The neuropsychological profile of Alzheimer disease.

Vulnerable Neural Systems and the Borderland of Brain Aging and Neurodegeneration

Intrinsic Connectivity Identifies the Hippocampus as a Main Crossroad between Alzheimer’s and Semantic Dementia-Targeted Networks

A Case of Frontotemporal Lobar Degeneration (FTLD) With Panic Attack as the First Symptom

Mild cognitive impairment (MCI) is defined as a pathological stage between 'healthy aging' and 'dementia' In this study, cases of MCI were compared with early-stage Alzheimer disease (AD) and age-related cognitive decline (ARCD) in terms of cognitive profiles in order to find a connection between MCI and AD. Patients who were comparable in terms of age and sex and who met the criteria of MCI, ARCD, or early-stage AD were included in the study retrospectively. Wechsler memory scale, executive function, visuospatial, language, and memory tests were applied to all subjects. Additionally, all patients completed a mini-mental state examination test, geriatric depression scale, and activities of daily living scale. Complex attention tests and long-term memory tests were more impaired in MCI patients when compared with ARCD. However, there were no significant differences between the MCI and ARCD cases in activities of daily living. Memory and executive functions were more deteriorated in patients with AD in comparison to MCI. During the follow-up period of ARCD, impairment in orientation, complex attention, and long-term memory should suggest the diagnosis of MCI. When personal information and executive functions are affected in MCI, AD should be carefully considered.

Enrichment of C-Terminal Fragments in TAR DNA-Binding Protein-43 Cytoplasmic Inclusions in Brain but not in Spinal Cord of Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis

Mild cognitive impairment and subjective cognitive impairment

Differences in cognition between frontotemporal dementia (FTD) and Alzheimer disease (AD) are well described in clinical cohorts, but have rarely been confirmed in studies with pathologic verification. For emerging therapeutics to succeed, determining underlying pathology early in the disease course is increasingly important. Neuropsychological evaluation is an important component of the diagnostic workup for AD and FTD. Patients with FTD are thought to have greater deficits in language and executive function while patients with AD are more likely to have deficits in memory. To determine if performance on initial cognitive testing can reliably distinguish between patients with frontotemporal lobar degeneration (FTLD) and AD neuropathology. In addition, are there other factors of the neuropsychological assessment that can be used to enhance the accuracy of underlying pathology? Using a logistic regression we retrospectively compared neurocognitive performance on initial evaluation of 106 patients with pathologically verified FTLD (pvFTLD), with 558 pathologically verified AD (pvAD) patients from the National Alzheimer's Coordinating Center using data from the Uniform Data Set (UDS) and the neuropathology data set. As expected, pvFTLD patients were younger, demonstrated better memory performance, and had more neuropsychiatric symptoms than pvAD patients. Other results were less predictable: pvFTLD patients performed better on one test of executive function (trail making test part B) but worse on another (digit span backward). Performance on language testing did not strongly distinguish the 2 groups. To determine what factors led to a misdiagnosis of AD in patients with FTLD, we further analyzed a small group of pvFTLD patients. These patients demonstrated older age and lower Neuropsychiatric Inventory Questionnaire counts compared with accurately diagnosed cases. Other than memory, numerical scores of neurocognitive performance on the UDS are of limited value in differentiating FTLD from AD at the initial visit. These results highlight the difficulty of obtaining an accurate early diagnosis of FTLD and argue for adding supplemental tests to those included in the UDS to assess cognition in FTD and AD patients.

Dementia, also now known as major neurocognitive disorder, is a syndrome involving decline in two or more areas of cognitive function sufficient to disrupt a person’s daily function. Mild cognitive impairment (MCI), also known as minor neurocognitive disorder, represents a syndrome on the continuum of cognitive decline that is a stage prior to development of functional deficits. It involves decline in one or more areas of cognitive function with independence in instrumental activities of daily living, even though they may require greater effort or compensation on the part of the individual. Neuropsychological assessment of cognition and behavior provides the most powerful biomarkers for MCI and dementia syndromes associated with neurodegenerative diseases. Discrete cognitive and behavioral patterns that occur early in the course of cognitive decline aids in differential clinical diagnosis. Additionally, all diagnostic schemes for dementia syndromes include criteria that require the appraisal of functional status, which tests an individual’s capacity to engage in decision making and carry out activities of daily living independently. Methods for assessing functional status have historically had poor reliability and validity. Nevertheless, in a clinical setting, neuropsychologists rely on a combination of self-report, collateral informants, caregiver questionnaires, and objective performance-based measures to better assess functional status. Revisions to clinical criteria for dementia reflect the adoption of new research diagnostic criteria for neurodegenerative diseases, largely driven by the National Institutes of Aging (NIA) and the Alzheimer’s Association 2011 research criteria for Alzheimer’s disease (AD). The new approach differentiates the syndromic presentations common to most neurodegenerative diseases from the etiologies (AD, LBD, VaD, etc.) based on biomarkers. In the preclinical stage, biomarker abnormalities are present years before clinical symptom manifestation. In mild cognitive impairment stage, there is a report/concern for cognitive change by the patient, informant, or clinician. There is objective cognitive decline from estimated premorbid functioning and preserved independence in functional abilities. In the dementia stage, in the context of impaired functional status, there may be prominent cognitive and behavioral symptoms that may involve impairment in memory, executive function, visuospatial functioning, and language, as well as changes in personality and behavior. The most common dementias are AD, dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), and vascular dementia (VaD). All can follow a trajectory of cognitive decline similar to the aforementioned stages and are associated with neuropathogenic mechanisms that may or may not be distinctive for a particular syndrome. Briefly, Alzheimer’s dementia is associated with accumulation of amyloid plaques and tau neurofibrillary tangles. Lewy body dementias (i.e., Parkinson’s disease dementia and DLB) are characterized by Lewy bodies (alpha-synuclein aggregates) and Lewy neurites in the brainstem, limbic system, and cortical regions; DLB is also associated with diffuse amyloid plaques. Frontotemporal dementia is a conglomerate of syndromes that may overlap and include behavioral variant FTD, semantic dementia, and primary progressive aphasia (PPA). FTD dementia syndromes are marked by frontotemporal lobar degeneration (FTLD) caused by pathophysiological processes involving FTLD-tau, FTLD-TDP, FTLD-FUS, or their combination, as well as beta amyloid. Lastly, vascular dementia is associated with cerebrovascular disease that can include large artery occlusions, microinfarcts, brain hemorrhages, and silent brain infarcts; comorbid AD pathology may lower the threshold for dementia conversion. There is an emerging shift in the field toward exploring prevention strategies for dementia. Given the lack of precision in our language regarding the distinction between dementia syndromes and etiologies, we can reallocate some of our efforts to preventing dementia more broadly rather than intervening on a certain pathology. Research already supports that many individuals have biomarker evidence of brain pathology without showing cognitive impairment or even sufficient levels of pathology in the brain to warrant a diagnosis without ever displaying the clinical syndrome of dementia. That said, building cognitive reserve or resilience through lifestyle and behavioral factors may slow the rate of cognitive decline and prevent the risk of a future dementia epidemic.

Do sleep complaints contribute to age-related cognitive decline?

A comprehensive investigation of the associations between tensor-based morphometry indices and executive functions, memory, language, and visuospatial abilities in patients in the Alzheimer's disease continuum

New unexpected role for Wolfram Syndrome protein WFS1: a novel therapeutic target for Alzheimer's disease?

Frontotemporal lobar degeneration (FTLD) includes different heterogeneous conditions, mainly characterised by personality changes, along with cognitive deficits in language and executive functions. Movement disorders are variably represented. Behavioural disturbances constitute...

BackgroundThere is initial evidence suggesting that biomarker neurogranin (Ng) may distinguish Alzheimer’s disease (AD) from other neurodegenerative diseases. Therefore, we assessed (a) the discriminant ability of cerebrospinal fluid (CSF) Ng levels to distinguish between AD and frontotemporal lobar degeneration (FTLD) pathology and between different stages within the same disease, (b) the relationship between Ng levels and cognitive performance in both AD and FTLD pathology, and (c) whether CSF Ng levels vary by apolipoprotein E (APOE) polymorphism in the AD continuum.MethodsParticipants with subjective cognitive decline (SCD) (n = 33), amnestic mild cognitive impairment (aMCI) due to AD (n = 109), AD dementia (n = 67), MCI due to FTLD (n = 25), and FTLD dementia (n = 29) were recruited from the Czech Brain Aging Study. One-way analysis of covariance (ANCOVA) assessed Ng levels in diagnostic subgroups. Linear regressions evaluated the relationship between CSF Ng levels, memory scores, and APOE polymorphism.ResultsNg levels were higher in aMCI-AD patients compared to MCI-FTLD (F[1, 134] = 15.16, p < .001), and in AD-dementia compared to FTLD-dementia (F[1, 96] = 4.60, p = .029). Additionally, Ng levels were higher in FTLD-dementia patients compared to MCI-FTLD (F[1, 54]= 4.35, p = .034), lower in SCD participants compared to aMCI-AD (F[1, 142] = 10.72, p = .001) and AD-dementia (F[1, 100] = 20.90, p < .001), and did not differ between SCD participants and MCI-FTLD (F[1, 58]= 1.02, p = .491) or FTLD-dementia (F[1, 62]= 2.27, p = .051). The main effect of diagnosis across the diagnostic subgroups on Aβ1−42/Ng ratio was significant too (F[4, 263]=, p < .001). We found a non-significant association between Ng levels and memory scores overall (β=-0.25, p = .154) or in AD diagnostic subgroups, and non-significant differences in this association between overall AD APOE ε4 carriers and non-carriers (β=-0.32, p = .358).ConclusionsIn this first study to-date to assess MCI and dementia due to AD or FTLD within one study, elevated CSF Ng appears to be an early biomarker of AD-related impairment, but its role as a biomarker appears to diminish after dementia diagnosis, whereby dementia-related underlying processes in AD and FTLD may begin to merge. The Aβ1−42/Ng ratio discriminated AD from FTLD patients better than Ng alone. CSF Ng levels were not related to memory in AD or FTLD, suggesting that Ng may be a marker of the biological signs of disease state rather than cognitive deficits.

With the aging population rapidly increasing worldwide, preventive measures and treatments for age-related cognitive decline and dementia are of utmost importance. We have previously demonstrated that the consumption of iso-α-acids (IAA), which are hop-derived bitter compounds in beer, prevents the formation of disease pathology in a transgenic mouse model of Alzheimer’s disease (AD). However, the effect of IAA consumption on age-related cognitive decline is unknown. In the present study, we examined the effect of long-term and short-term dietary consumption of IAA, on age-related memory impairments and inflammation in the hippocampus of aged mice. When compared with young mice, aged mice showed impairment in spatial working memory during the Y-maze spontaneous alternation test, impairment in object recognition memory during the novel object recognition test (NORT), a pro-inflammatory hippocampal microglial phenotype with increased CD86 expression and inflammatory cytokine production, increased levels of glutamate and amyloid β1–42, and decreased levels of dopamine (DA). In aged mice fed IAA for 3 months, the age-related alterations in memory, microglial inflammation, and glutamate, amyloid β1–42, and DA levels were all significantly attenuated. Additionally, the oral administration of IAA for 7 days in aged mice with memory impairment, also improved spatial and object recognition memory. These results suggest that IAA consumption prevents inflammation in the hippocampus and ameliorates age-related cognitive decline.

Objective:To identify genetic risk factors associated with susceptibility to age-related cognitive decline in African Americans (AAs).Methods:We performed a genome-wide association study (GWAS) and an admixture-mapping scan in 3,964 older AAs from 5 longitudinal cohorts; for each participant, we calculated a slope of an individual's global cognitive change from neuropsychological evaluations. We also performed a pathway-based analysis of the age-related cognitive decline GWAS.Results:We found no evidence to support the existence of a genomic region which has a strongly different contribution to age-related cognitive decline in African and European genomes. Known Alzheimer disease (AD) susceptibility variants in the ABCA7 and MS4A loci do influence this trait in AAs. Of interest, our pathway-based analyses returned statistically significant results highlighting a shared risk from lipid/metabolism and protein tyrosine signaling pathways between cognitive decline and AD, but the role of inflammatory pathways is polarized, being limited to AD susceptibility.Conclusions:The genetic architecture of aging-related cognitive in AA individuals is largely similar to that of individuals of European descent. In both populations, we note a surprising lack of enrichment for immune pathways in the genetic risk for cognitive decline, despite strong enrichment of these pathways among genetic risk factors for AD.