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Higher CSF Tau Levels Are Related to Hippocampal Hyperactivity and Object Mnemonic Discrimination in Older Adults.
Berron, D, Cardenas-Blanco, A, Bittner, D, Metzger, CD, Spottke, A, Heneka, MT, Fliessbach, K, Schneider, A, Teipel, SJ, Wagner, M, et al
The Journal of neuroscience : the official journal of the Society for Neuroscience. 2019;(44):8788-8797
Abstract
Mnemonic discrimination, the ability to distinguish similar events in memory, relies on subregions in the human medial temporal lobes (MTLs). Tau pathology is frequently found within the MTL of older adults and therefore likely to affect mnemonic discrimination, even in healthy older individuals. The MTL subregions that are known to be affected early by tau pathology, the perirhinal-transentorhinal region (area 35) and the anterior-lateral entorhinal cortex (alEC), have recently been implicated in the mnemonic discrimination of objects rather than scenes. Here we used an object-scene mnemonic discrimination task in combination with fMRI recordings and analyzed the relationship between subregional MTL activity, memory performance, and levels of total and phosphorylated tau as well as Aβ42/40 ratio in CSF. We show that activity in alEC was associated with mnemonic discrimination of similar objects but not scenes in male and female cognitively unimpaired older adults. Importantly, CSF tau levels were associated with increased fMRI activity in the hippocampus, and both increased hippocampal activity as well as tau levels were associated with mnemonic discrimination of objects, but again not scenes. This suggests that dysfunction of the alEC-hippocampus object mnemonic discrimination network might be a marker for tau-related cognitive decline.SIGNIFICANCE STATEMENT Subregions in the human medial temporal lobe are critically involved in episodic memory and, at the same time, affected by tau pathology. Impaired object mnemonic discrimination performance as well as aberrant activity within the entorhinal-hippocampal circuitry have been reported in earlier studies involving older individuals, but it has thus far remained elusive whether and how tau pathology is implicated in this specific impairment. Using task-related fMRI in combination with measures of tau pathology in CSF, we show that measures of tau pathology are associated with increased hippocampal activity and reduced mnemonic discrimination of similar objects but not scenes. This suggests that object mnemonic discrimination tasks could be promising markers for tau-related cognitive decline.
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2.
Memantine improves attention and episodic memory in Parkinson's disease dementia and dementia with Lewy bodies.
Wesnes, KA, Aarsland, D, Ballard, C, Londos, E
International journal of geriatric psychiatry. 2015;(1):46-54
Abstract
OBJECTIVE In both dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), attentional dysfunction is a core clinical feature together with disrupted episodic memory. This study evaluated the cognitive effects of memantine in DLB and PDD using automated tests of attention and episodic memory. METHODS A randomised double-blind, placebo-controlled, 24-week three centre trial of memantine (20 mg/day) was conducted in which tests of attention (simple and choice reaction time) and word recognition (immediate and delayed) from the CDR System were administered prior to dosing and again at 12 and 24 weeks. Although other results from this study have been published, the data from the CDR System tests were not included and are presented here for the first time. RESULTS Data were available for 51 patients (21 DLB and 30 PDD). In both populations, memantine produced statistically significant medium to large effect sized improvements to choice reaction time, immediate and delayed word recognition. CONCLUSIONS These are the first substantial improvements on cognitive tests of attention and episodic recognition memory identified with memantine in either DLB or PDD.
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Results of 2-year vitamin B treatment on cognitive performance: secondary data from an RCT.
van der Zwaluw, NL, Dhonukshe-Rutten, RA, van Wijngaarden, JP, Brouwer-Brolsma, EM, van de Rest, O, In 't Veld, PH, Enneman, AW, van Dijk, SC, Ham, AC, Swart, KM, et al
Neurology. 2014;(23):2158-66
Abstract
OBJECTIVE We investigated the effects of 2-year folic acid and vitamin B12 supplementation on cognitive performance in elderly people with elevated homocysteine (Hcy) levels. METHODS This multicenter, double-blind, randomized, placebo-controlled trial included 2,919 elderly participants (65 years and older) with Hcy levels between 12 and 50 µmol/L. Participants received daily either a tablet with 400 µg folic acid and 500 µg vitamin B12 (B-vitamin group) or a placebo tablet. Both tablets contained 15 µg vitamin D3. Data were available for global cognitive functioning assessed by Mini-Mental State Examination (n = 2,556), episodic memory (n = 2,467), attention and working memory (n = 759), information processing speed (n = 731), and executive function (n = 721). RESULTS Mean age was 74.1 (SD 6.5) years. Hcy concentrations decreased 5.0 (95% confidence interval -5.3 to -4.7) µmol/L in the B-vitamin group and 1.3 (-1.6 to -0.9) µmol/L in the placebo group. Cognitive domain scores did not differ over time between the 2 groups, as determined by analysis of covariance. Mini-Mental State Examination score decreased with 0.1 (-0.2 to 0.0) in the B-vitamin group and 0.3 (-0.4 to -0.2) in the placebo group (p = 0.05), as determined by an independent t test. CONCLUSIONS Two-year folic acid and vitamin B12 supplementation did not beneficially affect performance on 4 cognitive domains in elderly people with elevated Hcy levels. It may slightly slow the rate of decline of global cognition, but the reported small difference may be attributable to chance. CLASSIFICATION OF EVIDENCE This study provides Class I evidence that 2-year supplementation with folic acid and vitamin B12 in hyperhomocysteinemic elderly people does not affect cognitive performance.
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Practice effects in a longitudinal, multi-center Alzheimer's disease prevention clinical trial.
Abner, EL, Dennis, BC, Mathews, MJ, Mendiondo, MS, Caban-Holt, A, Kryscio, RJ, Schmitt, FA, , , Crowley, JJ, ,
Trials. 2012;:217
Abstract
BACKGROUND Practice effects are a known threat to reliability and validity in clinical trials. Few studies have investigated the potential influence of practice on repeated screening measures in longitudinal clinical trials with a focus on dementia prevention. The current study investigates whether practice effects exist on a screening measure commonly used in aging research, the Memory Impairment Screen (MIS). METHODS The PREADViSE trial is a clinical intervention study evaluating the efficacy of vitamin E and selenium for Alzheimer's disease prevention. Participants are screened annually for incident dementia with the MIS. Participants with baseline and three consecutive follow-ups who made less than a perfect score at one or more assessments were included in the current analyses (N=1,803). An additional subset of participants with four consecutive assessments but who received the same version of the MIS at baseline and first follow-up (N=301) was also assessed to determine the effects of alternate forms on mitigating practice. We hypothesized that despite efforts to mitigate practice effects with alternate versions, MIS scores would improve with repeated screening. Linear mixed models were used to estimate mean MIS scores over time. RESULTS Among men with four visits and alternating MIS versions, although there is little evidence of a significant practice effect at the first follow-up, mean scores clearly improve at the second and third follow-ups for all but the oldest participants. Unlike those who received alternate versions, men given the same version at first follow-up show significant practice effects. CONCLUSION While increases in the overall means were small, they represent a significant number of men whose scores improved with repeated testing. Such improvements could bias case ascertainment if not taken into account.