36-month LipiDiDiet multinutrient clinical trial in prodromal Alzheimer's disease.

INTRODUCTION: The LipiDiDiet trial investigates the effects of the specific multinutrient combination Fortasyn Connect on cognition and related measures in prodromal Alzheimer's disease (AD). Based on previous results we hypothesized that benefits increase with long-term intervention. METHODS: In this randomized, double-blind, placebo-controlled trial, 311 people with prodromal AD were recruited using the International Working Group-1 criteria and assigned to active product (125 mL once-a-day drink) or an isocaloric, same tasting, placebo control drink. Main outcome was change in cognition (Neuropsychological Test Battery [NTB] 5-item composite). Analyses were by modified intention-to-treat, excluding (ie, censoring) data collected after the start of open-label active product and/or AD medication. RESULTS: Of the 382 assessed for eligibility, 311 were randomized, of those 162 participants completed the 36-month study, including 81 with 36-month data eligible for efficacy analysis. Over 36 months, significant reductions in decline were observed for the NTB 5-item composite (-60%; between-group difference 0.212 [95% confidence interval: 0.044 to 0.380]; P = 0.014), Clinical Dementia Rating-Sum of Boxes (-45%; P = 0.014), memory (-76%; P = 0.008), and brain atrophy measures; small to medium Cohen's d effect size (0.25-0.31) similar to established clinically relevant AD treatment. DISCUSSION: This multinutrient intervention slowed decline on clinical and other measures related to cognition, function, brain atrophy, and disease progression. These results indicate that intervention benefits increased with long-term use.

Adherence to multidomain interventions for dementia prevention: Data from the FINGER and MAPT trials.

INTRODUCTION: Multidomain interventions, targeting multiple risk factors simultaneously, could be effective dementia prevention strategies, but may be burdensome and not universally acceptable. METHODS: We studied adherence rates and predictors in the Finnish Geriatric Intervevntion Study to Prevent Cognitive Impairment and Disability and Multidomain Alzheimer Preventive Trial prevention trials, for all intervention components (separately and simultaneously). Finnish Geriatric Intervevntion Study to Prevent Cognitive Impairment and Disability participants received a 2-year multidomain lifestyle intervention (physical training, cognitive training, nutritional counseling, and cardiovascular monitoring). Multidomain Alzheimer Preventive Trial participants received a 3-year multidomain lifestyle intervention (cognitive training, physical activity counseling, and nutritional counseling) with either an omega-3 supplement or placebo. RESULTS: Adherence decreased with increasing intervention complexity and intensity: it was highest for cardiovascular monitoring, nutritional counseling, and the omega-3 supplement, and lowest for unsupervised computer-based cognitive training. The most consistent baseline predictors of adherence were smoking and depressive symptoms. DISCUSSION: Reducing participant burden, while ensuring that technological tools are suitable for older individuals, maintaining face-to-face contacts, and taking into account participant characteristics may increase adherence in future trials.

A nutritional approach to ameliorate altered phospholipid metabolism in Alzheimer's disease.

Recently, a biomarker panel of 10 plasma lipids, including 8 phosphatidylcholine species, was identified that could predict phenoconversion from cognitive normal aged adults to amnestic mild cognitive impairment or Alzheimer's disease (AD) within 2-3 years with >90% accuracy. The reduced levels of these plasma phospholipids could reflect altered phospholipid metabolism in the brain and periphery. We show that a 24-week nutritional intervention in drug-naïve patients with very mild to mild AD significantly increased 5 of the 7 measured biomarker phosphatidylcholine species. By providing nutrients which normally rate-limit phospholipid synthesis, this nutritional intervention could be useful in asymptomatic subjects with a plasma lipid biomarker profile prognostic of AD.

Bepridil decreases Aß and calcium levels in the thalamus after middle cerebral artery occlusion in rats.

Alzheimer's disease (AD) and cerebral ischaemia share similar features in terms of altered amyloid precursor protein (APP) processing and ß-amyloid (Aß) accumulation. We have previously shown that Aß and calcium deposition, and ß-secretase activity, are robustly increased in the ipsilateral thalamus after transient middle cerebral artery occlusion (MCAO) in rats. Here, we investigated whether the non-selective calcium channel blocker bepridil, which also inhibits ß-secretase cleavage of APP, affects thalamic accumulation of Aß and calcium and in turn influences functional recovery in rats subjected to MCAO. A 27-day bepridil treatment (50 mg/kg, p.o.) initiated 2 days after MCAO significantly decreased the levels of soluble Aß40, Aß42 and calcium in the ipsilateral thalamus, as compared with vehicle-treated MCAO rats. Expression of seladin-1/DHCR24 protein, which is a potential protective factor against neuronal damage, was decreased at both mRNA and protein levels in the ipsilateral thalamus of MCAO rats. Conversely, bepridil treatment restored seladin-1/DHCR24 expression in the ipsilateral thalamus. Bepridil treatment did not significantly affect heme oxygenase-1- or NAD(P)H quinone oxidoreductase-1-mediated oxidative stress or inflammatory responses in the ipsilateral thalamus of MCAO rats. Finally, bepridil treatment mitigated MCAO-induced alterations in APP processing in the ipsilateral thalamus and improved contralateral forelimb use in MCAO rats. These findings suggest that bepridil is a plausible therapeutic candidate in AD or stroke owing to its multifunctional role in key cellular events that are relevant for the pathogenesis of these diseases.

Focal cerebral ischemia in rats alters APP processing and expression of Abeta peptide degrading enzymes in the thalamus.

We have previously demonstrated aggregation of amyloid precursor protein (APP) and beta-amyloid (Abeta) to dense plaque-like deposits in the thalamus of rats subjected to transient middle cerebral artery occlusion (MCAO). Here, we investigated the underlying molecular effects of MCAO on APP processing and expression profiles of Abeta degrading enzymes in the cortex adjacent to the infarct (penumbra) and ipsilateral thalamus 2, 7 and 30 days after ischemic insult. Enhanced beta-amyloidogenic processing of APP and altered insulin degrading enzyme and neprilysin expression were observed in the thalamus, but not the penumbral cortex, 7 and 30 days after MCAO coinciding with increased calcium levels and beta-secretase (BACE) activity. Consecutively, increased BACE activity associated with depletion of BACE trafficking protein GGA3, suggesting a post-translational stabilization of BACE. These results demonstrate that focal cerebral ischemia leads to complex pathogenic events in the thalamus long after the initial insult.

Midlife coffee and tea drinking and the risk of late-life dementia: a population-based CAIDE study.

Caffeine stimulates central nervous system on a short term. However, the long-term impact of caffeine on cognition remains unclear. We aimed to study the association between coffee and/or tea consumption at midlife and dementia/Alzheimer's disease (AD) risk in late-life. Participants of the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study were randomly selected from the survivors of a population-based cohorts previously surveyed within the North Karelia Project and the FINMONICA study in 1972, 1977, 1982 or 1987 (midlife visit). After an average follow-up of 21 years, 1409 individuals (71%) aged 65 to 79 completed the re-examination in 1998. A total of 61 cases were identified as demented (48 with AD). Coffee drinkers at midlife had lower risk of dementia and AD later in life compared with those drinking no or only little coffee adjusted for demographic, lifestyle and vascular factors, apolipoprotein E epsilon4 allele and depressive symptoms. The lowest risk (65% decreased) was found in people who drank 3-5 cups per day. Tea drinking was relatively uncommon and was not associated with dementia/AD. Coffee drinking at midlife is associated with a decreased risk of dementia/AD later in life. This finding might open possibilities for prevention of dementia/AD.

A multi-metabolite analysis of serum by 1H NMR spectroscopy: early systemic signs of Alzheimer's disease.

A three-molecular-window approach for (1)H NMR spectroscopy of serum is presented to obtain specific molecular data on lipoproteins, various low-molecular-weight metabolites, and individual lipid molecules together with their degree of (poly)(un)saturation. The multiple data were analysed with self-organising maps, illustrating the strength of the approach as a holistic metabonomics framework in solely data-driven metabolic phenotyping. We studied 180 serum samples of which 30% were related to mild cognitive impairment (MCI), a neuropsychological diagnosis with severely increased risk for Alzheimer's disease (AD). The results underline the association between MCI and the metabolic syndrome (MetS). Additionally, the low relativeamount of omega-3 fatty acids appears more indicative of MCI than low serum omega-3 or polyunsaturated fatty acid concentration as such. The analyses also feature the role of elevated glycoproteins in the risk for AD, supporting the view that coexistence of inflammation and the MetS forms a high risk condition for cognitive decline.

Fat intake at midlife and cognitive impairment later in life: a population-based CAIDE study.

OBJECTIVE: To investigate the association of midlife dietary fat intake to cognitive performance, and to the occurrence of clinical mild cognitive impairment (MCI) later in life in a non-demented population. DESIGN: A longitudinal population-based study. SETTING: Populations of Kuopio and Joensuu, Eastern Finland. PARTICIPANTS AND METHODS: Participants of the CAIDE study were derived from random, population-based samples studied at midlife (1972, 1977, 1982 or 1987). After an average follow-up of 21 years, a total of 1449 (72%) individuals aged 65-80 years participated in the re-examination in 1998. Altogether 82 (5.7%) people were diagnosed as having MCI. Dietary information was collected with a structured questionnaire and an interview at midlife. MAIN OUTCOME MEASURES: MCI, global cognitive and executive functions, episodic, semantic and prospective memory and psychomotor speed. RESULTS: Abundant saturated fat (SFA) intake from milk products and spreads at midlife was associated with poorer global cognitive function and prospective memory and with an increased risk of MCI (OR 2.36, 95% CI 1.17-4.74) after adjusting for demographic and vascular factors, other fats and ApoE. On the contrary, high intake of polyunsaturated fatty acids (PUFA) was associated with better semantic memory. Also frequent fish consumption was associated with better global cognitive function and semantic memory. Further, higher PUFA-SFA ratio was associated with better psychomotor speed and executive function. CONCLUSIONS: Our data suggests that dietary fat intake at midlife affects cognitive performance and occurrence of MCI later in life. The impact of dietary interventions needs to be tested in clinical trials.

Coaccumulation of calcium and beta-amyloid in the thalamus after transient middle cerebral artery occlusion in rats.

Transient occlusion of the middle cerebral artery (MCAO) in rats leads to abnormal accumulation of beta-amyloid (Abeta) peptides in the thalamus. This study investigated the chemical composition of these deposits. Adult male human beta-amyloid precursor protein (APP) overexpressing (hAPP695) rats and their wild-type littermates were subjected to transient MCAO for 2 h or sham operation. After 26-week survival time, histological examination revealed an overlapping distribution pattern for rodent and human Abeta in the thalamus of hAPP695 rats subjected to MCAO. X-ray microanalysis showed that the deposits did not contain significant amount of iron, zinc, or copper typical to senile plaques. In contrast, the deposit both in hAPP695 and non-transgenic rats contained calcium and phosphorus in a ratio (1.28+/-0.15) characteristic to hydroxyapatites. Alizarin red staining confirmed that calcium coaccumulated in these Abeta deposits. It is suggested that APP expression is induced by ischemic insult in cortical neurons adjacent to infarct, which in turn is reflected as increased release of Abeta peptides by their corticothalamic axon endings. This together with insufficient clearance or atypical degradation of Abeta peptides lead to dysregulation of calcium homeostatis and coaccumulation in the thalamus.