Ilona Hallikainen

Diffusion tensor imaging and Tract-Based Spatial Statistics in Alzheimer's disease and mild cognitive impairment

We aimed to explore the changes in fractional anisotropy (FA) in subjects with mild cognitive impairment (MCI) and Alzheimers disease (AD) by analyzing diffusion tensor imaging (DTI) data using the Tract-Based Spatial Statistics (TBSS). DTI data were collected from 17 AD patients, 27 MCI subjects and 19 healthy controls. Voxel-based analysis with TBSS was used to compare FA among the three groups. Additionally, guided by TBSS findings, a region of interest (ROI)-based analysis along the TBSS skeleton was performed on group-level and the accuracy of the method was assessed by the back-projection of ROIs to the native space FA. Neurofiber tracts with decreased FA included: the parahippocampal white matter, cingulum, uncinate fasciculus, inferior and superior longitudinal fasciculus, corpus callosum, fornix, tracts in brain stem, and cerebellar tracts. Quantitative ROI-analysis further demonstrated the significant decrease on FA values in AD patients relative to controls whereas FA values of MCI patients were found in between the controls and AD patients. We conclude that TBSS is a promising method in examining the degeneration of neurofiber tracts in MCI and AD patients.

CERAD‐neuropsychological battery in screening mild Alzheimer’s disease

Sotaniemi M, Pulliainen V, Hokkanen L, Pirttilä T, Hallikainen I, Soininen H, Hänninen T. CERAD‐neuropsychological battery in screening mild Alzheimer’s disease. 
Acta Neurol Scand: 2012: 125: 16–23. 
© 2011 John Wiley & Sons A/S.

24-month intervention with a specific multinutrient in people with prodromal Alzheimer's disease (LipiDiDiet): a randomised, double-blind, controlled trial

Summary Background Nutrition is an important modifiable risk factor in Alzheimers disease. Previous trials of the multinutrient Fortasyn Connect showed benefits in mild Alzheimers disease dementia. LipiDiDiet investigated the effects of Fortasyn Connect on cognition and related measures in prodromal Alzheimers disease. Here, we report the 24-month results of the trial. Methods LipiDiDiet was a 24-month randomised, controlled, double-blind, parallel-group, multicentre trial (11 sites in Finland, Germany, the Netherlands, and Sweden), with optional 12-month double-blind extensions. The trial enrolled individuals with prodromal Alzheimers disease, defined according to the International Working Group (IWG)-1 criteria. Participants were randomly assigned (1:1) to active product (125 mL once-a-day drink containing Fortasyn Connect) or control product. Randomisation was computer-generated centrally in blocks of four, stratified by site. All study personnel and participants were masked to treatment assignment. The primary endpoint was change in a neuropsychological test battery (NTB) score. Analysis was by modified intention to treat. Safety analyses included all participants who consumed at least one study product dose. This trial is registered with the Dutch Trial Register, number NTR1705. Findings Between April 20, 2009, and July 3, 2013, 311 of 382 participants screened were randomly assigned to the active group (n=153) or control group (n=158). Mean change in NTB primary endpoint was −0·028 (SD 0·453) in the active group and −0·108 (0·528) in the control group; estimated mean treatment difference was 0·098 (95% CI −0·041 to 0·237; p=0·166). The decline in the control group was less than the prestudy estimate of −0·4 during 24 months. 66 (21%) participants dropped out of the study. Serious adverse events occurred in 34 (22%) participants in the active group and 30 (19%) in control group (p=0·487), none of which were regarded as related to the study intervention. Interpretation The intervention had no significant effect on the NTB primary endpoint over 2 years in prodromal Alzheimers disease. However, cognitive decline in this population was much lower than expected, rendering the primary endpoint inadequately powered. Group differences on secondary endpoints of disease progression measuring cognition and function and hippocampal atrophy were observed. Further study of nutritional approaches with larger sample sizes, longer duration, or a primary endpoint more sensitive in this pre-dementia population, is needed. Funding European Commission 7th Framework Programme.

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 Alzheimers Disease Neuropsychological Battery (CERAD-NB) total score for monitoring Alzheimers 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 Alzheimers 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.

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.

Early diagnosis, initiation of Alzheimers 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.

Cognitive and Neuropsychiatric Symptom Differences in Early Stages of Alzheimer’s Disease: Kuopio ALSOVA Study

Background/Aim: Alzheimer’s disease (AD) causes impairment in memory and other cognitive functions as well as neuropsychiatric symptoms and limitations in the activities of daily living (ADL). The aim of this study was to examine whether demographic variables, dementia severity, ADL and neuropsychiatric symptoms are associated with cognition in very mild or mild AD. Methods: We analyzed the baseline data of 236 patients with very mild or mild AD participating in a prospective AD follow-up study (ALSOVA). The Consortium to Establish a Registry for Alzheimer’s Disease neuropsychological battery total score was used in the evaluation of the global cognitive performance. Results: Cognition was associated with dementia severity and ADL but not with neuropsychiatric symptoms. ADL functions were associated with both cognitive performance and neuropsychiatric symptoms. Conclusion: Even patients with very mild or mild AD may exhibit neuropsychiatric symptoms not related to cognitive impairment. The results of this study emphasize the importance of taking a multidimensional approach to the diagnostic and prognostic evaluation of AD patients already in the early stages of the disease.

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

To examine the association between neuropsychiatric symptoms (NPS) with self‐ and caregiver‐rated Quality of Life (QoL) for patients with Alzheimers disease (AD) during a 5‐year follow‐up.

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.

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

Reys 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 Alzheimers 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.

Depressive symptoms are associated with analgesic use in people with Alzheimer's disease: Kuopio ALSOVA study.

Neuropsychiatric symptoms of Alzheimer’s disease (AD) such as depression may be associated with pain, which according to the literature may be inadequately recognized and managed in this population. This study aimed to identify the factors associated with analgesic use in persons with AD; in particular, how AD severity, functional status, neuropsychiatric symptoms of AD, co-morbidities and somatic symptoms are associated with analgesic use. 236 community-dwelling persons with very mild or mild AD at baseline, and their caregivers, were interviewed over five years as part of the prospective ALSOVA study. Generalized Estimating Equations (GEEs) were used to estimate unadjusted and adjusted odds ratios (ORs) for the factors associated with analgesic use over a five year follow-up. The proportion of persons with AD using any analgesic was low (13.6%) at baseline and remained relatively constant during the follow-up (15.3% at Year 5). Over time, the most prevalent analgesic changed from non-steroidal anti-inflammatories (8.1% of persons with AD at Year 1) to acetaminophen (11.1% at Year 5). Depressive symptoms (measured by the Beck Depression Inventory, BDI) were independently associated with analgesic use, after effects of age, gender, education, AD severity, comorbidities and somatic symptoms were taken into account. For every one unit increase in BDI, the odds of analgesic use increased by 4% (OR = 1.04, 95% confidence interval CI = 1.02-1.07). Caregiver depressive symptoms were not statistically significantly associated with analgesic use of the person with AD. Depressive symptoms were significantly associated with analgesic use during the five year follow-up period. Possible explanations warranting investigation are that persons with AD may express depressive symptoms as painful somatic complaints, or untreated pain may cause depressive symptoms. Greater awareness of the association between depressive symptoms and analgesic use may lead to safer and more effective prescribing for these conditions.