V.2. Strengths and limits of the study
This study was novel in its recruitment of patients with three different eye diseases compared to a control group with good vision. No studies have been done to examine the relationship between eye diseases like glaucoma or Fuchs with cognitivefunction using the MMSE Blind version test. Cognitivefunction was measured by MMSE-Blind version test, which was validated by Busse et al against the full version. The test did not rely on vision because it omits 8 items that require image processing in a test situation (range 0-22). Data on potential confounders such as age, gender, ethnicity, living alone, comorbidities, education and lens opacity were also collected and included in the analysis. All potential patients were recruited from the same clinics and response rate was recorded. There was a representative sample of eligible patients from the clinic. There was a 67 % response rate in this study.
totally preserves cone functionand limits loss of function in rods, as well as photoreceptor degeneration and A2E accumulation. By contrast, during norbixin supplementation of younger mice (starting at 1.5 months), we only observed a slight but significant protective effect of norbixin on scotopic A wave ERG and on retinal accumulation of A2E. This might be related to the fact that sharp decrease in scotopic A wave amplitude and an important A2E accumulation occur during the early retinal degeneration phase. The neuroprotective effect of norbixin in Abca4 -/- Rdh8 -/- mice during the early curative supplementation confirms our previous observations in acute blue-light induced retinal degeneration model in vivo in the same mice . In the three supplementation protocols (preventive, early and late curative), norbixin prevented the loss of scotopic A wave amplitude measured by ERGs. This suggests a protective effect on rod photoreceptors by norbixin. Rods are the first neurons affected during the early stages of AMD and STGD [13, 14]. They are also much more abundant in the mouse retina than cones [13, 14]. In the preventive supplementation the protective effect of norbixin on rod function, was associated with a slight reduction of A2E concentration (Figure 2). This slight reduction however appears insufficient to prevent the loss of cone function as demonstrated by the absence of effect on photopic B wave. The loss of rod’s function is a progressive phenomenon observed even in 15-month-old Abca4 -/ -
However, this interpretation in terms of a reduction of the central execu- tive resources and of a frontal deficit affecting inhibition has been questioned recently by Fisk and Warr (1996). Fisk and Warr (1996) compared older and younger subjects on a random generation task similar to that conducted in Experiment 1. They asked subjects to generate letters in a random se- quence, at each of three production rates (4, 2, and 1 s). Only two measures of randomness were taken at each of the elicitation rates: the number of times any letter pair is repeated and the number of letter pairs which are alphabetically ordered (this yielded a total of six scores). Significant positive age correlations for five of the six scores were observed, which seems to indicate a decline of central executive function with age. In addition, the age effect in random generation (measured through one score which combined the preceding measures) remained significant after statistical control for the phonological loop functioning (measured through word span and digit span). However, these age differences in random generation were largely elimi- nated after controlling for age deficits in perceptual speed (measured by means of a letter and a pattern comparison speed task). These findings are consistent with the numerous studies conducted by Salthouse (for a review, see Salthouse, 1992; 1994) who showed that although increased age is asso- ciated with lower performance on working memory tasks, many of these age- related differences appear to be mediated by a slower speed of processing. Therefore, it appears that the main part of the age-related variations observed in random generation could be due to a general reduction of perceptual speed rather than to a specific problem affecting the central executive. According to Salthouse (1996), reduction in speed leads to impairments in cognitive functioning because relevant operations cannot be successfully executed (the limited time mechanism) and because the products of early processing may no longer be available when later processing is complete (the simultaneity mechanism). In the context of random generation, slowing (through either limited time or simultaneity mechanisms) would disrupt the different opera- tions of the central executive needed for random generation, that is to switch strategies, to access new strategies, and to monitor response output (Badde- ley, 1996).
of 5 seconds or less was indicative of a recent fall 29 . Falls were examined as having reported a fall in the last year or not.
Descriptive statistics were calculated including means, standard deviations, and percentages. Vision, demographic, health, and mobility variables were compared for the three eyedisease groups and the control group using ANOVA or chi-square tests. Next, to determine if eyedisease was independently associated with any of the mobility outcomes, regression was used to adjust for potential confounding. The different disease groups (AMD, glaucoma, and Fuchs dystrophy) were entered as indicator variables in the regression model with the control group as the reference. Linear regression was used to determine if LS-C or TUG scores differed for any of the eyedisease groups compared to the control group after adjustment for demographic and health variables including age, gender, education, body mass index, depression, number of comorbidities, benzodiazepine use, andcognitive status. Race was not included in the regression models due to the absence of non-white patients in certain eyedisease groups. The relationship between eyediseaseand the dichotomous outcomes (falls, balance) were examined using logistic regression.
lowing. reasoning was measured using the alice Heim 4-i test, which is composed of a series of 65 verbal and mathemati- cal reasoning items of increasing difficulty. the test measures inductive reasoning, the ability to identify patterns and infer principles and rules. Short-term verbal memory was measured with a 20-word free-recall test in which participants were pre- sented a list of 20 1 or 2 syllable words at 2-second intervals and were then asked to recall them in writing (in any order, within 2 minutes). two measures of verbal fluency were assessed: semantic and phonemic. to measure semantic fluency, partici- pants were asked to recall in writing as many animal names as they could within 1 minute. to measure phonemic fluency, par- ticipants were similarly asked to recall words beginning with “S.” We did not include neurodegenerative diseases in the anal- ysis because numbers are very small given the relatively young age of the cohort at the last follow-up (mean age = 66 years).
In accordance with these models, Braver and colleagues  developed a “context-processing” account to provide an explanation of the previously observed age-related de- cline in cognitive functions [15-19]. These authors defined “context” as all internal task-relevant representations (based on a particular previous stimulus, the processing of an entire sequence of stimuli, specific task instructions, or a particular goal) allowing to bias behavior to efficiently respond to task demands. Consequently, context repre- sentations may be particularly important to influence cognitive processing. Braver et al.  argued that age- related difficulties observed in working memory, inhibition, attention and executive function may be in fact influenced by the impairment of the ability to maintain context repre- sentations in an active state. Following this theoretical background, Braver and collaborators  also described a general framework of cognitive control (“the Dual Mecha- nisms of Control model”, DMC, see below for a detailed presentation) that postulates the existence of two distinct mechanisms: proactive and reactive control processes see also [21,22]. In the present study, we were interested in in- vestigating the potential age-relatedcognitive control de- cline by distinguishing proactive and reactive control processes. Indeed, the DMC account provides an elegant framework to subtly assess individual differences in cogni- tive control processes and complements the “context pro- cessing theory” [13,14].
the world and rates of coronary heart disease, certain cancers and other nutrition-related chronic diseases were among the lowest . Not a specific pattern but a collection of eating habits traditionally followed by the populations of the Mediterranean basin first defined the Mediterranean diet called “traditional”. This dietary pattern is characterized by abundant plant foods consumption in the form of fruits, vegetables, breads, other forms of cereals, potatoes, beans, nuts and seeds; fresh fruit as the typical dessert; olive oil as the main source of monounsaturated fat; dairy products as principally cheese and yogurt; a low to moderate consumption of fish depending of the proximity of the sea; a low to moderate consumption of poultry; fewer than four eggs consumed per week; low amount of red meat and wine
a critical role in optimal brain development andfunction  . This review aims to update
the potential protective role of dietary DHA intake in age-relatedcognitive decline which has been intensively investigated over the past decade. First, we will describe a selec- tion of the evidence from in vitro and animal studies highlighting the protective role of omega-3 PUFA against some neuropatholog- ical features of age-relatedcognitive decline, especially glucose hypometabolism. Then we will discuss the results obtained from human studies, especially the divergence of results obtained from epidemiological studies and randomized clinical trials (RCT). Finally, we will highlight some metabolic features that Challenges to determining whether DHA can protect against age-relatedcognitive decline
We examined the association between participation in leisure activities andcognitivefunction in a large cohort study. Cognitivefunction was assessed comprehensively in this study with measures on memory, verbal fluency, fluid (AH 4) and crystallised intelligence (Mill Hill). The overall ‘‘index of participation in leisure activities’’ was significantly related to cognitivefunction. Examination of leisure activities, one at a time, shows some activities to have a stronger relation with cognitivefunction than others. Activities that show a link with cognition entail investment in personal development (cultural visits, individual occupations like reading, courses and evening classes), social engagement (social indoor games) and involvement in the community (involvement in clubs and organisations, voluntary or official).
could still have occurred by chance. It would be injudicious to generalize cognitive findings in healthy postmenopausal midlife women — where serum levels of estrone and estradiol are relative low — to clinical populations (for example, women with frank dementia) or to women with hormone levels above the range included in our sample (for example, women of reproductive age or postmenopausal women receiving exogenous estrogens or testosterone). Data concerning some covariates were self-reported and thus may be subject to recall bias and misclassification. Bias may have been introduced through the exclusion of women who did not complete the cognitive testing or who used hormone therapy. In longitudinal analyses, we examined cognitive change over a two year period, and for most tests the average score had improved. This practice effect made it more difficult to detect associations between hormone levels andage-relatedcognitive decline, particularly as women were relatively young (mean age 60 years) and healthy. Because we did not measure hormone levels at the time of the second testing, we were unable to examine associations between hormone changes andcognitive change. Finally, there may have been unrecognized confounding factors that were not considered in these analyses.
Across development children show marked improvement in their executive functions (EFs), including the ability to hold information in working memory and to deploy cognitive control, allowing them to ignore prepotent responses in favor of newly learned behaviors. How does the brain support these age-related improvements? Age-related cortical gray-matter thinning, thought to result from selective pruning of inefficient synaptic connections and increases in myelination, may support age-related improvements in EFs. Here we used structural MRI to measure cortical thickness. We investigate the association between cortical thickness in three cortical regions of interest (ROIs), andage-related changes in cognitive control and working memory in 5–10 year old children. We found significant associations between reductions in cortical thickness andage- related improvements in performance on both working memory andcognitive control tasks. Moreover, we observed a dissociation between ROIs typically thought to underlie changes in cognitive control (right Inferior Frontal gyrus and Anterior Cingulate cortex) andage-related improvements in cognitive control, and ROIs for working memory (superior parietal cortex), andage-related changes in a working memory task. These data add to our growing understanding of how structural maturation of the brain supports vast behavioral changes in executive functions observed across childhood.
presented on the rear of a Ganzfeld bowl (white- adapting background, luminance of 40 cd/m 2 ). A
diffusing filter in front of the LED array made it appear as a circle of uniform red light. The fERGs were recorded in response to the sinusoidal 95% luminance modulation of a red uniform field (subtending 18° of visual angle) and centered on the fovea. Flicker- ing frequency was 41 Hz. The same apparatus was used throughout the years, with periodic controls of LED and background intensity. Under the constant monitoring of an external observer, patients fixed a central fixation mark monocularly at 0.25°. Pupils were dilated to a diameter of 8 mm using 1% tropicamide and 2.5% phenylephrine hydrochloride, and all subjects underwent a preadaptation period of 20 minutes to the stimulus mean illuminance. The fERGs were recorded by an Ag–AgCl electrode taped on the skin over the lower eyelid. A similar electrode, placed over the eyelid of the contralateral patched eye, was used as reference (interocular recording). The fERG signals were ampli- fied (100,000-fold), bandpass filtered between 1 and 100 Hz (6 decibels/octave), and averaged (12-bit resolu- tion, 2-kHz sampling rate, 200–600 repetitions in 2–6 blocks). Off-line discrete Fourier analysis quantified the peak-to-peak amplitude and phase lag of the response fundamental harmonic (first harmonic) at 41 Hz. The lower limit of the fERG amplitude normal range was 1.1 μV.
tau, particularly over the basal ganglia, which was taken into account by excluding basal ganglia from all computations of PET SUVR values for tau-PET. Cognitive assessment. Upon arrival for the wake-extension protocol and prior to being placed in dim-light (~7.5 h before habitual bedtime, corresponding to ~3:30PM for a representative subject with bedtime at 11:00PM), participants were administered the ﬁrst part (~1 h) of the extensive neuropsychological assessment including: (1) Mnemonic Similarity Task; (2) Category Verbal Fluency (letter and animals); (3) Digit Symbol Substitution Test; (4) Visual N-Back (1 −, 2−*, and 3-back variants); and (5) Choice Reaction Time. On another day while well-rested and during the day (from 12 to 6 h before habitual bedtime, i.e. between 11:00AM and 5:00PM for the same representative subject), the second part of the neu- ropsychological assessment was administered. This ~1.5 h session included: (1) Direct and Inverse Digit Span; (2) Free and Cued Selective Reminding Test; (3) Stroop Test; (4) Trail Making Test (part A and B); and (5) D2 Attention Test. The memory function composite score included Free and Cued Selective Reminding Test (sum of all free recalls) and Mnemonic Similarity Task (recognition memory score). The executive function composite score comprised verbal ﬂuency tests (2-min score for letter and animal variants), the digit span (inverse order), Trail Making Test (part B), N-Back (3-back variant), and Stroop (number of errors for interfering items). The attentional function composite score included Digit Symbol Substitution Test (2-min score), Trail Making Test (part A), N-Back (1-back variant), D2 (Gz - F score), and Choice Reaction Time (reaction time to dissimilar items). We computed a composite score for each cognitive domain based on the sum of Z-scores on domain-related tasks, with higher scores re ﬂecting better performance. Composite score for global cognitive performance score consisted of the standardized sum of the domain-speciﬁc composite scores.
disruption becomes evident in key components of the molecular clockwork (Roberts et al., 2012).
Circadian arousal regulation acts via indirect projections from the SCN to the arousal-promoting LC in the brainstem (Aston- Jones et al., 2001). Interestingly, the LC has the potential to impact on higher order cognitive performance and shows early vulnera- bility to the aging process, such that neuron density within the LC decreases with age due to a progressive loss of cell number and size of noradrenergic neurons both in animals and humans (Samuels and Szabadi, 2008). Furthermore, the loss of noradrenergic LC axons innervating the frontal cortex has been associated with mod- ifications in the electrophysiological properties of the remaining LC terminals (Samuels and Szabadi, 2008). The SCN has also a weak direct projection to the wake-active orexin-producing neu- rons in the lateral hypothalamic area (Saper et al., 2001). Since the densest projection of orexin fibers terminates in the LC, it has also been suggested that the LC controls the activity of orexin neurons directly by inhibiting orexin firing and indirectly via the DMH. Interestingly, orexin secretion follows a circadian variation in rats (Zhang et al., 2004), monkeys (Zeitzer et al., 2003), and humans (Salomon et al., 2003), which might be the result of direct or indirect inputs from the SCN to the orexin circuits. Indeed lesions of the SCN suppress the daily orexin rhythm (Deboer et al., 2004; Adamantidis and de Lecea, 2008). On the other side, orexin levels increased in response to sleep deprivation in both control and SCN-lesioned animals, demonstrating that sleep homeostatic control of orexin occurs independently from the SCN (Deboer et al., 2004). It is known that orexin in the lateral hypothala- mus influences many integrative homeostatic processes related to wakefulness and plays a crucial role in sleep architecture and state stabilization throughout the sleep-wake cycle (Saper et al., 2001). Kessler et al. (2011) observed that aged rats exhibited a loss of greater than 40% of orexin-immunoreactive neurons, sug- gesting that compromised orexin function could be an important mediator of age-related homeostatic disturbances of hypothalamic origin.
Public health interest in the association between vascular factors, hypertension in
particular, and dementia is driven by the fact that it is a treatable risk factor. Our results have
public health significance as elevated levels of blood pressure are found to be related to poor
cognitive performance even in a group with a low proportion of hypertensives. Furthermore, the
Reger et al., 2004; Reger et al., 2008). Ketones may be easily produced following the ingestion of medium chain triglycerides (Courchesne-Loyer et al., 2013).
In a pilot study, Reger et al. (2004) demonstrated that a one-time dose of MCT improved test scores on the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) in a sample of Alzheimer’s disease patients’ who did not have an APOE-ε4 allele. Medium chain triglycerides are readily metabolized to ketones with a peak in plasma ketone concentrations two hours post supplementation (Henderson, 2004). The oral dose of MCTs succeeded in elevating β-hB levels an average of 7.7-fold, 90 min after MCT treatment (Reger et al., 2004). In a ninety day trial, Henderson et al. (2009) demonstrated, in a sample of 152 mild to moderate Alzheimer’s disease patients,’ that MCT supplementation resulted in improvement on the ADAS-Cog test. The Alzheimer’s disease patients’ were able to continue with their normal diet and take their approved Alzheimer’s disease medications throughout the study. These studies suggest that neurons may simply be starved of energy and are still capable of using non-glucose derived energy. Studies using PET should further explore MCT supplementation in Alzheimer’s patients. A decrease in glucose metabolism when ketones are taken up by the brain would indicate that sufficient energy is being supplied to the brain by glucose itself. However, if glucose uptake does not decrease when ketones are supplied to the brain, this would indicate that the brain is in a starved state. In a sample of 23 older adults with mild cognitive impairment, Krikorian et al. (2012) randomly assigned a six week intervention of either a high carbohydrate (50% of calories) or very low carbohydrate (5% to 10% of calories) diet. Following the 6-week intervention period, improved performance was observed on the verbal paired associate learning test for the low carbohydrate participants (p=0.01) while the high carbohydrate participants did not demonstrate any differences. The diet also resulted in decreases in weight (-5%, p<0.0001), fasting glucose (-10%, p<0.009), and fasting insulin (-18%, p<0.005).
The cingulum bundle is one of the most studied white matter tracts running from the ante- rior to the posterior part of the brain that interconnects frontal, parietal, and temporal areas [ 58 – 60 ]. Due to this central location, the cingulum plays a central role in white matter archi- tecture and functional networks that support and contribute to optimal cognitivefunction [ 60 ]. Some previous studies [ 59 , 61 – 63 ] but not all [ 64 , 65 ] described a decrease in FA and an increase in AD, RD and/or MD along the cingulum bundle. These changes within this bundle due to aging were correlated with executive and memory deficits [ 26 , 59 , 61 , 66 – 68 ]. However, these observations still remain controversial considering that most of these studies did not consider CSF partial effect due to atrophy or WMH burden. Recent tractography studies con- sistently observed that atrophy-related partial volume effects [ 24 , 26 ] andage-related ventricu- lar enlargement [ 23 ] or WMH burden [ 54 ] affect diffusion measures of the cingulum in healthy older individuals. In this regard, Reginold and colleagues reported higher RD in cingu- lum tracts that crossed WMH than those outside WMH regions [ 23 , 54 ]. Atrophy and WMH burden might therefore impact cingulum diffusion measures suggesting a source of significant
Conclusions: Excessive alcohol consumption in men ($36 g/d) was associated with faster cogni- tive decline compared with light to moderate alcohol consumption. Neurology ® 2014;82:332 –339
Alcohol misuse is a leading preventable cause of morbidity and mortality. 1 In addition to chronic diseases, alcohol may affect aging outcomes, but this effect remains poorly understood. Light to moderate alcohol consumption is hypothesized to be associated with better cognitivefunctionand lower risk of dementia, 2–9 but less is known about the impact of alcohol on cognitive aging trajec- tories because much of the evidence comes from studies conducted in elderly populations 10–17 in which health-related changes in alcohol consumption are likely to influence results. 2 Because alcohol consumption declines with age, 18 the heavy drinking category is either small 12,13,15,17 or not repre- sented at all 10,11,14,16 in these studies. Besides notable exceptions, 19,20 few studies have examined the impact of alcohol consumption on cognitive aging trajectories before old age. Furthermore, alcohol consumption is often assessed only once, resulting in possible measurement error bias. The objective of the present study was to examine the association of midlife alcohol consumption assessed 3 times over a 10-year period with subsequent cognitive decline using 3 waves of cognitive data.
It could be reasonably contended that these mechanisms of interaction between AD and vascular pathways may not yet be detectable in asymptomatic individuals because they emerge later in the course of the disease. Challenging this proposition, however, recent work has provided evidence that Aβ deposition and total WMH volume in healthy older adults have synergistic associations with grey matter neurometabolic alterations typically associated with AD, especially in the posterior cingulate and precuneus (Schreiner et al., 2018). Therefore, AD and cerebrovascular disease pathophysiology may yield mutually potentiating effects which, albeit subtle, are detectable even in the absence of objective cognitive impairment (i.e. in the hypothetical preclinical stage of dementia). Pertaining to cognitive effects of Aβ deposition and WMH in normal older adults, our results advocate the existence of both additive and synergistic associations, depending on the cognitive domains. It is worth noting that the presence of synergy in several cognitive domains lends support to the notion that Aβ and WMH interact at a physiological level through one or several of the aforementioned mechanisms. Thus, despite reflecting initially independent disease pathways, Aβ and WMH pathologies appear to exert interactive effects on cognition in healthy older adults. This finding strongly suggests that AD and cerebrovascular disease pathways converge at some point in time in preclinical individuals, and that their interactive effects and co-occurrence are likely to increase with the disease progression.
level, cognitive changes preceding Alzheimer’s disease onset initially consist of subtle decreases in episodic memory. 33 The job control subscale asks questions like, ―In my work, I learn new things,‖ ―My
work requires me to be creative,‖ ―In my work, I have repetitive tasks,‖ and ―My work allows me to make decisions.‖ Control thus reflects task complexity, on-going learning, and self-direction, which in non- occupational settings are protective against cognitive decline or dementia. 34 Those findings help explain