheimer's Disease Neuroimaging Initiative. Informant-reported sleep disturbance (IRSD) was measured using the Neuropsychiatric Inventory (NPI). Changes in magnetic resonance imaging (MRI)-measured AD signature brain regions and cognitive performance and IRSD's interaction with cerebrospinal fluid amyloid-β (Aβ42) and p-Tau depositions and APOE4 status were examined using the linear mixed models.Results: Baseline IRSD was not significantly associated with the rate of atrophy after adjusting for covariates (age, sex, education, total NPI severity score, and sleep medications). However, there was a significant interaction between IRSD and AD biomarkers on faster atrophy rates in multiple brain regions, including the cortical and middle temporal volumes. Post-hoc analyses indicated that Aβ and p-Tau/Aβ predicted a faster decline in these regions/domains in IRSD, compared with biomarker-negative individuals with IRSD (ps≤0.001). There was a significant IRSD*APOE4 interaction for brain atrophy rate (ps≤0.02) but not for cognition.Conclusion: IRSD may increase the future risk of AD by contributing to faster brain atrophy and cognitive decline when combined with the presence of AD biomarkers and APOE4. Early intervention for sleep disturbance could help reduce the risk of developing AD. [ABSTRACT FROM AUTHOR]

Importance: Understanding associations of Alzheimer disease (AD) and related dementias (ADRD) pathologies with common neuropsychiatric symptoms (NPS) may have implications for diagnosis and management.Objective: To evaluate ADRD neuropathological diagnoses and NPS without consideration of clinical diagnosis.Design, Setting, and Participants: This retrospective cohort study evaluated 1808 brains from 39 sites in the US National Alzheimer Coordinating Center v. 10 collection for participants among whom the Neuropsychiatric Inventory Questionnaire (NPIQ) was administered annually. Brain autopsy diagnoses of AD, Lewy body disease (LBD), cerebral amyloid angiopathy, frontotemporal lobar degeneration, cerebrovascular disease, hippocampal sclerosis, and no known pathology were examined. Autopsy data collected from January 2012 to January 2018 were deidentified and compiled into the publicly available v. 10 database. Data were analyzed from February 2021 to August 2021.Main Outcomes and Measures: The primary outcome was NPIQ domain score, if present at any time point, and mean NPIQ domain score during follow-up was secondary. Associations of ADRD diagnoses with 12 NPIQ symptom domains were examined in regression analyses, correcting for multiple comparisons.Results: The study sample of 1808 adults had a mean (SD) age of 80.0 (11.0) years, and 987 participants (54.6%) were male. Apathy was the most prevalent NPS, reaching 80% (203 of 254 individuals) in those with hippocampal sclerosis. Cerebrovascular disease showed few NPS associations. Frontotemporal lobar degeneration was associated with increased apathy, increased disinhibition, and decreased psychosis and agitation compared with AD. Hippocampal sclerosis was associated with increased apathy (odds ratio, 2.60; 95% CI; 1.86-3.66, false discovery rate controlled P < .001) and disinhibition (odds ratio, 2.15; 95% CI, 1.63-2.84; false discovery rate controlled P < .001). In multiple regression analyses that included concomitant neuropathologies, the main findings remained. More severe pathology was consistently associated with increased NPS (eg, LBD was associated with an increase in hallucinations from brain stem [β, 0.23; 95% CI, 0.07-0.76; P = .02] to limbic [β, 1.69; 95% CI, 1.27-2.27; P < .001] to neocortical [β, 4.49; 95% CI, 3.27-6.16; P < .001] pathology). Hallucinations were more common in participants with AD and LBD (168 of 534 [31.5%]) compared with those with AD without LBD (152 of 704 [21.6%]) and those with LBD without AD (23 of 119 [19.6%]).Conclusions and Relevance: In this cohort study of 1808 brains from the US National Alzheimer Coordinating Center, patients with LBD and AD showed a higher prevalence of hallucinations compared with those with LBD without AD. Neuropsychiatric symptom criteria of apathy and disinhibition in behavioral variant frontotemporal lobar degeneration were supported in this study. In hippocampal sclerosis, the findings of increased apathy and disinhibition merit further investigation. Severity of neuropathology was associated with NPS severity, indicating that NPS may reflect underlying ADRD pathology and highlighting the importance of diagnosing and treating NPS. [ABSTRACT FROM AUTHOR]

Background: Digital cognitive tests offer several potential advantages over established paper-pencil tests but have not yet been fully evaluated for the clinical evaluation of mild cognitive impairment.Objective: The NeuroCognitive Performance Test (NCPT) is a web-based, self-directed, modular battery intended for repeated assessments of multiple cognitive domains. Our objective was to examine its relationship with the Alzheimer's Disease Assessment Scale-Cognition Subscale (ADAS-Cog) and Mini-Mental State Examination (MMSE) as well as with established paper-pencil tests of cognition and daily functioning in mild cognitive impairment (MCI).Methods: We used Spearman correlations, regressions and principal components analysis followed by a factor analysis (varimax rotated) to examine our objectives.Results: In MCI subjects, the NCPT composite is significantly correlated with both a composite measure of established tests (r = 0.78, p < 0.0001) as well as with the ADAS-Cog (r = -0.55, p < 0.0001). Both NCPT and paper-pencil test batteries had a similar factor structure that included a large "g" component with a high eigenvalue. The correlation for the analogous tests (e.g., Trails A and B, learning memory tests) were significant (p < 0.0001). Further, both the NCPT and established tests significantly (p < 0.0001) predicted the University of California San Diego Performance-Based Skills Assessment and Functional Activities Questionnaire, measures of daily functioning.Conclusion: The NCPT, a web-based, self-directed, computerized test, shows high concurrent validity with established tests and hence offers promise for use as a research or clinical tool in MCI. Despite limitations such as a relatively small sample, absence of control group and cross-sectional nature, these findings are consistent with the growing literature on the promise of self-directed, web-based cognitive assessments for MCI. [ABSTRACT FROM AUTHOR]

Introduction: This study evaluated acute change in odor identification following atropine nasal spray challenge, and 8-week change in odor identification ability, as a predictor of long-term improvement in patients with mild to moderate Alzheimer’s disease (AD) who received open-label cholinesterase inhibitor treatment. Methods: In patients with clinical AD, the University of Pennsylvania Smell identification Test (UPSIT) was administered before and after an anticholinergic atropine nasal spray challenge. Patients were then treated with donepezil for 52 weeks. Results: In 21 study participants, acute atropine-induced decrease in UPSIT was not associated with change in the Alzheimer’s Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) or Selective Reminding Test (SRT). Decline in odor identification performance from baseline to week 8 was indicative of a future decline in cognitive performance over 52 weeks. Discussion: Change in odor identification with atropine challenge is not a useful predictor of treatment response to cholinesterase inhibitors. Short-term change in odor identification performance needs further investigation as a potential predictor of cognitive improvement with cholinesterase inhibitor treatment. [ABSTRACT FROM AUTHOR]

Background: Apathy is a common and problematic symptom of several neurodegenerative illnesses, but its neuroanatomical bases are not understood.Objective: To determine the regions associated with apathy in subjects with mild Alzheimer's disease (AD) using a method that accounts for the significant co-linearity of regional atrophy and neuropsychiatric symptoms.Methods: We identified 57 subjects with mild AD (CDR = 1) and neuropsychiatric symptoms in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. We performed a multivariate multiple regression with LASSO regularization on all symptom subscales of the Neuropsychiatric Inventory and the whole-brain ROI volumes calculated from their baseline MRIs with FreeSurfer. We compared our results to those from a previous study using the same method in patients with frontotemporal dementia (FTD) and corticobasal syndrome (CBS).Results: Of neuropsychiatric symptoms, apathy showed the most robust neuroanatomical associations in the AD subjects. Atrophy of the following regions were independently associated with apathy: the ventromedial prefrontal cortex; ventrolateral prefrontal cortex; posterior cingulate cortex and adjacent lateral cortex; and the bank of the superior temporal sulcus. These results replicate previous studies using FTD and CBS patients, mostly agree with the previous literature on apathy in AD, and correspond to the Medial and Orbital Prefrontal Cortex networks identified in non-human primates.Conclusion: The current study, previous studies from our laboratory, and the previous literature suggest that impairment of the same brain networks involved in arousal, threat response, and reward processing are associated with apathy in AD and FTD. [ABSTRACT FROM AUTHOR]

Objective: To assess potential genetic influences on citalopram treatment efficacy for agitation in individuals with Alzheimer dementia (AD). Six functional genetic variants were studied in the following genes: serotonin receptor 2A (HTR2A-T102C), serotonin receptor 2C (HTR2C-Cys23Ser), serotonin transporter (5HTT-LPR), brain-derived neurotropic factor (BDNF-Val66Met), apolipoprotein E (ε2, ε3, ε4 variants), and cytochrome P450 (CYP2C19). Treatment response by genotype was measured by (1) the agitation domain of the Neurobehavioral Rating Scale, (2) the modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change scale (mADCS-CGIC), (3) the agitation domain of the Neuropsychiatric Inventory (NPI), and (4) the Cohen-Mansfield Agitation Inventory.Method: We utilized data from the Citalopram for Agitation in Alzheimer's Disease (CitAD) database. CitAD was a 9-week randomized, double-blind, placebo-controlled multicenter clinical trial showing significant improvement in agitation and caregiver distress in patients treated with citalopram. Proportional odds logistic regression and mixed effects models were used to examine the above-mentioned outcome measures.Results: Significant interactions were noted on the NPI agitation domain for HTR2A (likelihood ratio [LR] = 6.19, df = 2, P = .04) and the mADCS-CGIC for HTR2C (LR = 4.33, df = 2, P = .02) over 9 weeks.Discussion: Treatment outcomes in CitAD showed modest, although statistically significant, influence of genetic variation at HTR2A and HTR2C loci. Future studies should continue to examine the interaction of known genetic variants with antidepressant treatment in patients with AD having agitation. [ABSTRACT FROM AUTHOR]

Background: The utility of combining early markers to predict conversion from mild cognitive impairment (MCI) to Alzheimer''s Disease (AD) remains uncertain. Methods: Included in the study were 148 outpatients with MCI, broadly defined, followed at 6-month intervals. Hypothesized baseline predictors for follow-up conversion to AD (entire sample: 39/148 converters) were cognitive test performance, informant report of functional impairment, apolipoprotein E genotype, olfactory identification deficit, and magnetic resonance imaging (MRI) hippocampal and entorhinal cortex volumes. Results: In the 3-year follow-up patient sample (33/126 converters), five of eight hypothesized predictors were selected by backward and stepwise logistic regression: Pfeffer Functional Activities Questionnaire (FAQ; informant report of functioning), University of Pennsylvania Smell Identification Test (UPSIT; olfactory identification), Selective Reminding Test (SRT) immediate recall (verbal memory), MRI hippocampal volume, and MRI entorhinal cortex volume. For 10% false positives (90% specificity), this five-predictor combination showed 85.2% sensitivity, combining age and Mini-Mental State Examination (MMSE) showed 39.4% sensitivity; combining age, MMSE, and the three clinical predictors (SRT immediate recall, FAQ, and UPSIT) showed 81.3% sensitivity. Area under ROC curve was greater for the five-predictor combination (.948) than age plus MMSE (.821; p = .0009) and remained high in subsamples with MMSE ≥ 27/30 and amnestic MCI. Conclusions: The five-predictor combination strongly predicted conversion to AD and was markedly superior to combining age and MMSE. Combining the clinically administered measures also led to strong predictive accuracy. If independently replicated, the findings have potential utility for early detection of AD. [Copyright &y& Elsevier]

Temporoparietal and posterior cingulate metabolism deficits characterize patients with Alzheimer's disease (AD). A H215O resting PET scan covariance pattern, derived by using multivariate techniques, was previously shown to discriminate 17 mild AD patients from 16 healthy controls. This AD covariance pattern revealed hypoperfusion in bilateral inferior parietal lobule and cingulate; and left middle frontal, inferior frontal, precentral, and supramarginal gyri. The AD pattern also revealed hyperperfusion in bilateral insula, lingual gyri, and cuneus; left fusiform and superior occipital gyri; and right parahippocampal gyrus and pulvinar. In an independent sample of 23 outpatients with mild cognitive impairment (MCI) followed at 6-month intervals, the AD pattern score was evaluated as a predictor of cognitive decline. In this MCI sample, an H215O resting PET scan was carried out at baseline. Mean duration of follow-up was 48.8 (SD 15.5) months, during which time six of 23 MCI patients converted to AD. In generalized estimating equations (GEE) analyses, controlling for age, sex, education, and baseline neuropsychological scores, increased AD pattern score was associated with greater decline in each neuropsychological test score over time (Mini Mental State Exam, Selective Reminding Test delayed recall, Animal Naming, WAIS-R digit symbol; Ps<0.01–0.001). In summary, a resting PET covariance pattern previously reported to discriminate AD patients from control subjects was applied prospectively to an independent sample of MCI patients and found to predict cognitive decline. Independent replication in larger samples is needed before clinical application can be considered.Neuropsychopharmacology (2006) 31, 1327–1334. doi:10.1038/sj.npp.1300942; published online 9 November 2005 [ABSTRACT FROM AUTHOR]

Although multivariate analytic techniques might identify diagnostic patterns that are not captured by univariate methods, they have rarely been used to study the neural correlates of Alzheimer''s disease (AD) or cognitive impairment. Nonquantitative H215O PET scans were acquired during rest in 17 probable AD subjects selected for mild severity [mean-modified Mini Mental Status Examination (mMMS) 46/57; SD 5.1], 16 control subjects (mMMS 54; SD 2.5) and 23 subjects with minimal to mild cognitive impairment but no dementia (mMMS 53; SD 2.8). Expert clinical reading had low success in discriminating AD and controls. There were no significant mean flow differences among groups in traditional univariate SPM Noxel-wise analyses or region of interest (ROI) analyses. A covariance pattern was identified whose mean expression was significantly higher in the AD as compared to controls (P = 0.03; sensitivity 76–94%; specificity 63–81%). Sites of increased concomitant flow included insula, cuneus, pulvinar, lingual, fusiform, superior occipital and parahippocampal gyri, whereas decreased concomitant flow was found in cingulate, inferior parietal lobule, middle and inferior frontal, supramarginal and precentral gyri. The covariance analysis-derived pattern was then prospectively applied to the cognitively impaired subjects: as compared to subjects with Clinical Dementia Rating (CDR) = 0, subjects with CDR = 0.5 had significantly higher mean covariance pattern expression (P = 0.009). Expression of this pattern correlated inversely with Selective Reminding Test total recall (r = -0.401, P = 0.002), delayed recall (r = -0.351, P = 0.008) and mMMS scores (r = -0.401, P = 0.002) in all three groups combined. We conclude that patients with AD may differentially express resting cerebral blood flow covariance patterns even at very early disease stages. Significant alterations in expression of resting flow covariance patterns occur even for subjects with cognitive impairment. Expression of covariance patterns correlates with cognitive and functional performance measures, holding promise for meaningful associations with underlying biopathological processes. [Copyright &y& Elsevier]