Visual associative learning to detect early episodic memory deficits and distinguish Alzheimer's disease from other types of dementia.

OBJECTIVE: We investigated how well a visual associative learning task discriminates Alzheimer's disease (AD) dementia from other types of dementia and how it relates to AD pathology. METHODS: 3,599 patients (63.9 ± 8.9 years old, 41% female) from the Amsterdam Dementia Cohort completed two sets of the Visual Association Test (VAT) in a single test session and underwent magnetic resonance imaging. We performed receiver operating curve analysis to investigate the VAT's discriminatory ability between AD dementia and other diagnoses and compared it to that of other episodic memory tests. We tested associations between VAT performance and medial temporal lobe atrophy (MTA), and amyloid status (n = 2,769, 77%). RESULTS: Patients with AD dementia performed worse on the VAT than all other patients. The VAT discriminated well between AD and other types of dementia (area under the curve range 0.70-0.86), better than other episodic memory tests. Six-hundred forty patients (17.8%) learned all associations on VAT-A, but not on VAT-B, and they were more likely to have higher MTA scores (odds ratios range 1.63 (MTA 0.5) through 5.13 for MTA ≥ 3, all p < .001) and to be amyloid positive (odds ratio = 3.38, 95%CI = [2.71, 4.22], p < .001) than patients who learned all associations on both sets. CONCLUSIONS: Performance on the VAT, especially on a second set administered immediately after the first, discriminates AD from other types of dementia and is associated with MTA and amyloid positivity. The VAT might be a useful, simple tool to assess early episodic memory deficits in the presence of AD pathology.

A clinical-radiological framework of the right temporal variant of frontotemporal dementia.

The concept of the right temporal variant of frontotemporal dementia (rtvFTD) is still equivocal. The syndrome accompanying predominant right anterior temporal atrophy has previously been described as memory loss, prosopagnosia, getting lost and behavioural changes. Accurate detection is challenging, as the clinical syndrome might be confused with either behavioural variant FTD (bvFTD) or Alzheimer's disease. Furthermore, based on neuroimaging features, the syndrome has been considered a right-sided variant of semantic variant primary progressive aphasia (svPPA). Therefore, we aimed to demarcate the clinical and neuropsychological characteristics of rtvFTD versus svPPA, bvFTD and Alzheimer's disease. Moreover, we aimed to compare its neuroimaging profile against svPPA, which is associated with predominant left anterior temporal atrophy. Of 619 subjects with a clinical diagnosis of frontotemporal dementia or primary progressive aphasia, we included 70 subjects with a negative amyloid status in whom predominant right temporal lobar atrophy was identified based on blinded visual assessment of their initial brain MRI scans. Clinical symptoms were assessed retrospectively and compared with age- and sex-matched patients with svPPA (n = 70), bvFTD (n = 70) and Alzheimer's disease (n = 70). Prosopagnosia, episodic memory impairment and behavioural changes such as disinhibition, apathy, compulsiveness and loss of empathy were the most common initial symptoms, whereas during the disease course, patients developed language problems such as word-finding difficulties and anomia. Distinctive symptoms of rtvFTD compared to the other groups included depression, somatic complaints, and motor/mental slowness. Aside from right temporal atrophy, the imaging pattern showed volume loss of the right ventral frontal area and the left temporal lobe, which represented a close mirror image of svPPA. Atrophy of the bilateral temporal poles and the fusiform gyrus were associated with prosopagnosia in rtvFTD. Our results highlight that rtvFTD has a unique clinical presentation. Since current diagnostic criteria do not cover specific symptoms of the rtvFTD, we propose a diagnostic tree to be used to define diagnostic criteria and call for an international validation.

The bvFTD phenocopy syndrome: a case study supported by repeated MRI, [18F]FDG-PET and pathological assessment.

A clinical syndrome with neuropsychiatric features of bvFTD without neuroimaging abnormalities and a lack of decline is a phenocopy of bvFTD (phFTD). Growing evidence suggests that psychological, psychiatric and environmental factors underlie phFTD. We describe a patient diagnosed with bvFTD prior to the revision of the diagnostic guidelines of FTD. Repeated neuroimaging was normal and there was no FTD pathology at autopsy, rejecting the diagnosis. We hypothesize on etiological factors that on hindsight might have played a role. This case report contributes to the understanding of phFTD and adds to the sparse literature of the postmortem assessment of phFTD.

Determinants of Cross-Sectional and Longitudinal Health-Related Quality of Life in Memory Clinic Patients Without Dementia.

OBJECTIVE: To identify determinants within 3 different domains (ie, somatic comorbidities, cognitive functioning, and neuropsychiatric symptoms [NPS]) of health-related quality of life (HRQoL) over time in memory clinic patients without dementia. METHODS: This longitudinal multicenter cohort study with a 3-year observation period recruited 315 individuals (age: 69.8 ± 8.6, 64.4% males, Mini-Mental State Examination score 26.9 ± 2.6). A multivariable explanatory model was built using linear mixed effects models (forward selection per domain) to select determinants for self-perceived HRQoL over time, as measured by the EuroQoL-5D visual analogue scale (EQ VAS). RESULTS: Mean HRQoL at study entry was 69.4 ± 15.6. The presence of agitation, appetite and eating abnormalities, and eyes/ears/nose (ie, sensory impairment) comorbidities were associated with a change in HRQoL over time. Agitation was most strongly associated with HRQoL over time. CONCLUSIONS: The association of somatic comorbidities and NPS in memory clinic patients with course of HRQoL shows that these should receive more awareness, detection, and monitoring by clinicians.

Cortical phase changes measured using 7-T MRI in subjects with subjective cognitive impairment, and their association with cognitive function.

Studies have suggested that, in subjects with subjective cognitive impairment (SCI), Alzheimer's disease (AD)-like changes may occur in the brain. Recently, an in vivo study has indicated the potential of ultra-high-field MRI to visualize amyloid-beta (Aß)-associated changes in the cortex in patients with AD, manifested by a phase shift on T2 *-weighted MRI scans. The main aim of this study was to investigate whether cortical phase shifts on T2 *-weighted images at 7 T in subjects with SCI can be detected, possibly implicating the deposition of Aß plaques and associated iron. Cognitive tests and T2 *-weighted scans using a 7-T MRI system were performed in 28 patients with AD, 18 subjects with SCI and 27 healthy controls (HCs). Cortical phase shifts were measured. Univariate general linear modeling and linear regression analysis were used to assess the association between diagnosis and cortical phase shift, and between cortical phase shift and the different neuropsychological tests, adjusted for age and gender. The phase shift (mean, 1.19; range, 1.00-1.35) of the entire cortex in AD was higher than in both SCI (mean, 0.85; range, 0.73-0.99; p < 0.001) and HC (mean, 0.94; range, 0.79-1.10; p < 0.001). No AD-like changes, e.g. increased cortical phase shifts, were found in subjects with SCI compared with HCs. In SCI, a significant association was found between memory function (Wechsler Memory Scale, WMS) and cortical phase shift (ß = -0.544, p = 0.007). The major finding of this study is that, in subjects with SCI, an increased cortical phase shift measured at high field is associated with a poorer memory performance, although, as a group, subjects with SCI do not show an increased phase shift compared with HCs. This increased cortical phase shift related to memory performance may contribute to the understanding of SCI as it is still unclear whether SCI is a sign of pre-clinical AD. Copyright © 2014 John Wiley & Sons, Ltd.

Alzheimer's disease risk variants modulate endophenotypes in mild cognitive impairment.

INTRODUCTION: We evaluated the effect of Alzheimer's disease (AD) susceptibility loci on endophenotypes closely related with AD pathology in patients with mild cognitive impairment (MCI). METHODS: We selected 1730 MCI patients from four independent data sets. Weighted polygenic risk scores (PGS) were constructed of 18 non-apolipoprotein E (APOE) AD risk variants. In addition, we determined APOE genotype. AD endophenotypes were cognitive decline over time and cerebrospinal fluid (CSF) biomarkers (aß, tau, ptau). RESULTS: PGS was modestly associated with cognitive decline over time, as measured by mini-mental state examination (MMSE) (ß ± SE:-0.24 ± 0.10; P = .012), and with CSF levels of tau and ptau (tau: 1.38 ± 0.36, P = 1.21 × 10(-4); ptau: 1.40 ± 0.36, P = 1.02 × 10(-4)). DISCUSSION: In MCI, we observed a joint effect of AD susceptibility loci on nonamyloid endophenotypes, suggesting a link of these genetic loci with neuronal degeneration in general rather than with Alzheimer-related amyloid deposition.

Cognitive correlates of cerebrospinal fluid biomarkers in frontotemporal dementia.

OBJECTIVE: In this study we investigated the relationships between cerebrospinal fluid (CSF) biomarkers (tau and amyloid-ß1-42 [Aß1-42]) and cognition or behavior in patients with frontotemporal dementia (the behavioral variant, bvFTD). METHODS: We included 58 patients with bvFTD. All patients underwent a neuropsychological assessment and lumbar puncture. Relationships between CSF biomarkers and cognition or behavior were assessed with linear regression analysis. RESULTS: After correction for age, sex, and education, CSF tau levels were found to be negatively related to the Visual Association Test (standardized ß = -0.3, P < .05), whereas CSF Aß1-42 levels were found to be positively related to the Mini-Mental State Examination (ß = 0.3, P < .05), the frontal assessment battery (ß = 0.5, P < .05), and digit span backwards test (ß = 0.3, P = .01). We did not find relations between CSF biomarkers and behavior (measured by the neuropsychiatric inventory). After excluding all patients with a CSF biomarker profile often seen in Alzheimer's disease (high levels of tau and low levels of Aß1-42), we still found relations between CSF Aß1-42 levels and Visual Association Test object naming (ß = 0.4, P < .05), as well as between CSF Aß1-42 levels and the frontal assessment battery (ß = 0.5, P < .05, but there was no relation between CSF tau and cognition. CONCLUSION: Low CSF Aß1-42 levels are associated with worse general cognitive function and worse executive function in patients with bvFTD. Our results provide circumstantial evidence for a pathophysiological role of Aß1-42 in bvFTD.

Disturbed oscillatory brain dynamics in subcortical ischemic vascular dementia.

BACKGROUND: White matter hyperintensities (WMH) can lead to dementia but the underlying physiological mechanisms are unclear. We compared relative oscillatory power from electroencephalographic studies (EEGs) of 17 patients with subcortical ischemic vascular dementia, based on extensive white matter hyperintensities (SIVD-WMH) with 17 controls to investigate physiological changes underlying this diagnosis. RESULTS: Differences between the groups were large, with a decrease of relative power of fast activity in patients (alpha power 0.25 ± 0.12 versus 0.38 ± 0.13, p = 0.01; beta power 0.08 ± 0.04 versus 0.19 ± 0.07; p<0.001) and an increase in relative powers of slow activity in patients (theta power 0.32 ± 0.11 versus 0.14 ± 0.09; p<0.001 and delta power 0.31 ± 0.14 versus 0.23 ± 0.09; p<0.05). Lower relative beta power was related to worse cognitive performance in a linear regression analysis (standardized beta = 0.67, p<0.01). CONCLUSIONS: This pattern of disturbance in oscillatory brain activity indicate loss of connections between neurons, providing a first step in the understanding of cognitive dysfunction in SIVD-WMH.

Clinical Phenotypes of Behavioral Variant Frontotemporal Dementia by Age at Onset.

BACKGROUND: Behavioral variant frontotemporal dementia (bvFTD) is generally considered a young-onset dementia, although age at onset is highly variable. While several studies indicate clinical differences regarding age at onset, no biomarker validated cohort studies with updated clinical criteria have been performed. OBJECTIVE: We aimed to examine behavior, cognition, and mortality over the full age spectrum in a cohort of bvFTD patients with neuroimaging, genetic, or histopathological confirmation and exclusion of positive Alzheimer's disease biomarkers or severe cerebrovascular damage. METHODS: In total, 315 patients with a clinical diagnosis of probable or definite bvFTD were included from the Amsterdam Dementia Cohort and grouped into quartiles by age-at-diagnosis. Neuropsychiatric symptoms and cognitive functioning were assessed with the neuropsychiatric inventory, the geriatric depression scale and a neuropsychological test battery. Data on mortality was obtained from the Dutch municipal register. Associations between age-at-diagnosis and clinical features and mortality risk were examined. RESULTS: Age-at-diagnosis ranged from 26 to 85 years and established quartiles with mean ages of 52±6, 61±2, 66±2, and 74±3 years. In the total sample, 44.4%exceeded an age of 65 years at time of diagnosis. Earlier age-at-diagnosis was associated with more severe behavioral symptoms, while later age-at-diagnosis was associated with more severe memory impairment. Unexpectedly, mortality risk was not associated with age-at-diagnosis. CONCLUSION: In bvFTD, symptom profile is associated with age-at-diagnosis. This should be taken into account with regard to diagnostics, patient management, and trial design. Additionally, based on our sample, the prevalence of late-onset bvFTD is higher than generally thought.

Clinical characteristics of patients with frontotemporal dementia with and without lobar atrophy on MRI.

INTRODUCTION: The presence of frontal and/or temporal atrophy on neuroimaging has been designated as supportive in the clinical consensus criteria for behavioral variant frontotemporal dementia (bvFTD). As magnetic resonance imaging (MRI) has a relatively low sensitivity for bvFTD, a substantial proportion of patients may present with a normal MRI. Thus, there may be clinical differences between patients with and without lobar abnormalities on MRI. We compared clinical characteristics of bvFTD patients with frontotemporal lobar atrophy on MRI to those lacking the typical pattern at presentation. METHODS: MRIs of 49 patients from our memory clinic, diagnosed with bvFTD were rated for the presence or absence of frontal and/or temporal atrophy. Demographic, behavioral, and cognitive features were compared between subjects with and without typical bvFTD atrophy pattern. RESULTS: Twenty-three patients showed lobar atrophy on MRI, whereas 26 patients lacked the characteristic frontotemporal lobar atrophy, including 13 patients with a normal MRI and 13 with other abnormalities. Disinhibition occurred more often in the group with frontal and/or temporal atrophy on MRI compared with the group with other abnormalities, whereas imitation did not occur in patients lacking the typical bvFTD atrophy pattern. No differences were found in neuropsychologic profiles. There was a trend for a lower mean Clinical Dementia Rating and less severe language impairment in patients with a normal MRI compared with the group with frontal and/or temporal atrophy. CONCLUSIONS: The clinical phenotype of FTD cannot be predicted by the presence or absence of lobar atrophy on MRI, although imitation and disinhibition are more prevalent in bvFTD patients with characteristic MRI abnormalities. Furthermore, patients with a normal MRI seem to be less severely demented in comparison to patients with frontal and/or temporal atrophy.

A Suboptimal Diet is Associated with Poorer Cognition: The NUDAD Project.

Nutrition is one of the modifiable risk factors for cognitive decline and Alzheimer's disease (AD) dementia, and is therefore highly relevant in the context of prevention. However, knowledge of dietary quality in clinical populations on the spectrum of AD dementia is lacking, therefore we studied the association between dietary quality and cognitive impairment in Alzheimer's disease (AD) dementia, mild cognitive impairment (MCI) and controls. We included 357 participants from the NUDAD project (134 AD dementia, 90 MCI, 133 controls). We assessed adherence to dietary guidelines (components: vegetables, fruit, fibers, fish, saturated fat, trans-fat, salt, and alcohol), and cognitive performance (domains: memory, language, visuospatial functioning, attention, and executive functioning). In the total population, linear regression analyses showed a lower vegetable intake is associated with poorer global cognition, visuospatial functioning, attention and executive functioning. In AD dementia, lower total adherence to dietary guidelines and higher alcohol intake were associated with poorer memory, a lower vegetable intake with poorer global cognition and executive functioning, and a higher trans-fat intake with poorer executive functioning. In conclusion, a suboptimal diet is associated with more severely impaired cognition-this association is mostly attributable to a lower vegetable intake and is most pronounced in AD dementia.

Disease-related determinants are associated with mortality in dementia due to Alzheimer's disease.

BACKGROUND: Survival after dementia diagnosis varies considerably. Previous studies were focused mainly on factors related to demographics and comorbidity rather than on Alzheimer's disease (AD)-related determinants. We set out to answer the question whether markers with proven diagnostic value also have prognostic value. We aimed to identify disease-related determinants associated with mortality in patients with AD. METHODS: We included 616 patients (50% female; age 67 ± 8 years; mean Mini Mental State Examination score 22 ± 3) with dementia due to AD from the Amsterdam Dementia Cohort. Information on mortality was obtained from the Dutch Municipal Register. We used age- and sex-adjusted Cox proportional hazards analysis to study associations of baseline demographics, comorbidity, neuropsychology, magnetic resonance imaging (MRI) (medial temporal lobe, global cortical and parietal atrophy, and measures of small vessel disease), and cerebrospinal fluid (CSF) (ß-amyloid 1-42, total tau, and tau phosphorylated at threonine 181 [p-tau]) with mortality (outcome). In addition, we built a multivariate model using forward selection. RESULTS: After an average of 4.9 ± 2.0 years, 213 (35%) patients had died. Age- and sex-adjusted Cox models showed that older age (HR 1.29 [95% CI 1.12-1.48]), male sex (HR 1.60 [95% CI 1.22-2.11]), worse scores on cognitive functioning (HR 1.14 [95% CI 1.01-1.30] to 1.31 [95% CI 1.13-1.52]), and more global and hippocampal atrophy on MRI (HR 1.18 [95% CI 1.01-1.37] and HR 1.18 [95% CI 1.02-1.37]) were associated with increased risk of mortality. There were no associations with comorbidity, level of activities of daily living, apolipoprotein E (APOE) ε4 status, or duration of disease. Using forward selection, the multivariate model included a panel of age, sex, cognitive tests, atrophy of the medial temporal lobe, and CSF p-tau. CONCLUSIONS: In this relatively young sample of patients with AD, disease-related determinants were associated with an increased risk of mortality, whereas neither comorbidity nor APOE genotype had any prognostic value.

Cognitive Deficits in Patients With Neuropsychiatric Symptoms: A Comparative Study Between Behavioral Variant Frontotemporal Dementia and Primary Psychiatric Disorders.

OBJECTIVE: To compare neuropsychological profiles in behavioral variant frontotemporal dementia (bvFTD) with its most common primary psychiatric differential diagnoses, major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia, in older patients with active symptoms. METHODS: We included patients from different cohorts with MDD (DSM-IV-TR: 296.20-296.23, 296.30-296.33; n = 42; mean ± SD age, 72.0 ± 8.0 years; female = 57.1%) included from 2002 to 2007, noneuthymic BD (DSM-IV-TR: 296.00-296.06, 296.40-296.46, 296.50-296.56, 296.60-296.66, 296.7; DSM-IV-TR: 296.89; DSM-IV-TR: 296.80; n = 41; age, 71.7 ± 8.8 years; female = 53.7%) included from 2011 to 2015, nonremitted schizophrenia (DSM-IV-TR: 295.10, 295.20, 295.30, 295.60, 295.90; n = 47; age, 67.5 ± 7.1 years; female = 66%) included from 2006 to 2008, or probable/definite bvFTD (n = 173; age, 62.6 ± 8.0 years; female = 39.9%) (Frontotemporal Dementia Consensus criteria) included from 2000 to 2015 and healthy controls (n = 78; age, 71.9 ± 8.0 years; female = 71.8%) included from 2005 to 2007. Neuropsychological tests concerned the domains of attention and working memory, verbal memory, verbal fluency, and executive functioning. Analyses of variance were performed with age, gender, and education level as covariates. Post hoc Bonferroni tests were used to detail group differences. RESULTS: Compared to the healthy controls, both the bvFTD and primary psychiatric disorder groups showed significant impairment on all cognitive domains. Executive function was more disturbed in all primary psychiatric disorders compared to bvFTD (P < .001). Attention and working memory were significantly better in the bvFTD and schizophrenia groups compared to the MDD and BD groups (P < .001). For verbal memory, the bvFTD group scored significantly higher compared to patients with schizophrenia, BD, or MDD (P < .001). Patients with bvFTD had significantly lower scores on verbal fluency, especially due to Animal Naming, in comparison with the BD group (P < .001); however, these scores were not significantly different from those of MDD or schizophrenia patients. CONCLUSIONS: Cognitive deficits in bvFTD are less severe than in primary psychiatric disorders with active symptoms. This indicates that in the differential diagnosis of bvFTD, disturbances on tests for cognitive performance do not rule out primary psychiatric diagnoses.

The metabolic syndrome in a memory clinic population: relation with clinical profile and prognosis.

BACKGROUND: The metabolic syndrome (MetS) refers to a cluster of cardiovascular risk factors that is associated with an increased risk of cognitive impairment and dementia. It is unclear however, if the presence of the MetS is associated with a particular clinical profile or a different prognosis in patients with cognitive complaints or early dementia. OBJECTIVES: To compare 1) the clinical profile and 2) the prognosis of patients attending a memory clinic according to the presence or absence of MetS. DESIGN: Longitudinal cohort. SETTING: Memory clinic. PARTICIPANTS: We included and followed 86 consecutive patients (average age of 66.7 (SD 9.7)) from the Amsterdam Dementia Cohort with an MMSE>22. MEASUREMENTS: Clinical profile (neuropsychological examination, brain MRI, cerebrospinal fluid (CSF) biomarkers, clinical diagnosis) on an initial standardized diagnostic assessment was compared according to MetS status. Progression to dementia was assessed in initially nondemented patients (subjective complaints n=40, mild cognitive impairment n=24, follow-up available in 59). RESULTS: 35 (41%) patients met the MetS criteria. Demographics were similar between patients with or without the MetS. At baseline, diagnosis, cognitive performance, severity of degenerative or vascular abnormalities on MRI, and CSF amyloid and tau levels did not differ between the groups (all p>0.05). Among nondemented patients, however, MetS was associated with worse performance on executive function, attention & speed and visuoconstructive ability (z-scores, p<0.05). During a mean follow-up of 3.4years a similar proportion of patients with (4; 17%) and without (6; 17%) the MetS progressed to dementia (p=0.45). CONCLUSION: Among nondemented patients presenting at a memory clinic MetS was associated with slightly worse cognitive performance (worse on tasks assessing executive functions, visuo-constructive ability, attention & speed), but conversion rate to dementia was not increased.

Progression to dementia in memory clinic patients without dementia: a latent profile analysis.

OBJECTIVE: To identify the existence of discrete cognitive subtypes among memory clinic patients without dementia and test their prognostic values. METHODS: In a retrospective cohort study of 635 patients without dementia visiting the Alzheimer centers in Maastricht or Amsterdam, latent profile analysis identified cognitive subtypes based on immediate and delayed memory recall, delayed recognition, information-processing speed, attention, verbal fluency, and executive functions. Time to dementia was tested in weighted Cox proportional hazard models adjusted for confounders. RESULTS: Five latent classes represented participants with high-normal cognition (15%), low-normal cognition (37%), primary memory impairment in recall (MI) (36%), memory impairment in recall and recognition (MI+) (5%), and primary nonmemory impairment (NMI) (6%). Compared with low-normal cognition, participants with NMI had the highest risk of dementia (hazard ratio [HR] = 5.94, 95% confidence interval [CI] = 3.46-10.18) followed by MI (HR = 3.05, 95% CI = 2.09-4.46) and MI+ (HR = 3.26, 95% CI = 1.72-6.17), while participants with high-normal cognition had the lowest risk (HR = 0.24, 95% CI = 0.07-0.80). Subtypes further showed differential relationships with dementia types, with MI and MI+ most often converting to Alzheimer-type dementia and NMI to other forms of dementia. CONCLUSIONS: Cognitive subtypes can be empirically identified in otherwise heterogeneous samples of memory clinic patients and largely confirm current strategies to distinguish between amnestic and nonamnestic impairment. Studying more homogeneous cognitive subtypes may improve understanding of disease mechanisms and outcomes.