Education-Based Cutoffs for Cognitive Screening of Alzheimer's Disease.

INTRODUCTION: The educational background and size of the elderly population are undergoing significant changes in Finland during the 2020s. A similar process is likely to occur also in several European countries. For cognitive screening of early Alzheimer's disease (AD), using outdated norms and cutoff scores may negatively affect clinical accuracy. The aim of the present study was to examine the effects of education, age, and gender on the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery (CERAD-nb) in a large register-based, clinical sample of patients with mild AD and nondemented at-risk persons from the general population (controls) and to examine whether corrected cutoff scores would increase the accuracy of differentiation between the 2 groups. METHODS: CERAD-nb scores were obtained from AD patients (n = 389, 58% women, mean age 74.0 years) and from controls (n = 1,980, 52% women, mean age 68.5 years). The differences in CERAD-nb performance were evaluated by univariate GLM. Differentiation between the 2 groups was evaluated using a receiver operating characteristic (ROC) curve, where a larger area under the ROC curve represents better discrimination. Youden's J was calculated for the overall performance and accuracy of each of the measures. RESULTS: Of the demographic factors, education was the strongest predictor of CERAD-nb performance, explaining more variation than age or gender in both the AD patients and the controls. Education corrected cutoff scores had better diagnostic accuracy in discriminating between the AD patients and controls than existing uncorrected scores. The highest level of discrimination between the 2 groups overall was found for two CERAD-nb total scores. CONCLUSIONS: Education-corrected cutoff scores were superior to uncorrected scores in differentiating between controls and AD patients especially for the highest level of education and should therefore be used in clinical cognitive screening, also as the proportion of the educated elderly is increasing substantially during the 2020s. Our results also indicate that total scores of the CERAD-nb are better at discriminating AD patients from controls than any single subtest score. A digital tool for calculating the total scores and comparing education-based cutoffs would increase the efficiency and usability of the test.

Different Trajectories of Depressive Symptoms in Alzheimer's Disease Caregivers - 5-Year Follow-Up.

OBJECTIVES: The care of individuals with Alzheimer's disease (AD) relies on family caregivers (FCs) who face increasing demands. This study aimed to identify trajectories of depressive symptoms in FCs. METHODS: 226 FCs and individuals with AD were followed up for 5 years as a part of the ALSOVA study. Depressive symptoms in FCs were measured with the Beck Depression Inventory from the time of the AD diagnosis to the 5-year follow-up. We compared the trajectory of groups regarding age, education, and sex of both FC distress and AD symptoms. RESULTS: We identified three trajectories of FC depressive symptoms throughout follow-up: (1) declining (7.5% of FCs), (2) minor (59.7% of FCs), and (3) increased (32.7% of FCs). These groups exhibited differences in demographic variables, FC distress, and individuals with AD neuropsychiatric symptoms. CONCLUSIONS: The present study showed that FC depressive symptoms existed, and one-third of caregivers experienced increasing depressive symptoms over five years. CLINICAL IMPLICATIONS: Family caregivers' health should be followed in clinical practice, and those at risk of depression could be recognized early in caregiving.

Neuropsychiatric symptoms and activities of daily living in Alzheimer's disease: ALSOVA 5-year follow-up study.

BACKGROUND: Neuropsychiatric symptoms (NPSs) in Alzheimer's disease (AD) are related to activities of daily living (ADLs), but longitudinal studies are sparse. OBJECTIVES: We investigated which NPSs were related to decline in instrumental ADLs (IADLs) and basic ADLs (BADLs) in a 5-year follow-up of individuals with AD. METHODS: ALSOVA 5-year follow-up study data of 236 individuals with very mild or mild AD at baseline and their caregiver were analyzed. IADLs and BADLs were assessed with Alzheimer's Disease Cooperative Study ADL inventory, and NPSs with Neuropsychiatric Inventory at annual follow-up visits. Generalized estimating equations (GEEs) were used for longitudinal data analysis, and NPS-ADL networks were estimated to demonstrate symptom interactions. RESULTS: Apathy [rate ratio (RR) 1.23, 95% CI 1.06-1.44, p = 0.007], aberrant motor behavior (RR 1.24, 95% CI 1.07-1.44, p = 0.005), and appetite disturbances (RR 1.22, 95% CI 1.06-1.41, p = 0.005) were related to impairment in BADLs, and the same symptoms (RR 1.13, 95% CI 1.07-1.21, p < 0.001; RR 1.13, 95% CI 1.07-1.20, p < 0.001; RR 1.14; 95% CI 1.08-1.21, p < 0.001, for apathy, aberrant motor behavior, and appetite disturbances, respectively), in addition to delusions (RR 1.09, 95% CI 1.03-1.15, p = 0.004), were related to IADL impairment. Symptom networks varied at different time points. CONCLUSION: As AD progresses, common (apathy) and uncommon NPSs (aberrant motor behavior, appetite disturbances, delusions) seem to be related to ADLs through various symptom interactions. Previous literature suggests that frontal pathology could underlie these relationships.

Third follow-up of the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) cohort investigating determinants of cognitive, physical, and psychosocial wellbeing among the oldest old: the CAIDE85+ study protocol.

BACKGROUND: The oldest old is the fastest growing age group worldwide and the most prone to severe disability, especially in relation to loss of cognitive function. Improving our understanding of the predictors of cognitive, physical and psychosocial wellbeing among the oldest old can result in substantial benefits for the individuals and for the society as a whole. The Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study investigated risk factors and determinants of cognitive impairment in a population-based longitudinal cohort, which was first examined between 1972 and 1992, when individuals were in their midlife, and re-assessed in 1998 and 2005-2009. Most of the study participants are currently aged 85 years or older. We aim to re-examine the cohort's survivors and gain further insights on the mechanisms underlying both cognitive and overall healthy ageing at old age. METHODS: CAIDE85+ is the third follow-up of the CAIDE study participants. All individuals still alive and living in the Kuopio and Joensuu areas of Eastern Finland, from the original CAIDE cohort (two random samples, N = 2000 + ~ 900), will be invited to a re-examination. The assessment includes self-reported data related to basic demographics and lifestyle, as well as psychosocial and physical health status. Cognitive and physical evaluations are also conducted. Blood biomarkers relevant for dementia and ageing are assessed. Primary outcomes are the measurements related to cognition and daily life functioning (CERAD, Trail Making Test-A, Letter-Digit Substitution Test, Clinical Dementia Rating and Activities of Daily Living). Secondary endpoints of the study are outcomes related to physical health status, psychosocial wellbeing, as well as age-related health indicators. DISCUSSION: Through a follow-up of more than 40 years, CAIDE85+ will provide invaluable information on the risk and protective factors that contribute to cognitive and physical health, as well as ageing and longevity. STUDY REGISTRATION: The present study protocol has been registered at https://clinicaltrials.gov/ (registration nr NCT03938727 , date 03.05.2019).

The influence of the individual neuropsychiatric symptoms of people with Alzheimer disease on family caregiver distress-A longitudinal ALSOVA study.

OBJECTIVES: Family caregivers (FCs) face a variety of demands while caring for persons with Alzheimer disease (AD). Longitudinal studies identifying the specific AD-related neuropsychiatric symptoms (NPS) that contribute to FC distress are rare. We analyzed which NPS in association with care recipient and caregiver demographic factors are associated with FC psychological distress over a 36-month follow-up period. DESIGN: This is a longitudinal study with annual follow-up. Participants were people with AD (n = 226) and their FCs (n = 226). MEASUREMENTS: The Neuropsychiatric Inventory was used to assess NPS, and The General Health Questionnaire was used as a measure of caregiver distress. The effect of NPS on FC psychological distress over time was analyzed using a linear-mixed effect model. RESULTS: Delusions (P = .003), agitation (P < .001), and sleep disturbance (P = .005) are associated with FC psychological distress. One of four people with AD developed delusions and agitation during the early stages of the disease. Sleep disturbances increased over the follow-up time. A marital relationship was associated with FC distress, while some prevalent symptoms, such as depression, did not affect distress. CONCLUSIONS: Delusions, agitation, and sleep disturbances may cause distress to the FCs of persons with AD, especially if they live together. Clinicians should meet with FCs regularly and recognize those FCs at risk for a decline in psychosocial health.

Quality of Life in relation to neuropsychiatric symptoms in Alzheimer's disease: 5-year prospective ALSOVA cohort study.

OBJECTIVE: To examine the association between neuropsychiatric symptoms (NPS) with self- and caregiver-rated Quality of Life (QoL) for patients with Alzheimer's disease (AD) during a 5-year follow-up. METHODS: The ALSOVA 5-year follow-up study included, at baseline, 236 patients with either very mild (Clinical Dementia Rating Scale (CDR) 0.5), or mild (CDR 1) AD, together with their caregivers from three Finnish hospital districts. QoL was evaluated using patient self-reported, and caregiver-rated, QoL in AD (QoL-AD) scores. NPS were assessed using the Neuropsychiatric Inventory (NPI), and AD severity was evaluated using the CDR, with cognition tested by the mini-mental state examination. The performance of daily activities was assessed using the Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory. RESULTS: Over the 5-year follow-up period, patient self-reported QoL-AD scores did not change significantly (p = 0.245), despite increases in their NPS. However, caregiver-rated patient QoL-AD scores declined significantly (p ≤ 0.001), as total NPI scores increased during follow-up. No NPS at baseline, and only apathy at follow-up, correlated significantly (p = 0.007) with patient self-rated QoL-AD scores. Caregiver-rated patient QoL-AD scores correlated significantly with most NPS, especially (p ≤ 0.001) apathy, agitation, anxiety, irritability, depression, and delusions at baseline, and delusions, hallucinations, apathy, appetite disturbances, and anxiety during follow-up. CONCLUSIONS: Patient rated QoL-AD scores are an unreliable tool with which to evaluate the success of therapy for NPS. Instead, caregiver-rated scores for patients correlated well with NPI scores, and health care professionals in the clinic should preferentially use these. Copyright © 2017 John Wiley & Sons, Ltd.

Use of psychotropic medications in relation to neuropsychiatric symptoms, cognition and functional performance in Alzheimer's disease over a three-year period: Kuopio ALSOVA study.

BACKGROUND: Psychotropic medications are widely prescribed to manage neuropsychiatric symptoms (NPS) of Alzheimer's disease (AD). Our objective was to investigate the longitudinal associations between psychotropic medication use and NPS, cognition, and functional performance in persons with very mild or mild AD at baseline. METHODS: Data were collected as part of the prospective three-year study of home-dwelling persons with AD and their caregivers (n = 236 dyads). The associations between psychotropic medication use and clinical measures were analyzed using repeated measures Generalized Estimating Equation (GEE) models. NPS, cognition, daily functioning, and disease severity were assessed with NPI, CERAD-NB, or MMSE, ADCS-ADL, and CDR-SOB, respectively. All analyses were adjusted for age, gender, education, and co-morbidities. RESULTS: The prevalence of benzodiazepines and related medications increased from 16% to 24% (p = 0.031), antidepressants from 11% to 18% (p = 0.057), and antipsychotics from 4% to 16% (p = 0.011) in the three years following AD diagnosis. In adjusted multivariable analyses, a one-point increase in NPI increased the odds of using any psychotropic medication class by 4% (odds ratio (OR) 1.04, 95% confidence interval (CI) 1.01-1.07). ADCS-ADL (1/OR 1.04, 95% CI 1.02-1.06) and CDR-SOB (OR 1.27, 95% CI 1.13-1.42) were associated with use of antipsychotics. CERAD-NB and MMSE were not associated with any psychotropic medication class use in the models. CONCLUSIONS: Psychotropic medication use increased significantly in relation to increasing dependency in AD, especially with NPS. Furthermore, the use of antipsychotics increased with disease severity, and with decline in daily functioning. Cognitive performance was not associated with psychotropic medication use.

Early psychosocial intervention does not delay institutionalization in persons with mild Alzheimer disease and has impact on neither disease progression nor caregivers' well-being: ALSOVA 3-year follow-up.

OBJECTIVES: Early diagnosis, initiation of Alzheimer's disease (AD) therapy and programs that support care of persons with AD at home are recommended. The objective of this study was to assess the effect of early psychosocial intervention on delaying the institutionalization of persons with AD. We also assessed the influence of intervention on AD progression, behavioral symptoms, and health-related quality of life (HRQoL) in persons with AD and caregivers. METHODS: Kuopio ALSOVA study, a prospective, randomized intervention study with a 3-year follow-up, was carried out at memory clinics. Home-dwelling persons with very mild or mild AD (n = 236) and AD-targeted therapy and their family caregivers (n = 236) were randomized to the intervention or control group (1:2). Psychosocial intervention including education, counseling, and social support was given during the first 2 years (16 days). The primary outcome was the cumulative risk (controlled for death) of institutionalization over 36 months. Secondary outcomes were adjusted mean changes from baseline in disease severity, cognition, daily activities, behavior, and HRQoL for persons with AD; and change in psychological distress, depression, and HRQoL for caregivers. RESULTS: No differences were found in nursing home placement after the 36-month follow-up between intervention and control groups. No beneficial effects of the intervention were found on the secondary outcomes. CONCLUSIONS: The psychosocial intervention did not delay nursing home placement in persons with AD and had no effect on patient well-being, disease progression, or AD-related symptoms or caregiver well-being. Instead of automatically providing psychosocial intervention courses, individualized support programs may be more effective.

Self-Rated and Caregiver-Rated Quality of Life in Alzheimer Disease with a Focus on Evolving Patient Ability to Respond to Questionnaires: 5-Year Prospective ALSOVA Cohort Study.

OBJECTIVE: To examine and compare self-rated and caregiver-rated measures of quality of life (QoL) in relation to disease progression in patients with very mild or mild Alzheimer disease (AD) and at what disease stage patient's ability to respond to QoL questionnaires with or without assistance begins to diminish. METHODS: 236 patients with very mild or mild AD and their family caregivers from three Finnish hospital districts participated in this prospective, longitudinal study with 5 years of follow-up. Three patient-reported instruments were used to assess QoL (the generic 15D, the Quality of Life in Alzheimer Disease [QoL-AD] questionnaire, and a visual analogue scale) as well as one caregiver-rated assessment of patient QoL (QoL-AD). AD severity was evaluated with the Clinical Dementia Rating Scale - Sum of Boxes (CDR-SOB). RESULTS: All self- and caregiver-rated QoL estimates correlated with AD severity. The self- and caregiver-rated QoL scores began to diverge even with very mild cognitive impairment after CDR-SOB reached 4, the value that corresponds with a Mini-Mental State Examination (MMSE) score of 25-30. Patients also began to need assistance in responding to questionnaires at very early stages of AD (CDR-SOB score: 4-6). Furthermore, their ability to respond to QoL questionnaires with or without assistance declined after CDR-SOB reached 11 points, a value that correlates with an early moderate stage of AD and MMSE score of 11-20. CONCLUSIONS: AD patients' self-rated QoL ratings are much more insensitive to disease progression than caregiver ratings.

Depressed Spousal Caregivers Have Psychological Stress Unrelated to the Progression of Alzheimer Disease: A 3-Year Follow-Up Report, Kuopio ALSOVA Study.

OBJECTIVE: To explore family caregiver (FC) long-term psychological distress after Alzheimer disease (AD) diagnosis in a family member. METHODS: FC (n = 236) and patients with AD were prospectively followed up to 36 months after AD diagnosis. FC psychological distress was evaluated using the General Health Questionnaire (GHQ). Furthermore, caregiver depressive symptoms and sense of coherence, along with AD patient measurements, were measured at baseline and annually. Generalized estimating equation models were applied to study associations of these baseline factors to caregiver GHQ. RESULTS: After 36 months of follow-up, spousal caregivers (SCs) GHQ was significantly higher (P < .001) than in the nonspousal caregivers (NSCs). The difference in GHQ scores was associated by depressive symptoms (P < .001) at baseline, and the depressed SCs have more severe distress than NSCs over the observation period. CONCLUSION: During longitudinal caregiving, spousal and depressed caregivers of patients with AD report higher and increasing psychological stress than nonspousal and nondepressed caregivers. Spousal relationship, caregivers' depressive symptoms, and the severity of patients' neuropsychological symptoms at the time of AD diagnosis predict the trajectory of psychological distress. The current study highlights the need for evaluating AD caregiver mental health and level of coping.

Decreasing sense of coherence and its determinants in spousal caregivers of persons with mild Alzheimer's disease in three year follow-up: ALSOVA study.

BACKGROUND: Sense of coherence (SOC) is associated with the capability to cope with caregiving. Our aims were (1) to describe the trajectory of SOC in aged spousal caregivers of persons with mild Alzheimer's disease (AD) in 3-year follow-up and (2) to identify baseline determinants influencing SOC change. METHODS: Both AD (n = 170) (CDR-SOB, MMSE, NPI, ADCS-ADL) and caregiver- (n = 170) (BDI, SOC) related efficacy parameters were evaluated annually. Follow-up time was 3 years. The relationship of potential baseline factors with longitudinal SOC was analyzed using linear mixed models. RESULTS: The mean drop-out-adjusted SOC score (148.5 at baseline) was decreased by 4.56 points (p = 0.002) during the follow-up. Caregivers' depression at baseline predicted the significant decrease of SOC (every + 1 BDI point decreases 2.181 points in SOC, p = 0.0001). When caregiver's depression was not taken into account in the analysis, female gender, and higher age and AD patient's lower baseline MMSE were associated significantly (p < 0.05) with decreasing SOC score in the follow-up. Other studied covariates were not associated with SOC change. CONCLUSIONS: SOC is not as stable as expected, but decreases during long-lasting caregiving. Caregiver's depression at baseline predicts SOC decrease over time. In the future, caregiver dependent factors should be evaluated at the beginning of caregiving to target individualized support programmes to the vulnerable caregivers.

Progression of Alzheimer's disease during a three-year follow-up using the CERAD-NB total score: Kuopio ALSOVA study.

BACKGROUND: We studied the suitability of The Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Battery (CERAD-NB) total score for monitoring Alzheimer's disease (AD) progression in early-diagnosed medicated patients. We also investigated possible differences in progression between patients with very mild or mild baseline AD. METHODS: In this three-year follow-up of 115 ALSOVA study patients with clinical dementia ratings (CDR) of very mild (0.5) or mild (1) AD, we analyzed total CERAD-NB, Mini-Mental State Examination (MMSE), Neuropsychiatric Inventory (NPI), The Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory, and Clinical Dementia Rating Sum of Boxes scores. Correlations were identified with efficacy parameters. RESULTS: Over three years, total CERAD-NB declined significantly in both groups. Annual change rates of total CERAD-NB were also significant. Total CERAD-NB revealed annual differences in cognition between study groups, while MMSE did not. Total CERAD-NB correlated well with other cognitive and global measures, but not with NPI. For almost two years, the CDR-0.5 group maintained a higher activities of daily living than the CDR-1 group exhibited at baseline. Furthermore, the CDR-0.5 group showed milder neuropsychiatric symptoms at the end of follow-up than the CDR-1 group showed at baseline. CONCLUSIONS: The CERAD total score is a suitable and sensitive follow-up tool in longitudinal AD trials. Cognition progression rates did not significantly differ between study groups; however, patients with very mild AD at baseline had milder neuropsychiatric symptoms after long-term follow-up. This emphasizes the importance of early diagnosis and assessment of neuropsychiatric symptoms at the diagnostic visit and during follow-up.

Psychometric Properties of the Neuropsychiatric Inventory: A Review.

Neuropsychiatric symptoms cause a significant burden to individuals with neurocognitive disorders and their families. Insights into the clinical associations, neurobiology, and treatment of these symptoms depend on informant questionnaires, such as the commonly used Neuropsychiatric Inventory (NPI). As with any scale, the utility of the NPI relies on its psychometric properties, but the NPI faces unique challenges related to its skip-question and scoring formats. In this narrative review, we examined the psychometric properties of the NPI in a framework including properties pertinent to construct validation, and health-related outcome measurement in general. We found that aspects such as test-retest and inter-rater reliability are major strengths of the NPI in addition to its flexible and relatively quick administration. These properties are desired in clinical trials. However, the reported properties appear to cover only some of the generally examined psychometric properties, representing perhaps necessary but insufficient reliability and validity evidence for the NPI. The psychometric data seem to have significant gaps, in part because small sample sizes in the relevant studies have precluded more comprehensive analyses. Regarding construct validity, only one study has examined structural validity with the NPI subquestions. Measurement error was not assessed in the reviewed studies. For future validation, we recommend using data from all subquestions, collecting larger samples, paying specific attention to construct validity and formulating hypotheses a priori. Because the NPI is an outcome measure of interest in clinical trials, examining measurement error could be of practical importance.

Cognitive Performance at Time of AD Diagnosis: A Clinically Augmented Register-Based Study.

We aimed to evaluate the feasibility of using real-world register data for identifying persons with mild Alzheimer's disease (AD) and to describe their cognitive performance at the time of diagnosis. Patients diagnosed with AD during 2010-2013 (aged 60-81 years) were identified from the Finnish national health registers and enlarged with a smaller private sector sample (total n = 1,268). Patients with other disorders impacting cognition were excluded. Detailed clinical and cognitive screening data (the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery [CERAD-nb]) were obtained from local health records. Adequate cognitive data were available for 389 patients with mild AD (31%) of the entire AD group. The main reasons for not including patients in analyses of cognitive performance were AD diagnosis at a moderate/severe stage (n = 266, 21%), AD diagnosis given before full register coverage (n = 152, 12%), and missing CERAD-nb data (n = 139, 11%). The cognitive performance of persons with late-onset AD (n = 284), mixed cerebrovascular disease and AD (n = 51), and other AD subtypes (n = 54) was compared with that of a non-demented sample (n = 1980) from the general population. Compared with the other AD groups, patients with late-onset AD performed the worst in word list recognition, while patients with mixed cerebrovascular disease and AD performed the worst in constructional praxis and clock drawing tests. A combination of national registers and local health records can be used to collect data relevant for cognitive screening; today, the process is laborious, but it could be improved in the future with refined search algorithms and electronic data.

The CERAD Neuropsychological Battery in Patients with Idiopathic Normal Pressure Hydrocephalus Compared with Normal Population and Patients with Mild Alzheimer's Disease.

BACKGROUND: The usefulness of CERAD Neuropsychological Battery for describing the cognitive impairment in idiopathic normal pressure hydrocephalus (iNPH) is unknown. OBJECTIVE: To compare the cognitive profile of patients with iNPH to patients with mild Alzheimer's disease (AD) and age-matched cognitively healthy individuals by using the CERAD-NB. METHODS: We studied CERAD-NB subtest results, including the Mini-Mental State Examination (MMSE), between 199 patients with probable iNPH, 236 patients with mild AD, and 309 people with normal cognition, using age, education, and gender adjusted multivariate linear regression model. In addition, the effects of AD-related brain pathology detected in frontal cortical brain biopsies in iNPH patients' cognitive profiles were examined. RESULTS: The iNPH patients performed worse than cognitively healthy people in all CERAD-NB subtests. Despite similar performances in the MMSE, AD patients outperformed iNPH patients in Verbal Fluency (p = 0.016) and Clock Drawing (p < 0.001) tests. However, iNPH patients outperformed AD patients in the Boston Naming Test and Word List Recall and Recognition (p < 0.001). AD-related pathology in brain biopsies did not correlate with the CERAD-NB results. CONCLUSION: At the time of the iNPH diagnosis, cognitive performances differed from cognitively healthy people in all CERAD-NB subtests. When the iNPH and AD patients' results were compared, the iNPH patients performed worse in Verbal Fluency and Clock Drawing tests while the AD group had more pronounced episodic memory dysfunctions. This study demonstrates significant differences in the CERAD-NB subtests between cognitive profiles of iNPH and AD patients. These differences are not captured by the MMSE alone.

Cognitive Performance among Cognitively Healthy Adults Aged 30-100 Years.

BACKGROUND/AIMS: To detect cognitive decline in older adults, measures of verbal fluency and verbal memory are widely used. Less is known about performance in these measures in younger persons or according to education level and gender. We investigated cognitive performance according to age, education and gender among cognitively healthy adults aged 30-100 years. METHODS: The study population comprised 4,174 cognitively healthy persons participating in the nationally representative Finnish Health 2011 survey. Cognitive assessment included verbal fluency, word list memory, word list recall and word list savings from the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery. RESULTS: Total variance in the cognitive test performance explained by age, education and gender varied from 12.3 to 31.2%. A decreasing trend in cognitive performance existed in all subtests by advancing age, with differences appearing between 50 and 55 years. Persons with the highest-education level performed best for all measures. For the participants < 55 years, education explained part of the variance, while age and gender did not. CONCLUSIONS: When assessing cognition, age and education should be accounted for in more detail in research and clinical practice. Additionally, the cohort effect and its potential impact on the renewal cycle of future normative values for cognitive tests should be considered.

The Association Between Distinct Frontal Brain Volumes and Behavioral Symptoms in Mild Cognitive Impairment, Alzheimer's Disease, and Frontotemporal Dementia.

Our aim was to investigate the association between behavioral symptoms of agitation, disinhibition, irritability, elation, and aberrant motor behavior to frontal brain volumes in a cohort with various neurodegenerative diseases. A total of 121 patients with mild cognitive impairment (MCI, n = 58), Alzheimer's disease (AD, n = 45) and behavioral variant frontotemporal dementia (bvFTD, n = 18) were evaluated with a Neuropsychiatric Inventory (NPI). A T1-weighted MRI scan was acquired for each participant and quantified with a multi-atlas segmentation method. The volumetric MRI measures of the frontal lobes were associated with neuropsychiatric symptom scores with a linear model. In the regression model, we included CDR score and TMT B time as covariates to account for cognitive and executive functions. The brain volumes were corrected for age, gender and head size. The total behavioral symptom score of the five symptoms of interest was negatively associated with the volume of the subcallosal area (ß = -0.32, p = 0.002). High disinhibition scores were associated with reduced volume in the gyrus rectus (ß = -0.30, p = 0.002), medial frontal cortex (ß = -0.30, p = 0.002), superior frontal gyrus (ß = -0.28, p = 0.003), inferior frontal gyrus (ß = -0.28, p = 0.005) and subcallosal area (ß = -0.28, p = 0.005). Elation scores were associated with reduced volumes of the medial orbital gyrus (ß = -0.30, p = 0.002) and inferior frontal gyrus (ß = -0.28, p = 0.004). Aberrant motor behavior was associated with atrophy of frontal pole (ß = -0.29, p = 0.005) and the subcallosal area (ß = -0.39, p < 0.001). No significant associations with frontal brain volumes were found for agitation and irritability. We conclude that the subcallosal area may be common neuroanatomical area for behavioral symptoms in neurodegenerative diseases, and it appears to be independent of disease etiology.

The Progression of Neuropsychiatric Symptoms in Alzheimer's Disease During a Five-Year Follow-Up: Kuopio ALSOVA Study.

BACKGROUND: An improved understanding of the role of neuropsychiatric symptoms (NPS) in the course of Alzheimer's disease (AD) has recently emerged. NPS lead to hospitalization and caregiver stress, but are more variable during the course of the disease than other symptoms. Knowledge about the role of specific NPS in disease progression and prognosis is especially limited. OBJECTIVES: To examine the relationship between specific NPS and AD severity during a 5-year follow-up period, and to determine which baseline NPS predict AD progression. METHODS: 236 persons with very mild (CDR 0.5) or mild (CDR 1) AD at baseline and their caregivers were followed up for five years as part of the ALSOVA study. The Neuropsychiatric Inventory was used to assess NPS, and AD severity progression was measured with the Clinical Dementia Rating Sum of Boxes. Data was analyzed with Generalized Estimated Equations and Linear Mixed Models. RESULTS: The baseline NPS that best predicted AD progression were delusions, agitation, and aberrant motor behavior, while AD severity during follow-up was associated with hallucinations, delusions, agitation, apathy, aberrant motor behavior, and sleep and appetite disturbances. CONCLUSIONS: Persons with mild AD presenting delusions, agitation, and aberrant motor behavior at the time of diagnosis could have a more rapidly progressing disease, and some NPS are associated with AD severity. These results highlight the importance of evaluating NPS at the time of AD diagnosis, and the need to offer additional support to persons presenting delusions, agitation and aberrant motor behavior, and their caregivers.

Relationships between Cognition and Activities of Daily Living in Alzheimer's Disease During a 5-Year Follow-Up: ALSOVA Study.

BACKGROUND: Impaired cognition and activities of daily living (ADL) are core symptoms of Alzheimer's disease (AD), but their relationship is unclear. OBJECTIVES: To explore relationships between cognitive domains and functional ability during 5-year follow-up in persons with AD. METHODS: We analyzed ALSOVA study data from 236 individuals with very mild or mild AD at baseline. The CERAD Neuropsychological Battery (CERAD-NB) was used as a cognitive measure and Alzheimer's Disease Cooperative Study ADL (ADCS-ADL) as a functional measure, analyzing the IADL and BADL sub-scores separately. Annual regression models and linear mixed-effect models (LMMs) covering a 5-year follow-up period were used. RESULTS: Annually, the CERAD-NB total and especially Verbal Fluency, Clock Drawing, and Constructional Praxis were associated with the total ADCS-ADL and IADL scores increasingly yet modestly, and to a lesser extent the BADL score. In the LMMs, the same measures and MMSE were associated with ADL. CONCLUSION: Measures of executive function and visuoconstructive skills appear to be associated with caregiver-interview based ADL measure during the progression of AD.

Rey's Auditory Verbal Learning Test scores can be predicted from whole brain MRI in Alzheimer's disease.

Rey's Auditory Verbal Learning Test (RAVLT) is a powerful neuropsychological tool for testing episodic memory, which is widely used for the cognitive assessment in dementia and pre-dementia conditions. Several studies have shown that an impairment in RAVLT scores reflect well the underlying pathology caused by Alzheimer's disease (AD), thus making RAVLT an effective early marker to detect AD in persons with memory complaints. We investigated the association between RAVLT scores (RAVLT Immediate and RAVLT Percent Forgetting) and the structural brain atrophy caused by AD. The aim was to comprehensively study to what extent the RAVLT scores are predictable based on structural magnetic resonance imaging (MRI) data using machine learning approaches as well as to find the most important brain regions for the estimation of RAVLT scores. For this, we built a predictive model to estimate RAVLT scores from gray matter density via elastic net penalized linear regression model. The proposed approach provided highly significant cross-validated correlation between the estimated and observed RAVLT Immediate (R = 0.50) and RAVLT Percent Forgetting (R = 0.43) in a dataset consisting of 806 AD, mild cognitive impairment (MCI) or healthy subjects. In addition, the selected machine learning method provided more accurate estimates of RAVLT scores than the relevance vector regression used earlier for the estimation of RAVLT based on MRI data. The top predictors were medial temporal lobe structures and amygdala for the estimation of RAVLT Immediate and angular gyrus, hippocampus and amygdala for the estimation of RAVLT Percent Forgetting. Further, the conversion of MCI subjects to AD in 3-years could be predicted based on either observed or estimated RAVLT scores with an accuracy comparable to MRI-based biomarkers.