Diagnostic evaluation and monitoring of patients with posterior cortical atrophy.

Posterior cortical atrophy (PCA) is a progressive neurocognitive syndrome, most commonly associated with the loss of complex visuospatial functions. Diagnosis is challenging, and international consensus classification and nomenclature for PCA subtypes have only recently been reached. Presently, no established treatments exist.

Associations between baseline amyloid, sex, and APOE on subsequent tau accumulation in cerebrospinal fluid.

We investigated the effect of baseline Aβ, sex, and APOE on longitudinal tau accumulation in cerebrospinal fluid (CSF) in clinically normal older adults. Two hundred thirty-nine participants (aged 56-89 years, clinical dementia rating = 0) underwent serial CSF collection for Aβ, total-tau (t-tau) and phospho-tau (p-tau). We used preprocessed data from fully automated Roche Elecsys immunoassays.

Measuring instrumental activities of daily living in non-demented elderly: a comparison of the new performance-based Harvard Automated Phone Task with other functional assessments.

Background: Impairment in instrumental activities of daily living (IADL) may occur in the earliest stages of mild cognitive impairment (MCI). However, there are few reliable measures of IADL in MCI or that have a sufficient range of scores in clinically normal (CN) elderly. The objective of this pilot study was to examine the convergent validity of a phone performance-based IADL instrument, the Harvard Automated Phone Task (APT), designed to measure the earliest IADL changes in Alzheimer's disease (AD), with other sensitive performance-based and subjective measures of everyday functional capacity among CN and MCI participants.

Cerebrospinal fluid biomarkers predict frontotemporal dementia trajectory.

Objective: The prognostic value of cerebrospinal fluid neurofilament light chain, total tau, phosphorylated tau, and amyloid beta was examined in frontotemporal dementia subtypes.

Methods: We compared baseline biomarkers between 49 controls, 40 patients with behavioral variant frontotemporal dementia, 24 with semantic variant primary progressive aphasia, and 26 with nonfluent variant primary progressive aphasia. Linear mixed effect models were used to assess the value of baseline biomarkers in predicting clinical and radiographic change in patient cohorts over multiple yearly follow up visits.

Prevalence of amyloid-β pathology in distinct variants of primary progressive aphasia.

Objective: To estimate the prevalence of amyloid positivity, defined by positron emission tomography (PET)/cerebrospinal fluid (CSF) biomarkers and/or neuropathological examination, in primary progressive aphasia (PPA) variants.

Methods: We conducted a meta-analysis with individual participant data from 1,251 patients diagnosed with PPA (including logopenic [lvPPA, n = 443], nonfluent [nfvPPA, n = 333], semantic [svPPA, n = 401], and mixed/unclassifiable [n = 74] variants of PPA) from 36 centers, with a measure of amyloid-β pathology (CSF [n = 600], PET [n = 366], and/or autopsy [n = 378]) available. The estimated prevalence of amyloid positivity according to PPA variant, age, and apolipoprotein E (ApoE) ε4 status was determined using generalized estimating equation models.

Challenges associated with biomarker-based classification systems for Alzheimer's disease.

Introduction: We aimed to evaluate the consistency of the A/T/N classification system.

Methods: We included healthy controls, mild cognitive impairment, and dementia patients from Alzheimer's disease Neuroimaging Initiative. We assessed subject classification consistency with different biomarker combinations and the agreement and correlation between biomarkers.

The personalized Alzheimer's disease cortical thickness index predicts likely pathology and clinical progression in mild cognitive impairment.

Introduction: An Alzheimer's disease (AD) biomarker adjusted for age-related brain changes should improve specificity for AD-related pathological burden.

Methods: We calculated a brain-age-adjusted "personalized AD cortical thickness index" (pADi) in mild cognitive impairment patients from the Alzheimer's Disease Neuroimaging Initiative. We performed receiver operating characteristic analysis for discrimination between patients with and without cerebrospinal fluid evidence of AD and logistic regression in an independent sample to determine if a dichotomized pADi predicted conversion to AD dementia.

Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums.

Considerable overlap has been identified in the risk factors, comorbidities and putative pathophysiological mechanisms of Alzheimer disease and related dementias (ADRDs) and type 2 diabetes mellitus (T2DM), two of the most pressing epidemics of our time. Much is known about the biology of each condition, but whether T2DM and ADRDs are parallel phenomena arising from coincidental roots in ageing or synergistic diseases linked by vicious pathophysiological cycles remains unclear. Insulin resistance is a core feature of T2DM and is emerging as a potentially important feature of ADRDs.

Clinical outcomes in older surgical patients with mild cognitive impairment.

Introduction: Older adults, including those with mild cognitive impairment (MCI), are increasingly undergoing surgery.

Methods: Relative risks (RRs) of MCI alone or with delirium on adverse outcomes were estimated in an ongoing prospective, observational cohort study of 560 nondemented adults aged ≥70 years.

Results: MCI (n = 61, 11%) was associated with increased RR of delirium (RR = 1.

Activities of daily living measured by the Harvard Automated Phone Task track with cognitive decline over time in non-demented elderly.

Background: Impairment in activities of daily living is a major burden to both patients and caregivers. Mild impairment in instrumental activities of daily living is often seen at the stage of mild cognitive impairment. The field of Alzheimer's disease is moving toward earlier diagnosis and intervention and more sensitive and ecologically valid assessments of instrumental or complex activities of daily living are needed.

Context is everything: From cardiovascular disease to cerebral microbleeds.

Increasingly, our approach to cerebrovascular disease has become blurred by evidence published in literature often without careful consideration of what this evidence implies for specific patients at hand. In this essay, we analyze key contextual issues in cerebrovascular small vessel disease, in an attempt to highlight the symbolic gap that exists between research and clinical practice, a recurring theme in medicine. We highlight the importance of considering context when using data from epidemiologic, neuroimaging, and biomarker studies in determining relevance to the patient at hand.

Risk Factors, Neuroanatomical Correlates, and Outcome of Neuropsychiatric Symptoms in Alzheimer's Disease.

Background: An integrative model of neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) is lacking.

Objective: In this study, we investigated the risk factors, anatomy, biology, and outcomes of NPS in AD.

Methods: 181 subjects were included from the Alzheimer's Disease Neuroimaging Study (ADNI).

Alzheimer's-related cortical atrophy is associated with postoperative delirium severity in persons without dementia.

Patients with dementia due to Alzheimer's disease (AD) have increased risk of developing delirium. This study investigated the relationship between a magnetic resonance imaging (MRI)-derived biomarker associated with preclinical AD and postoperative delirium. Participants were older adults (≥70 years) without dementia who underwent preoperative MRI and elective surgery.

Effects of cognitive reserve depend on executive and semantic demands of the task.

Background: Cognitive reserve (CR) is one factor that helps to maintain cognitive function in patients with Alzheimer's disease (AD). Whether the effects of CR depend on the semantic/executive components of the task remains unknown.

Methods: 470 patients (138 with AD, 332 with mild cognitive impairment (MCI)) were selected from the Alzheimer's Disease Neuroimaging Initiative database.

Endosulfine-alpha inhibits membrane-induced α-synuclein aggregation and protects against α-synuclein neurotoxicity.

Neuropathological and genetic findings suggest that the presynaptic protein α-synuclein (aSyn) is involved in the pathogenesis of synucleinopathy disorders, including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy. Evidence suggests that the self-assembly of aSyn conformers bound to phospholipid membranes in an aggregation-prone state plays a key role in aSyn neurotoxicity. Accordingly, we hypothesized that protein binding partners of lipid-associated aSyn could inhibit the formation of toxic aSyn oligomers at membrane surfaces.

Amyloid structure exhibits polymorphism on multiple length scales in human brain tissue.

Aggregation of Aβ amyloid fibrils into plaques in the brain is a universal hallmark of Alzheimer's Disease (AD), but whether plaques in different individuals are equivalent is unknown. One possibility is that amyloid fibrils exhibit different structures and different structures may contribute differentially to disease, either within an individual brain or between individuals. However, the occurrence and distribution of structural polymorphisms of amyloid in human brain is poorly documented.

Retinal blood flow in mild cognitive impairment and Alzheimer's disease.

Background: Patients with Alzheimer's disease (AD) demonstrate the narrowing of retinal veins and decreased retinal venous blood flow compared with control subjects. We assessed whether these abnormalities are present in patients with mild cognitive impairment (MCI).

Methods: After the determination of the global clinical dementia rating, 52 subjects (10 AD, 21 MCI, and 21 normal controls) underwent retinal hemodynamic profiling.

The Harvard Automated Phone Task: new performance-based activities of daily living tests for early Alzheimer's disease.

Background: Impairment in activities of daily living is a major burden for Alzheimer's disease dementia patients and caregivers. Multiple subjective scales and a few performance-based instruments have been validated and proven to be reliable in measuring instrumental activities of daily living in Alzheimer's disease dementia but less so in amnestic mild cognitive impairment and preclinical Alzheimer's disease.

Objective: To validate the Harvard Automated Phone Task, a new performance-based activities of daily living test for early Alzheimer's disease, which assesses high level tasks that challenge seniors in daily life.

Multisite assessment of NIA-AA guidelines for the neuropathologic evaluation of Alzheimer's disease.

Introduction: Neuropathologic assessment is the current "gold standard" for evaluating the Alzheimer's disease (AD), but there is no consensus on the methods used.

Methods: Fifteen unstained slides (8 brain regions) from each of the 14 cases were prepared and distributed to 10 different National Institute on Aging AD Centers for application of usual staining and evaluation following recently revised guidelines for AD neuropathologic change.

Results: Current practice used in the AD Centers Program achieved robustly excellent agreement for the severity score for AD neuropathologic change (average weighted κ = .

Use of the Progressive Aphasia Severity Scale (PASS) in monitoring speech and language status in PPA.

Background: Primary progressive aphasia (PPA) is a devastating neurodegenerative syndrome involving the gradual development of aphasia, slowly impairing the patient's ability to communicate. Pharmaceutical treatments do not currently exist and intervention often focuses on speech-language behavioral therapies, although further investigation is warranted to determine how best to harness functional benefits. Efforts to develop pharmaceutical and behavioral treatments have been hindered by a lack of standardized methods to monitor disease progression and treatment efficacy.

Template based rotation: a method for functional connectivity analysis with a priori templates.

Functional connectivity magnetic resonance imaging (fcMRI) is a powerful tool for understanding the network level organization of the brain in research settings and is increasingly being used to study large-scale neuronal network degeneration in clinical trial settings. Presently, a variety of techniques, including seed-based correlation analysis and group independent components analysis (with either dual regression or back projection) are commonly employed to compute functional connectivity metrics. In the present report, we introduce template based rotation,(1) a novel analytic approach optimized for use with a priori network parcellations, which may be particularly useful in clinical trial settings.

Subjective cognitive concerns and neuropsychiatric predictors of progression to the early clinical stages of Alzheimer disease.

Objective: To examine neuropsychiatric and neuropsychological predictors of progression from normal to early clinical stages of Alzheimer disease (AD).

Methods: From a total sample of 559 older adults from the Massachusetts Alzheimer's Disease Research Center longitudinal cohort, 454 were included in the primary analysis: 283 with clinically normal cognition (CN), 115 with mild cognitive impairment (MCI), and 56 with subjective cognitive concerns (SCC) but no objective impairment, a proposed transitional group between CN and MCI. Two latent cognitive factors (memory-semantic, attention-executive) and two neuropsychiatric factors (affective, psychotic) were derived from the Alzheimer's Disease Centers' Uniform Data Set neuropsychological battery and Neuropsychiatric Inventory brief questionnaire.

Regional cortical thinning and cerebrospinal biomarkers predict worsening daily functioning across the Alzheimer's disease spectrum.

Background: Impairment in instrumental activities of daily living (IADL) heralds the transition from mild cognitive impairment (MCI) to dementia and is a major source of burden for both the patient and caregiver.

Objective: To investigate the relationship between IADL and regional cortical thinning and cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers cross-sectionally and longitudinally in clinically normal (CN) elderly, MCI, and mild AD dementia subjects.

Methods: Two hundred and twenty nine CN, 395 MCI, and 188 AD dementia subjects participating in the Alzheimer's Disease Neuroimaging Initiative underwent baseline magnetic resonance imaging, baseline lumbar puncture, and clinical assessments, including the Functional Activities Questionnaire used to measure IADL, every 6 to 12 months up to 3 years.

Biomarker-based prediction of progression in MCI: Comparison of AD signature and hippocampal volume with spinal fluid amyloid-β and tau.

Objective: New diagnostic criteria for mild cognitive impairment (MCI) due to Alzheimer's disease (AD) have been developed using biomarkers aiming to establish whether the clinical syndrome is likely due to underlying AD. We investigated the utility of magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) biomarkers in predicting progression from amnesic MCI to dementia, testing the hypotheses that (1) markers of amyloid and neurodegeneration provide distinct and complementary prognostic information over different time intervals, and that (2) evidence of neurodegeneration in amyloid-negative MCI individuals would be useful prognostically.

Methods: Data were obtained from the ADNI-1 (Alzheimer's Disease Neuroimaging Initiative Phase 1) database on all individuals with a baseline diagnosis of MCI, baseline MRI and CSF data, and at least one follow-up visit.