Novel measures of cognition and function for the AD spectrum in the Novel Measures for Alzheimer's Disease Prevention Trials (NoMAD) project: Psychometric properties, convergent validation, and contrasts with established measures.

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.

The identification and cognitive correlation of perfusion patterns measured with arterial spin labeling MRI in Alzheimer's disease.

BACKGROUND: Vascular dysfunction, including cerebral hypoperfusion, plays an important role in the pathogenesis and progression of Alzheimer's disease (AD), independent of amyloid and tau pathology. We established an AD-related perfusion pattern (ADRP) measured with arterial spin labeling (ASL) MRI using multivariate spatial covariance analysis. METHODS: We obtained multimodal MRI including pseudo-continuous ASL and neurocognitive testing in a total of 55 patients with a diagnosis of mild to moderate AD supported by amyloid PET and 46 normal controls (NCs). An ADRP was established from an identification cohort of 32 patients with AD and 32 NCs using a multivariate analysis method based on scaled subprofile model/principal component analysis, and pattern expression in individual subjects was quantified for both the identification cohort and a validation cohort (23 patients with AD and 14 NCs). Subject expression score of the ADRP was then used to assess diagnostic accuracy and cognitive correlations in AD patients and compared with global and regional cerebral blood flow (CBF) in specific areas identified from voxel-based univariate analysis. RESULTS: The ADRP featured negative loading in the bilateral middle and posterior cingulate and precuneus, inferior parietal lobule, and frontal areas, and positive loading in the right cerebellum and bilateral basal areas. Subject expression score of the ADRP was significantly elevated in AD patients compared with NCs (P < 0.001) and showed good diagnostic accuracy for AD with area under receiver-operator curve of 0.87 [95% CI (0.78-0.96)] in the identification cohort and 0.85 in the validation cohort. Moreover, there were negative correlations between subject expression score and global cognitive function and performance in various cognitive domains in patients with AD. The characteristics of the ADRP topography and subject expression scores were supported by analogous findings obtained with regional CBF. CONCLUSIONS: We have reported a characteristic perfusion pattern associated with AD using ASL MRI. Subject expression score of this spatial covariance pattern is a promising MRI biomarker for the identification and monitoring of AD.

Semiquantitative Approach to Amyloid Positron Emission Tomography Interpretation in Clinical Practice.

Objective Amyloid positron emission tomography (PET) plays a vital role in the in vivo detection of ß-amyloid accumulation in Alzheimer's disease. Increasingly, trainees and infrequent readers are relying on semiquantitative analyses to support clinical diagnostic efforts. Our objective was to determine if the visual assessment of amyloid PET may be facilitated by relying on semiquantitative analysis. Methods We conducted a retrospective review of [ 18 F]-florbetaben PET/computed tomographies (CTs) from 2016 to 2018. Visual interpretation to determine Aß+ status was conducted by two readers blinded to each other's interpretation. Scans were then post-processed utilizing the MIMneuro software, which generated regional-based semiquantitative Z-scores indicating cortical Aß-burden. Results Of 167 [ 18 F]-florbetaben PET/CTs, 92/167 (reader-1) and 101/167 (reader-2) were positive for amyloid deposition (agreement = 92.2%, κ = 0.84). Additional nine scans were identified as possible Aß-positive based solely on semiquantitative analyses. Largest semiquantitative differences were identified in the left frontal lobe (Z = 7.74 in Aß + ; 0.50 in Aß - ). All unilateral regions showed large statistically significant differences in Aß-burden ( P ≤ 2.08E-28). Semiquantitative scores were highly sensitive to Aß+ status and accurate in their ability to identify amyloid positivity, defined as a positive scan by both readers (AUC ≥ 0.90 [0.79-1.00]). Spread analyses suggested that amyloid deposition was most severe in the left posterior cingulate gyrus. The largest differences between Aß +/Aß- were in the left frontal lobe. Analyses using region-specific cutoffs indicated that the presence of amyloid in the temporal and anterior cingulate cortex, while exhibiting relatively low Z-scores, was most common. Conclusion Visual assessment and semiquantitative analysis provide highly congruent results, thereby enhancing reader confidence and improving scan interpretation. This is particularly relevant, given recent advances in amyloid-targeting disease-modifying therapeutics.

Overview of tau PET molecular imaging.

PURPOSE OF REVIEW: This article reviews tau PET imaging with an emphasis on first-generation and second-generation tau radiotracers and their application in neurodegenerative disorders, including Alzheimer's disease and non-Alzheimer's disease tauopathies. RECENT FINDINGS: Tau is a critical protein, abundant in neurons within the central nervous system, which plays an important role in maintaining microtubules by binding to tubulin in axons. In its abnormal hyperphosphorylated form, accumulation of tau has been linked to a variety of neurodegenerative disorders, collectively referred to as tauopathies, which include Alzheimer's disease and non-Alzheimer's disease tauopathies [e.g., corticobasal degeneration (CBD), argyrophilic grain disease, progressive supranuclear palsy (PSP), and Pick's disease]. A number of first-generation and second-generation tau PET radiotracers have been developed, including the first FDA-approved agent [18F]-flortaucipir, which allow for in-vivo molecular imaging of underlying histopathology antemortem, ultimately guiding disease staging and development of disease-modifying therapeutics. SUMMARY: Tau PET is an emerging imaging modality in the diagnosis and staging of tauopathies.

Clinical, Neuropsychological, and Neuroimaging Characteristics of Amyloid- positive vs. Amyloid-negative Patients with Clinically Diagnosed Alzheimer's Disease and Amnestic Mild Cognitive Impairment.

BACKGROUND: A significant proportion of patients with clinically diagnosed Alzheimer's Disease (AD) and an even higher proportion of patients with amnestic mild cognitive impairment (aMCI) do not show evidence of amyloid deposition on Positron Emission Tomography (PET) with amyloid-binding tracers such as 11C-labeled Pittsburgh Compound B (PiB). OBJECTIVE: This study aimed to identify clinical, neuropsychological and neuroimaging factors that might suggest amyloid neuropathology in patients with clinically suspected AD or aMCI. METHODS: Forty patients with mild to moderate AD and 23 patients with aMCI who were clinically diagnosed in our memory clinic and had PiB PET scans were included. Clinical, neuropsychological, and imaging characteristics, such as Medial Temporal lobe Atrophy (MTA) and White Matter Hyperintensities (WMH) on MRI and metabolic pattern on 18F-labeled fluorodeoxyglucose (FDG) PET, were compared between patients with PiB positive and negative PET results for AD, aMCI, and all subjects combined, respectively. RESULTS: Compared with PiB positive patients, PiB negative patients had a higher prevalence of hypertension history, better performance on the Mini-Mental State Examination, the Rey Auditory Verbal Learning Test, and the Judgement of Line Orientation, lower score of MTA, and were less likely to have temporoparietal-predominant hypometabolism on FDG PET. Affective symptoms were less common in PiB negative patients diagnosed with AD, and the Animal Fluency Test score was higher in PiB negative patients diagnosed with aMCI. CONCLUSION: In patients with clinically diagnosed AD or aMCI, absence of a history of hypertension, deficits in verbal learning and memory, visuospatial function, semantic verbal fluency, presence of affective symptoms, MTA on MRI, and temporoparietal hypometabolism on FDG PET suggested amyloid deposition in the brain.

Progressive Multifocal Leukoencephalopathy in a Patient With Progressive Multiple Sclerosis Treated With Ocrelizumab Monotherapy.

Importance: Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection caused by the JC virus that has no proven effective treatment. Although rare cases of PML have occurred with other anti-CD20 therapies, there had been no prior cases associated with ocrelizumab. Objective: To report the first ever case of PML occurring with ocrelizumab monotherapy in a patient with progressive multiple sclerosis without prior immunomodulation. Design, Setting, and Participant: This case was reported from an academic medical center. The patient had multiple sclerosis while receiving ocrelizumab monotherapy. Exposures: Ocrelizumab monotherapy. Results: A 78-year-old man with progressive multiple sclerosis treated with ocrelizumab monotherapy for 2 years presented with 2 weeks of progressive visual disturbance and confusion. Examination demonstrated a right homonymous hemianopia, and magnetic resonance imaging revealed an enlarging nonenhancing left parietal lesion without mass effect. Cerebrospinal fluid revealed 1000 copies/mL of JC virus, confirming the diagnosis of PML. Blood work on diagnosis revealed grade 2 lymphopenia, with absolute lymphocyte count of 710/µL, CD4 of 294/µL (reference range, 325-1251/µL), CD8 of 85/µL (reference range, 90-775/µL), CD19 of 1/µL, preserved CD4/CD8 ratio (3.45), and negative HIV serology. Retrospective absolute lymphocyte count revealed intermittent grade 1 lymphopenia that preceded ocrelizumab (absolute lymphocyte count range, 800-1200/µL). The patient's symptoms progressed over weeks to involve bilateral visual loss, right-sided facial droop, and dysphasia. Ocrelizumab was discontinued and off-label pembrolizumab treatment was initiated. The patient nevertheless declined rapidly and ultimately died. PML was confirmed at autopsy. Conclusions and Relevance: In this case report, PML occurrence was likely a result of the immunomodulatory function of ocrelizumab as well as age-related immunosenescence. This case report emphasizes the importance of a thorough discussion of the risks and benefits of ocrelizumab, especially in patients at higher risk for infections such as elderly patients.

Parkinson's Disease With Visual Hallucinations Is Associated With Epileptiform Activity on EEG.

Background: Visual hallucinations (VHs) in Parkinson's disease (PD) are the cardinal symptoms which declare the onset of PD psychosis (PDP). The anthropomorphic and zoomorphic VHs of PD resemble those of Charles Bonnet syndrome and temporal lobe epilepsy. In both of these disorders electroencephalography (EEG) abnormalities have been described. We therefore sought to examine whether VHs in PD were associated with similar EEG abnormalities. Methods: This retrospective observational study searched the medical records of 300 PD patients and filtered for those containing clinical 20-min scalp EEGs. Remaining records were separated into two groups: patients with reported VHs and those without. The prevalence of epileptiform discharges in the EEGs of both groups was identified. Results: Epileptiform discharges were present in 5 of 13 (38.5%) PD patients with VHs; all localized to the temporal lobe. No epileptiform discharges were observed in the EEGs of the 31 PD patients without VHs. Conclusion: The significantly high incidence of temporal lobe epileptiform discharges in PD patients with VHs as compared to those without VHs lends to the possibility of an association visual cortex epileptogenic focus. Accordingly, for treatment-refractory patients, antiepileptic drugs might be considered, as in the case of Charles Bonnet syndrome, temporal lobe epilepsy and migraine with visual aura. Future prospective studies involving larger samples and multi-center cohorts are required to validate these observational findings.

Greater effect of polygenic risk score for Alzheimer's disease among younger cases who are apolipoprotein E-ε4 carriers.

To evaluate how age and apolipoprotein E-ε4 (APOE4) status interact with APOE-independent polygenic risk score (PRSnon-APOE), we estimated PRSnon-APOE in superagers (age ≥ 90 years, N = 346), 89- controls (age 60-89, N = 2930), and Alzheimer's disease (AD) cases (N = 1760). Using superagers, we see a nearly 5 times greater odds ratio (OR) for AD comparing the top PRSnon-APOE decile to the lowest decile (OR = 4.82, p = 2.5 × 10-6), which is twice the OR as using 89- controls (OR = 2.38, p = 4.6 × 10-9). Thus PRSnon-APOE is correlated with age, which in turn is associated with APOE. Further exploring these relationships, we find that PRSnon-APOE modifies age at onset among APOE4 carriers, but not among noncarriers. More specifically, PRSnon-APOE in the top decile predicts an age at onset 5 years earlier compared with the lowest decile (70.1 vs. 75.0 years; t-test p = 2.4 × 10-5) among APOE4 carriers. This disproportionally large PRSnon-APOE among younger APOE4-positive cases is reflected in a significant statistical interaction between APOE4 status and age at onset (ß = -0.02, p = 4.8 × 10-3) as a predictor of PRSnon-APOE. Thus, the known AD risk variants are particularly detrimental in young APOE4 carriers.

Elevated matrix metalloproteinase-9 levels in neuronal extracellular vesicles in Alzheimer's disease.

OBJECTIVE: This study aimed to investigate plasma neuronally derived extracellular vesicle (NDEV) levels of core pathological markers [amyloid-ß (Aß) and phosphorylated tau] and inflammatory biomarkers, including interleukin 6 (IL-6) and matrix metalloproteinase-9 (MMP-9) in patients with Alzheimer's disease (AD). METHODS: Thirty-one patients with AD and 15 cognitively normal controls (NCs) were recruited. The diagnosis of AD was supported by fluorodeoxyglucose and Pittsburgh Compound-B PET scans. Plasma extracellular vesicles were extracted, precipitated, and enriched for neuronal source by anti-L1CAM antibody absorption. Levels of Aß42, P-T181-tau, P-S396-tau, IL-6, and MMP-9 in plasma NDEVs were quantified by enzyme-linked immunosorbent assay (ELISA). RESULTS: Aß42, P-T181-tau, and MMP-9 levels in plasma NDEVs were significantly higher in patients with AD than NCs. However, P-S396-tau and IL-6 levels in plasma NDEVs did not differ between AD patients and NCs. Moreover, there was no correlation between any of these biomarker levels and cognitive function as measured with Mini-Mental State Examination in patients with AD. CONCLUSIONS: These findings provide further support that levels of core pathological markers, including Aß42 and P-T181-tau, are elevated in plasma NDEVs of patients with AD. Furthermore, MMP-9 might play an important role in the pathogenesis of AD, and is a promising inflammatory biomarker for AD.

TDP-43 Is Elevated in Plasma Neuronal-Derived Exosomes of Patients With Alzheimer's Disease.

BACKGROUND: Recently, TDP-43 has been recognized as a common proteinopathy in the "oldest old" and a neuropathological comorbidity in patients with Alzheimer's disease (AD). However, since it has a low concentration in cerebrospinal fluid, the presence of TDP-43 in AD is rarely investigated in vivo. METHODS: Twenty-four patients with amyloid PET confirmed AD and 15 healthy controls (HCs) were included in this study. TDP-43 level in plasma neuronal-derived exosomes (NDEs) was measured by enzyme-linked immunosorbent assay. RESULTS: TDP-43 level was elevated in patients with AD compared with HCs (median 1.08 ng/ml, IQR 0.72-1.37 ng/ml vs. median 0.66 ng/ml, IQR 0.48-0.76 ng/ml, P = 0.002). There was no correlation between TDP-43 level and cognitive function, neuropsychiatric symptoms or APOE genotype in patients with AD. CONCLUSION: This study demonstrated increased TDP-43 accumulation in AD patients by examining plasma NDEs, which may provide a window into the effects of TDP-43 on AD progression.

A multivariate metabolic imaging marker for behavioral variant frontotemporal dementia.

INTRODUCTION: The heterogeneity of behavioral variant frontotemporal dementia (bvFTD) calls for multivariate imaging biomarkers. METHODS: We studied a total of 148 dementia patients from the Feinstein Institute (Center-A: 25 bvFTD and 10 Alzheimer's disease), Technical University of Munich (Center-B: 44 bvFTD and 29 FTD language variants), and Alzheimer's Disease Neuroimaging Initiative (40 Alzheimer's disease subjects). To identify the covariance pattern of bvFTD (behavioral variant frontotemporal dementia-related pattern [bFDRP]), we applied principal component analysis to combined 18F-fluorodeoxyglucose-positron emission tomography scans from bvFTD and healthy subjects. The phenotypic specificity and clinical correlates of bFDRP expression were assessed in independent testing sets. RESULTS: The bFDRP was identified in Center-A data (24.1% of subject × voxel variance; P < .001), reproduced in Center-B data (P < .001), and independently validated using combined testing data (receiver operating characteristics-area under the curve = 0.97; P < .0001). The expression of bFDRP was specifically elevated in bvFTD patients (P < .001) and was significantly higher at more advanced disease stages (P = .035:duration; P < .01:severity). DISCUSSION: The bFDRP can be used as a quantitative imaging marker to gauge the underlying disease process and aid in the differential diagnosis of bvFTD.

Clinical efficacy and safety of donepezil in the treatment of Alzheimer's disease in Chinese patients.

Donepezil, an acetylcholinesterase inhibitor (AChEI), has been widely used to treat Alzheimer's disease (AD) in China. However, there are few studies focusing on the efficacy and safety of donepezil in Chinese patients. In this review, we discuss 1) the efficacy of donepezil and its comparison with other AChEIs or memantine, 2) the therapeutic responses to donepezil and its influencing factors, and 3) the safety and tolerability of donepezil in Chinese patients with different stages of AD and amnestic mild cognitive impairment, and further compare the similarities and differences of the results between Chinese studies and previous Western studies that predominantly enrolled Caucasian subjects. We include Chinese clinical trials and other well-designed studies investigating donepezil or using donepezil as a positive control, in which the efficacy and/or safety of donepezil have been analyzed. Based on these studies, donepezil has been shown to be effective and safe in Chinese AD patients and may impact AD biomarkers, such as hippocampal atrophy, Aß, and tau. In addition, the therapeutic response to donepezil may be influenced by apolipoprotein E or cytochrome P450 2D6 polymorphism.

The Age-Related Perfusion Pattern Measured With Arterial Spin Labeling MRI in Healthy Subjects.

Aim: To analyze age-related cerebral blood flow (CBF) using arterial spin labeling (ASL) MRI in healthy subjects with multivariate principal component analysis (PCA). Methods: 50 healthy subjects (mean age 45.8 ± 18.5 years, range 21-85) had 3D structural MRI and pseudo-continuous ASL MRI at resting state. The relationship between CBF and age was examined with voxel-based univariate analysis using multiple regression and two-sample t-test (median age 41.8 years as a cut-off). An age-related CBF pattern was identified using multivariate PCA. Results: Age correlated negatively with CBF especially anteriorly and in the cerebellum. After adjusting by global value, CBF was relatively decreased with aging in certain regions and relatively increased in others. The age-related CBF pattern showed relative reductions in frontal and parietal areas and cerebellum, and covarying increases in temporal and occipital areas. Subject scores of this pattern correlated negatively with age (R2 = 0.588; P < 0.001) and discriminated between the older and younger subgroups (P < 0.001). Conclusion: A distinct age-related CBF pattern can be identified with multivariate PCA using ASL MRI.

Neovascularization and Synaptic Function Regulation with Memantine and Rosuvastatin in a Rat Model of Chronic Cerebral Hypoperfusion.

Cerebral hypoperfusion is an important factor in the pathogenesis of cerebrovascular diseases and neurodegenerative disorders. We investigated the effects of memantine and rosuvastatin on both neovascularization and synaptic function in a rat model of chronic cerebral hypoperfusion, which was established by the bilateral common carotid occlusion (2VO) method. We tested learning and memory ability, synaptic function, circulating endothelial progenitor cell (EPC) number, expression of neurotrophic factors, and markers of neovasculogenesis and cell proliferation after memantine and/or rosuvastatin treatment. Rats treated with memantine and/or rosuvastatin showed significant improvement in Morris water maze task and long-term potentiation (LTP) in the hippocampus, compared with untreated 2VO model rats. Circulating EPCs, expression of brain-derived neurotrophic factor, and vascular endothelial growth factor, markers of microvessel density were increased by each of the three interventions. Rosuvastatin also increased cell proliferation in the hippocampus. Combined treatment with memantine and rosuvastatin showed greater effect on enhancement of LTP and expression of neurotrophic factors than either single medication treatment alone. Both memantine and rosuvastatin improved learning and memory, enhanced neovascularization and synaptic function, and upregulated neurotrophic factors in a rat model of chronic cerebral hypoperfusion.

Urine AD7c-NTP Predicts Amyloid Deposition and Symptom of Agitation in Patients with Alzheimer's Disease and Mild Cognitive Impairment.

BACKGROUND: Expression of neuronal thread protein (NTP), which is considered to be related to neuritic sprouting and neuronal death, may be elevated in brain tissue, cerebrospinal fluid, and even urine in patients with Alzheimer's disease (AD). OBJECTIVE: In this study, we analyzed the correlation between urine AD-associated NTP (AD7c-NTP) level, and amyloid-ß (Aß) deposition, and clinical symptoms in AD and mild cognitive impairment (MCI). METHODS: Twenty-two patients with mild to moderate AD and 8 subjects with MCI were recruited. Aß deposition was measured with [11C]-labeled Pittsburgh compound B (PiB)-positron emission tomography (PET) in all participants. Urine AD7c-NTP levels were measured using enzyme-linked immunosorbent assay. Mini-Mental State Examination (MMSE) and Neuropsychiatric Inventory (NPI) were used to evaluate cognitive function and behavioral psychological symptoms, respectively. RESULTS: Fourteen (63.6%) of AD patients and 2 (25.0%) of MCI subjects were Aß positive on PiB-PET. There was a significant difference in urine AD7c-NTP level between Aß positive (2.27±2.22 ng/ml) and negative (0.55±0.60 ng/ml) subjects (p = 0.018). Using 1.46 ng/ml as a cut-off value, 68.8% of Aß positive subjects showed elevated urine AD7c-NTP level, and 92.9% of Aß negative subjects showed normal urine AD7c-NTP level. There were no relationships between urine AD7c-NTP level and MMSE and total NPI scores. However, AD7c-NTP level positively correlated with agitation score on NPI. CONCLUSIONS: Urine AD7c-NTP had high specificity and moderate sensitivity in predicting Aß deposition among patients with cognitive impairment. Furthermore, urine AD7c-NTP level strongly correlated with the symptom of agitation.

Cerebral blood flow measured by arterial spin labeling MRI at resting state in normal aging and Alzheimer's disease.

Arterial spin labeling (ASL) magnetic resonance imaging uses arterial blood water as an endogenous tracer to measure cerebral blood flow (CBF). In this review, based on ASL studies in the resting state, we discuss state-of-the-art technical and data processing improvements in ASL, and ASL CBF changes in normal aging, mild cognitive impairment (MCI), Alzheimer's disease (AD), and other types of dementia. We propose that vascular and AD risk factors should be considered when evaluating CBF changes in aging, and that other validated biomarkers should be used as inclusion criteria or covariates when evaluating CBF changes in MCI and AD. With improvements in hardware and experimental design, ASL is proving to be an increasingly promising tool for exploring pathogenetic mechanisms, early detection, monitoring disease progression and pharmacological response, and differential diagnosis of AD.

Distinct brain networks underlie cognitive dysfunction in Parkinson and Alzheimer diseases.

OBJECTIVE: To determine whether cognitive impairment in Parkinson disease (PD) and Alzheimer disease (AD) derives from the same network pathology. METHODS: We analyzed 18F-fluorodeoxyglucose PET scans from 40 patients with AD and 40 age-matched healthy controls from the Alzheimer's Disease Neuroimaging Initiative and scanned an additional 10 patients with AD and 10 healthy controls at The Feinstein Institute for Medical Research to derive an AD-related metabolic pattern (ADRP) analogous to our previously established PD cognition-related pattern (PDCP) and PD motor-related pattern (PDRP). We computed individual subject expression values for ADRP and PDCP in 89 patients with PD and correlated summary scores for cognitive functioning with network expression. We also evaluated changes in ADRP and PDCP expression in a separate group of 15 patients with PD scanned serially over a 4-year period. RESULTS: Analysis revealed a significant AD-related metabolic topography characterized by covarying metabolic reductions in the hippocampus, parahippocampal gyrus, and parietal and temporal association regions. Expression of ADRP, but not PDCP, was elevated in both AD groups and correlated with worse cognitive summary scores. Patients with PD showed slight ADRP expression, due to topographic overlap with the network underlying PD motor-related pattern degeneration, but only their PDCP expression values increased as cognitive function and executive performance declined. Longitudinal data in PD disclosed an analogous dissociation of network expression. CONCLUSIONS: Cognitive dysfunction in PD is associated with a specific brain network that is largely spatially and functionally distinct from that seen in relation to AD.

The Relational and Item-Specific Encoding Task in Mild Cognitive Impairment and Alzheimer Disease.

BACKGROUND: The Relational and Item-Specific Encoding task (RISE) measures episodic memory subcomponents, including item-specific and relational encoding of to-be-remembered stimuli. These memory components are neurobiologically relevant because they may engage distinct subregions of the medial temporal lobe, perirhinal and entorhinal cortices, parahippocampus, and hippocampus. METHODS: A total of 125 participants, including 84 healthy controls (HC), 22 mild cognitive impairment-diagnosed and 19 Alzheimer disease (AD)-diagnosed participants, were administered the RISE and neuropsychological measures. Stepwise linear regressions assessed prediction of functional ability from RISE d' measures. ANOVAs and logistic regressions determined the ability of the RISE to discriminate between the diagnostic groups. In addition, the psychometric properties of the RISE were examined. RESULTS: RISE measures predicted diagnosis with pseudo R2 values in the range of 0.25-0.30. Receiver operating characteristic curves demonstrated adequate sensitivity and specificity with areas under the curve in the range of 0.78-0.98. Memory following relational encoding was a significant predictor of everyday functional competence. The RISE had acceptable psychometric properties, with the exception of floor effects in the AD group. CONCLUSION: The RISE measures significantly predicted diagnosis and predicted everyday functional competence. The RISE offers unique advantages in the assessment of HC and individuals with preclinical AD.