APOE ε4 influences cognitive decline positively in APP and negatively in PSEN1 mutation carriers with autosomal-dominant Alzheimer's disease.

BACKGROUND AND PURPOSE: The aim was to investigate the effect of APOE ε4 allele on cognitive decline in adAD. Presence of the APOE ε4 allele reduces age of symptom onset, increases disease progression, and lowers cognitive performance in sporadic Alzheimer's disease (AD), while the impact of the APOE ε4 allele in autosomal-dominant AD (adAD) is incompletely known. METHODS: Mutation carriers (MCs; n = 39) and non-carriers (NCs; n = 40) from six adAD families harbouring a mutation in the APP (28 MCs and 25 NCs) or the PSEN1 genes (11 MCs and 15 NCs) underwent repeated cognitive assessments. A timeline of disease course was defined as years to expected age of clinical onset (YECO) based on history of disease onset in each family. The MC and NC groups were comparable with regard to demographics and prevalence of the APOE ε4 allele. The relationship between cognitive decline and YECO, YECO2 , education, APOE, and APOE-by-YECO interaction was analysed using linear mixed-effects models. RESULTS: The trajectory of cognitive decline was significantly predicted by linear and quadratic YECO and education in MCs and was determined by age and education in NCs. Adding APOE ε4 allele (presence/absence) as a predictor did not change the results in the MC and NC groups. The outcome also remained the same for MCs and NCs after adding the APOE-by-YECO interaction as a predictor. Analyses of APP and PSEN1 MCs separately showed favourable APOE-by-YECO interaction in APP (less steep decline) and unfavourable interaction in PSEN1 (steeper decline), linked to the APOE ε4 allele. CONCLUSION: The APOE ε4 allele influences cognitive decline positively in APP and negatively in PSEN1 mutation carriers with adAD, indicating a possible antagonistic pleiotropy.

Tau PET imaging in neurodegenerative tauopathies-still a challenge.

The accumulation of pathological misfolded tau is a feature common to a collective of neurodegenerative disorders known as tauopathies, of which Alzheimer's disease (AD) is the most common. Related tauopathies include progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), Down's syndrome (DS), Parkinson's disease (PD), and dementia with Lewy bodies (DLB). Investigation of the role of tau pathology in the onset and progression of these disorders is now possible due the recent advent of tau-specific ligands for use with positron emission tomography (PET), including first- (e.g., [18F]THK5317, [18F]THK5351, [18F]AV1451, and [11C]PBB3) and second-generation compounds [namely [18F]MK-6240, [18F]RO-948 (previously referred to as [18F]RO69558948), [18F]PI-2620, [18F]GTP1, [18F]PM-PBB3, and [18F]JNJ64349311 ([18F]JNJ311) and its derivative [18F]JNJ-067)]. In this review we describe and discuss findings from in vitro and in vivo studies using both initial and new tau ligands, including their relation to biomarkers for amyloid-ß and neurodegeneration, and cognitive findings. Lastly, methodological considerations for the quantification of in vivo ligand binding are addressed, along with potential future applications of tau PET, including therapeutic trials.

Subjective working and declarative memory in dementia and normal aging.

OBJECTIVE: Subjective memory complaints are common in both elderly individuals and patients with dementia. This study investigated the power of subjective memory, divided into declarative and working memory, to differentiate between patients with dementia and normal elderly individuals. METHOD: Two groups of participants, patients with dementia (n = 117) and normal elderly individuals (n = 117), individually matched with regard to age, gender, and education. All subjects had participated in the third wave of the HUNT population health survey in Nord-Trøndelag County in Norway and completed the Meta-Memory Questionnaire (MMQ) in the HUNT study. The MMQ was subdivided into two components, one associated with declarative memory (episodic and semantic) and the other with working memory. RESULTS: Patients with dementia reported significantly more subjective memory concerns than normal elderly individuals. The difference between working and declarative memory components was significantly greater in patients with dementia than in normal elderly individuals. This finding made it possible to differentiate patients with dementia from the normal elderly individuals. Mental and somatic health conditions did not significantly add power to differentiating the two groups. CONCLUSION: In clinical and research applications, subjective memory components could contribute to differentiation of patients with dementia and normal elderly individuals by using self-reported impairment in working memory, rather than declarative memory.

Dual tracer tau PET imaging reveals different molecular targets for 11C-THK5351 and 11C-PBB3 in the Alzheimer brain.

PURPOSE: Several tau PET tracers have been developed, but it remains unclear whether they bind to the same molecular target on the heterogeneous tau pathology. In this study we evaluated the binding of two chemically different tau-specific PET tracers (11C-THK5351 and 11C-PBB3) in a head-to-head, in vivo, multimodal design. METHODS: Nine patients with a diagnosis of mild cognitive impairment or probable Alzheimer's disease and cerebrospinal fluid biomarker evidence supportive of the presence of Alzheimer's disease brain pathology were recruited after thorough clinical assessment. All patients underwent imaging with the tau-specific PET tracers 11C-THK5351 and 11C-PBB3 on the same day, as well as imaging with the amyloid-beta-specific tracer 11C-AZD2184, a T1-MRI sequence, and neuropsychological assessment. RESULTS: The load and regional distribution of binding differed between 11C-THK5351 and 11C-PBB3 with no statistically significant regional correlations observed between the tracers. The binding pattern of 11C-PBB3, but not that of 11C-THK5351, in the temporal lobe resembled that of 11C-AZD2184, with strong correlations detected between 11C-PBB3 and 11C-AZD2184 in the temporal and occipital lobes. Global cognition correlated more closely with 11C-THK5351 than with 11C-PBB3 binding. Similarly, cerebrospinal fluid tau measures and entorhinal cortex thickness were more closely correlated with 11C-THK5351 than with 11C-PBB3 binding. CONCLUSION: This research suggests different molecular targets for these tracers; while 11C-PBB3 appeared to preferentially bind to tau deposits with a close spatial relationship to amyloid-beta, the binding pattern of 11C-THK5351 fitted the expected distribution of tau pathology in Alzheimer's disease better and was more closely related to downstream disease markers.

Challenge levels of everyday technologies as perceived over five years by older adults with mild cognitive impairment.

ABSTRACTBackground:In clinical practice, efficient and valid functional markers are needed to detect subtle cognitive and functional decline in mild cognitive impairment (MCI). This prospective study explored whether changes in perceived challenge of certain everyday technologies (ETs) can be used to detect signs of functional change in MCI. METHODS: Baseline and five-year data from 37 older adults (mean age 67.5 years) with MCI regarding their perceived ability to use ET were used to generate Rasch-based ET item measures reflecting the relative challenge of 46 ETs. Actual differential item functioning in relation to time was analyzed based on these item measures. Data collection took place in 2008-2014. RESULTS: Seven (15%) of the ETs included were perceived to be significantly more challenging to use at year five compared to at baseline, while 39 ETs (85%) were perceived to be equally challenging to use, despite the fact that the participants' perceived ability to use ET had decreased. Common characteristics among the ETs that became more challenging to use could not be identified. The dropout rate was 43%, which limits the power of the study. CONCLUSIONS: Changes in the perceived challenge of ETs seem to capture functional change in persons with cognitive decline. Both easier and more challenging ETs typically used at home and in society need to be addressed to capture this functional change because significant changes occurred among ETs of all challenge levels and within all types of ETs.

Longitudinal uncoupling of cerebral perfusion, glucose metabolism, and tau deposition in Alzheimer's disease.

INTRODUCTION: Cross-sectional findings using the tau tracer [18F]THK5317 (THK5317) have shown that [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) data can be approximated using perfusion measures (early-frame standardized uptake value ratio; ratio of tracer delivery in target to reference regions). In this way, a single PET study can provide both functional and molecular information. METHODS: We included 16 patients with Alzheimer's disease who completed follow-up THK5317 and FDG studies 17 months after baseline investigations. Linear mixed-effects models and annual percentage change maps were used to examine longitudinal change. RESULTS: Limited spatial overlap was observed between areas showing declines in THK5317 perfusion measures and FDG. Minimal overlap was seen between areas showing functional change and those showing increased retention of THK5317. DISCUSSION: Our findings suggest a spatiotemporal offset between functional changes and tau pathology and a partial uncoupling between perfusion and metabolism, possibly as a function of Alzheimer's disease severity.

Predicting Cognitive Decline across Four Decades in Mutation Carriers and Non-carriers in Autosomal-Dominant Alzheimer's Disease.

OBJECTIVES: The aim of this study was to investigate cognitive performance including preclinical and clinical disease course in carriers and non-carriers of autosomal-dominant Alzheimer's disease (adAD) in relation to multiple predictors, that is, linear and non-linear estimates of years to expected clinical onset of disease, years of education and age. METHODS: Participants from five families with early-onset autosomal-dominant mutations (Swedish and Arctic APP, PSEN1 M146V, H163Y, and I143T) included 35 carriers (28 without dementia and 7 with) and 44 non-carriers. All participants underwent a comprehensive clinical evaluation, including neuropsychological assessment at the Memory Clinic, Karolinska University Hospital at Huddinge, Stockholm, Sweden. The time span of disease course covered four decades of the preclinical and clinical stages of dementia. Neuropsychological tests were used to assess premorbid and current global cognition, verbal and visuospatial functions, short-term and episodic memory, attention, and executive function. RESULTS: In carriers, the time-related curvilinear trajectory of cognitive function across disease stages was best fitted to a formulae with three predictors: years to expected clinical onset (linear and curvilinear components), and years of education. In non-carriers, the change was minimal and best predicted by two predictors: education and age. The trajectories for carriers and non-carriers began to diverge approximately 10 years before the expected clinical onset in episodic memory, executive function, and visuospatial function. CONCLUSIONS: The curvilinear trajectory of cognitive functions across disease stages was mimicked by three predictors in carriers. In episodic memory, executive and visuospatial functions, the point of diverging trajectories occurred approximately 10 years ahead of the clinical onset compared to non-carriers. (JINS, 2017, 23, 195-203).

Diverging longitudinal changes in astrocytosis and amyloid PET in autosomal dominant Alzheimer's disease.

Alzheimer's disease is a multifactorial dementia disorder characterized by early amyloid-ß, tau deposition, glial activation and neurodegeneration, where the interrelationships between the different pathophysiological events are not yet well characterized. In this study, longitudinal multitracer positron emission tomography imaging of individuals with autosomal dominant or sporadic Alzheimer's disease was used to quantify the changes in regional distribution of brain astrocytosis (tracer (11)C-deuterium-L-deprenyl), fibrillar amyloid-ß plaque deposition ((11)C-Pittsburgh compound B), and glucose metabolism ((18)F-fluorodeoxyglucose) from early presymptomatic stages over an extended period to clinical symptoms. The 52 baseline participants comprised autosomal dominant Alzheimer's disease mutation carriers (n = 11; 49.6 ± 10.3 years old) and non-carriers (n = 16; 51.1 ± 14.2 years old; 10 male), and patients with sporadic mild cognitive impairment (n = 17; 61.9 ± 6.4 years old; nine male) and sporadic Alzheimer's disease (n = 8; 63.0 ± 6.5 years old; five male); for confidentiality reasons, the gender of mutation carriers is not revealed. The autosomal dominant Alzheimer's disease participants belonged to families with known mutations in either presenilin 1 (PSEN1) or amyloid precursor protein (APPswe or APParc) genes. Sporadic mild cognitive impairment patients were further divided into (11)C-Pittsburgh compound B-positive (n = 13; 62.0 ± 6.4; seven male) and (11)C-Pittsburgh compound B-negative (n = 4; 61.8 ± 7.5 years old; two male) groups using a neocortical standardized uptake value ratio cut-off value of 1.41, which was calculated with respect to the cerebellar grey matter. All baseline participants underwent multitracer positron emission tomography scans, cerebrospinal fluid biomarker analysis and neuropsychological assessment. Twenty-six of the participants underwent clinical and imaging follow-up examinations after 2.8 ± 0.6 years. By using linear mixed-effects models, fibrillar amyloid-ß plaque deposition was first observed in the striatum of presymptomatic autosomal dominant Alzheimer's disease carriers from 17 years before expected symptom onset; at about the same time, astrocytosis was significantly elevated and then steadily declined. Diverging from the astrocytosis pattern, amyloid-ß plaque deposition increased with disease progression. Glucose metabolism steadily declined from 10 years after initial amyloid-ß plaque deposition. Patients with sporadic mild cognitive impairment who were (11)C-Pittsburgh compound B-positive at baseline showed increasing amyloid-ß plaque deposition and decreasing glucose metabolism but, in contrast to autosomal dominant Alzheimer's disease carriers, there was no significant longitudinal decline in astrocytosis over time. The prominent initially high and then declining astrocytosis in autosomal dominant Alzheimer's disease carriers, contrasting with the increasing amyloid-ß plaque load during disease progression, suggests astrocyte activation is implicated in the early stages of Alzheimer's disease pathology.

Prevalence and correlates of successful aging in a population-based sample of older adults: the HUNT study.

BACKGROUND: The factors influencing successful aging (SA) are of great interest in an aging society. The aims of this study were to investigate the prevalence of SA, the relative importance across age of the three components used to define it (absence of disease and disability, high cognitive and physical function, and active engagement with life), and its correlates. METHODS: Data were extracted from the population-based cross-sectional Nord-Trøndelag Health Study (HUNT3 2006-2008). Individuals aged 70-89 years with complete datasets for the three components were included (N = 5773 of 8,040, 71.8%). Of the respondents, 54.6% were women. Univariate and multivariate regression analyses were used to analyze possible correlates of SA. RESULTS: Overall, 35.6% of the sample met one of the three criteria, 34.1% met combinations, and 14.5% met all of the three criteria. The most demanding criterion was high function, closely followed by absence of disease, while approximately two-thirds were actively engaged in life. The relative change with age was largest for the high cognitive and physical function component and smallest for active engagement with life. The significant correlates of SA were younger age, female gender, higher education, weekly exercise, more satisfaction with life, non-smoking, and alcohol consumption, whereas marital status was not related to SA. CONCLUSIONS: The prevalence of SA in this study (14.5%) is comparable to previous studies. It may be possible to increase the prevalence by intervention directed toward more exercise, non-smoking, and better satisfaction with life.

Do adapted vignettes improve medical decision-making capacity for individuals with Alzheimer's disease?

Medical decision-making capacity (MDC) is known to decline in individuals with Alzheimer's disease (AD). The vignette method uses hypothetical information as a prerequisite for measuring the capacity to make well-informed decisions to clinical trials. Our aim was to investigate if adapted vignettes can help individuals with mild AD to assimilate information, make decisions and express them in an understandable way, compared to corresponding decisions based on linguistically more demanding vignettes, as measured by the Swedish Linguistic Instrument for Medical Decision-making (LIMD). Two vignettes from LIMD were altered linguistically with the aim to facilitate understanding for individuals with AD. An experimental within-subject design was used to study the influence on MDC of readability (original/adapted vignettes) and content (two different clinical trials). We included 24 patients with mild AD in this prospective study, which read all four vignettes along with a few other tests. This allowed us to investigate the association between MDC and cognitive function. Adapted vignettes did not yield significant differences regarding MDC as compared with original vignettes using a two-way repeated measures analysis of variance. A difference was found between the two clinical trials where LIMD score was significantly higher for Kidney disease than hypertension vignettes. Our results indicate that adapted vignettes may not improve MDC for individuals with mild AD. MDC was affected by which clinical trial the vignettes regarded, which implies that other factors affecting MDC need to be investigated, like length of text and vocabulary used.

Imaging in-vivo tau pathology in Alzheimer's disease with THK5317 PET in a multimodal paradigm.

PURPOSE: The aim of this study was to explore the cerebral distribution of the tau-specific PET tracer [(18)F]THK5317 (also known as (S)-[(18)F]THK5117) retention in different stages of Alzheimer's disease; and study any associations with markers of hypometabolism and amyloid-beta deposition. METHODS: Thirty-three individuals were enrolled, including nine patients with Alzheimer's disease dementia, thirteen with mild cognitive impairment (MCI), two with non-Alzheimer's disease dementia, and nine healthy controls (five young and four elderly). In a multi-tracer PET design [(18)F]THK5317, [(11)C] Pittsburgh compound B ([(11)C]PIB), and [(18)F]FDG were used to assess tau pathology, amyloid-beta deposition and cerebral glucose metabolism, respectively. The MCI patients were further divided into MCI [(11)C]PIB-positive (n = 11) and MCI [(11)C]PIB-negative (n = 2) groups. RESULTS: Test-retest variability for [(18)F]THK5317-PET was very low (1.17-3.81 %), as shown by retesting five patients. The patients with prodromal (MCI [(11)C]PIB-positive) and dementia-stage Alzheimer's disease had significantly higher [(18)F]THK5317 retention than healthy controls (p = 0.002 and p = 0.001, respectively) in areas exceeding limbic regions, and their discrimination from this control group (using the area under the curve) was >98 %. Focal negative correlations between [(18)F]THK5317 retention and [(18)F]FDG uptake were observed mainly in the frontal cortex, and focal positive correlations were found between [(18)F]THK5317 and [(11)C]PIB retentions isocortically. One patient with corticobasal degeneration syndrome and one with progressive supranuclear palsy showed no [(11)C]PIB but high [(18)F]THK5317 retentions with a different regional distribution from that in Alzheimer's disease patients. CONCLUSIONS: The tau-specific PET tracer [(18)F]THK5317 images in vivo the expected regional distribution of tau pathology. This distribution contrasts with the different patterns of hypometabolism and amyloid-beta deposition.

Health-adjusted neuropsychological test norms based on 463 older Swedish car drivers.

There is a need for improved normative information in particular for older persons. The present study provides neuropsychological test norms on seven cognitive tests used in a sample representing the general older driving population, when uncontrolled and controlled for physical health. A group of 463 healthy Swedish car drivers, aged 65 to 84 years, participated in a medical and neuropsychological examination. The latter included tests of visual scanning, mental shifting, visual spatial function, memory, reaction time, selective attention, and simultaneous capacity. Hierarchical regression analyses demonstrated that, when uncontrolled for health, old age was associated with significant impairment on all seven tests. Education was associated with a significant advantage for all tests except most reaction time subtests. Women outperformed men on selective attention. Controlling for health did not consistently change the associations with education, but generally weakened those with age, indicating rises in normative scores of up to 0.36 SD (residual). In terms of variance explained, impaired health predicted on average 2.5%, age 2.9%, education 2.1% and gender 0.1%. It was concluded (1) that individual regression-based predictions of expected values have the advantage of allowing control for the impact of health on normative scores in addition to the adjustment for various demographic and performance-related variables and (2) that health-adjusted norms have the potential to classify functional status more accurately, to the extent that these norms diverge from norms uncontrolled for physical health.

Degree of abnormality is associated with rate of change in measures of beta-amyloid, glucose metabolism and cognition in an autopsy-verified Alzheimer's disease case.

The degree of abnormality and rate of change in cognitive functions, positron emission tomography Pittsburg compound B (PET PIB), and fluorodeoxyglucose (FDG) measures were studied for 8 years in an autopsy-confirmed Alzheimer's disease (AD) patient, who died 61 years old (Mini-Mental State Examination (MMSE) score 7). At first encounter with medical care, the patient was very mildly demented (MMSE score 27). She had four cognitive assessments and two examinations with PET PIB and FDG in 23 bilateral brain regions. The onset of cognitive decline was retrospectively estimated to have started in the early forties. The degree of impairment was inversely related to the rate of decline. A similar relationship was seen between the rate of change and the level of abnormality in both PIB and FDG. To conclude, rate of change in cognition, PIB, and FDG was associated with the degree of abnormality.

Neuropsychological test norms controlled for physical health: does it matter?

The objective of the present study was to investigate the effects of physical health on neuropsychological test norms. Medical and neuropsychological data from 118 healthy volunteer controls, aged 26-91 years, were collected during five recruitment occasions. The examinations included a clinical investigation, brain neuroimaging, and a comprehensive neuropsychological test battery. Test-specific statistical regression-weights for age, education and gender were calculated to establish preliminary test norms. Hierarchical regression analyses demonstrated that control in addition for physical health moved best performance from age 60 to 65 for abstraction; replaced a plateau above age 70 for verbal fluency, with a continued rise in performance; eliminated significant negative influences of age on auditory learning, spatial reasoning and complex copying; reduced them on wordlist recall, psychomotor speed, visual scanning and mental shifting; and slightly reduced negative influences of low education on most verbal tests, several memory tests, and psychomotor speed, indicating rises in normative scores of up to 0.8 SD at age 80 and 0.4 SD at age 60. No differences were found at age 40. Although the sample size is not adequate to be used for normative data, the findings indicate that norms uncontrolled for health overestimate the negative influence of advanced age and low education, implying a risk of drawing false diagnostic conclusions.

Cognitive predictors of medical decision-making capacity in mild cognitive impairment and Alzheimer's disease.

OBJECTIVE: Impaired capacity to make decisions in everyday life and situations of medical treatment is an inevitable consequence of the cognitive decline in Alzheimer's disease (AD). The objective of this study was to identify the most powerful cognitive component(s) that best predicted medical decision-making capacity (MDMC) in patients with AD and mild cognitive impairment. METHOD: Three groups of subjects participated in the study: patients with AD (n = 20), mild cognitive impairment (n = 21), and healthy control subjects (n = 33). MDMC was assessed by the linguistic instrument for medical decision-making (LIMD) and related to demographics and 27 cognitive test measures. RESULTS: The cognitive tests were found to aggregate into four components using a principle component analysis. The four components, which correspond to verbal knowledge, episodic memory, cognitive speed, and working memory, accounted for 73% of the variance in LIMD according to a stepwise regression analysis. Verbal knowledge was the most powerful predictor of LIMD (beta = 0.66) followed by episodic memory (beta = 0.43), cognitive speed (beta = 0.32), and working memory (beta = 0.23). The best single test as shown by the highest correlation with LIMD was Reading speed (R = 0.77). CONCLUSION: Multiple factors are involved in MDMC in subjects with cognitive impairment. The component of verbal knowledge was the best predictor of MDMC and Reading speed was the most important single cognitive test measurement, which assessed both rapid Reading and understanding of text.

Odor Identification Across Time in Mutation Carriers and Non-Carriers in Autosomal-Dominant Alzheimer's Disease.

BACKGROUND: Impaired odor identification is a characteristic of sporadic Alzheimer'sdisease(AD), but its presence in autosomal-dominantAD (adAD) remains uncertain. OBJECTIVE: To investigate odor identification ability in mutation carriers (MC) and non-carriers (NC) of adAD in relation to years to estimated clinical onset clinical onset (YECO) of disease. METHODS: Participants from six families with autosomal-dominant mutations (APP Swedish, APP Arctic, and PSEN1 mutations) included 20 MC and 20 NC. The groups were comparable in age, gender, education, number of APOE ɛ4 alleles, and YECO, but differed in global cognition (Mini-Mental State Examination). The MC group included individuals in asymptomatic, symptomatic cognitively unimpaired, mild cognitive impairment, and dementia stages of disease, spanning approximately 40 years of the AD continuum. All NC were asymptomatic. Olfactory function was assessed by means of free and cued identification of common odors summarized as total identification. RESULTS: MC performed poorer than NC in free and total identification. Four MC and none of the NC were anosmic. Olfactory functions in MC and NC were significantly and inversely related to time course (YECO) for both free and total identification. The decline in free identification began approximately 10 years prior to the estimated clinical onset of AD in MC. Odor identification proficiency was associated with episodic memory and executive function in MC and NC. CONCLUSIONS: Impaired odor identification is present well before the clinical diagnosis of AD in MC and is associated with disease progression. Odor identification ability may be a useful early biomarker for adAD.

Altered empathy processing in frontotemporal dementia A task-based fMRI study.

A lack of empathy, and particularly its affective components, is a core symptom of behavioural variant frontotemporal dementia (bvFTD). Visual exposure to images of a needle pricking a hand (pain condition) and Q-tips touching a hand (control condition) is an established functional magnetic resonance imaging (fMRI) paradigm used to investigate empathy for pain (EFP; pain condition minus control condition). EFP has been associated with increased blood oxygen level dependent (BOLD) signal in regions known to become atrophic in the early stages in bvFTD, including the anterior insula and the anterior cingulate. We therefore hypothesized that patients with bvFTD would display altered empathy processing in the EFP paradigm. Here we examined empathy processing using the EFP paradigm in 28 patients with bvFTD and 28 sex and age matched controls. Participants underwent structural MRI, task-based and resting-state fMRI. The Interpersonal Reactivity Index (IRI) was used as a measure of different facets of empathic function outside the scanner. The EFP paradigm was analysed at a whole brain level and using two regions-of-interest approaches, one based on a metanalysis of affective perceptual empathy versus cognitive evaluative empathy and one based on the controls activation pattern. In controls, EFP was linked to an expected increase of BOLD signal that displayed an overlap with the pattern of atrophy in the bvFTD patients (insula and anterior cingulate). Additional regions with increased signal were the supramarginal gyrus and the occipital cortex. These latter regions were the only ones that displayed increased BOLD signal in bvFTD patients. BOLD signal increase under the affective perceptual empathy but not the cognitive evaluative empathy region of interest was significantly greater in controls than in bvFTD patients. The controls rating on their empathic concern subscale of the IRI was significantly correlated with the BOLD signal in the EFP paradigm, as were an informants ratings of the patients empathic concern subscale. This correlation was not observed on other subscales of the IRI or when using the patient's self-ratings. Finally, controls and patients showed different connectivity patterns in empathy related networks during resting-state fMRI, mainly in nodes overlapping the ventral attention network. Our results indicate that reduced neural activity in regions typically affected by pathology in bvFTD is associated with reduced empathy processing, and a predictor of patients capacity to experience affective empathy.

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

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

Single-domain amnestic mild cognitive impairment identified by cluster analysis predicts Alzheimer's disease in the european prospective DESCRIPA study.

BACKGROUND/AIMS: To identify prodromal Alzheimer's disease (AD) subjects using a data-driven approach to determine cognitive profiles in mild cognitive impairment (MCI). METHODS: A total of 881 MCI subjects were recruited from 20 memory clinics and followed for up to 5 years. Outcome measures included cognitive variables, conversion to AD, and biomarkers (e.g. CSF, and MRI markers). Two hierarchical cluster analyses (HCA) were performed to identify clusters of subjects with distinct cognitive profiles. The first HCA included all subjects with complete cognitive data, whereas the second one selected subjects with very mild MCI (MMSE ≥28). ANOVAs and ANCOVAs were computed to examine whether the clusters differed with regard to conversion to AD, and to AD-specific biomarkers. RESULTS: The HCAs identified 4-cluster solutions that best reflected the sample structure. One cluster (aMCIsingle) had a significantly higher conversion rate (19%), compared to subjective cognitive impairment (SCI, p < 0.0001), and non-amnestic MCI (naMCI, p = 0.012). This cluster was the only one showing a significantly different biomarker profile (Aß42, t-tau, APOE ε4, and medial temporal atrophy), compared to SCI or naMCI. CONCLUSION: In subjects with mild MCI, the single-domain amnestic MCI profile was associated with the highest risk of conversion, even if memory impairment did not necessarily cross specific cut-off points. A cognitive profile characterized by isolated memory deficits may be sufficient to warrant applying prevention strategies in MCI, whether or not memory performance lies below specific z-scores. This is supported by our preliminary biomarker analyses. However, further analyses with bigger samples are needed to corroborate these findings.

Patterns of functioning in older adults with mild cognitive impairment: a two-year study focusing on everyday technology use.

OBJECTIVES: Early detection is vital for persons with mild cognitive impairment (MCI) who are at risk of activity and participation limitations, and crosssectional studies suggest the ability to use everyday technology (ET) to be a sensible tool. However, group level analyses fail to inform us about how functioning can vary over time for individuals. This study aimed at exploring and describing patterns of functioning over two years in a sample newly classified with MCI, with a special focus on perceived difficulty in ET use and involvement in everyday activities. In addition, cognitive functioning and conversion to dementia were studied. METHOD: 37 older adults (aged ≥ 55) with MCI were assessed at inclusion, and at 6, 12, and 24 months. Longitudinal case plots for the variables under study were analyzed based on strict criteria using a person-oriented approach. Paired t-tests from baseline and 24 months were also conducted to analyze change. RESULTS: The 32 participants who remained in the study after two years showed three distinct patterns of functioning over time: stable/ascending (n = 10), fluctuating (n = 10), and descending (n = 12), with the highest conversion to dementia in the descending pattern (58%). The perceived ability to use ET decreased or fluctuated in 50% of the sample. However, on a group level, a significant difference between baseline and 24 months was found only regarding cognitive function. CONCLUSION: As the need for support is individual and likely to alter over time, repeated evaluations of activity involvement and difficulty in ET use are suggested to target timely interventions for persons with MCI.