Cancer-related cognitive impairment: an update on state of the art, detection, and management strategies in cancer survivors.

BACKGROUND: Advances in diagnostic and therapeutic strategies in oncology have significantly increased the chance of survival of cancer patients, even those with metastatic disease. However, cancer-related cognitive impairment (CRCI) is frequently reported in patients treated for non-central nervous system cancers, particularly during and after chemotherapy. DESIGN: This review provides an update of the state of the art based on PubMed searches between 2012 and March 2019 on 'cognition', 'cancer', 'antineoplastic agents' or 'chemotherapy'. It includes the most recent clinical, imaging and pre-clinical data and reports management strategies of CRCI. RESULTS: Evidence obtained primarily from studies on breast cancer patients highlight memory, processing speed, attention and executive functions as the most cognitive domains impaired post-chemotherapy. Recent investigations established that other cancer treatments, such as hormone therapies and targeted therapies, can also induce cognitive deficits. Knowledge regarding predisposing factors, biological markers or brain functions associated with CRCI has improved. Factors such as age and genetic polymorphisms of apolipoprotein E, catechol-O-methyltransferase and BDNF may predispose individuals to a higher risk of cognitive impairment. Poor performance on neuropsychological tests were associated with volume reduction in grey matter, less connectivity and activation after chemotherapy. In animals, hippocampus-based memory and executive functions, mediated by the frontal lobes, were shown to be particularly susceptible to the effects of chemotherapy. It involves altered neurogenesis, mitochondrial dysfunction or brain cytokine response. An important next step is to identify strategies for managing cognitive difficulties, with primary studies to assess cognitive training and physical exercise regimens. CONCLUSIONS: CRCI is not limited to chemotherapy. A multidisciplinary approach has improved our knowledge of the complex mechanisms involved. Nowadays, studies evaluating cognitive rehabilitation programmes are encouraged to help patients cope with cognitive difficulties and improve quality of life during and after cancer.

Dramatic changes to well-known places go unnoticed.

How well do we know our city? It turns out, much more poorly than we might imagine. We used declarative memory and eye-tracking techniques to examine people's ability to detect modifications to real-world landmarks and scenes in Toronto locales with which they have had extensive experience. Participants were poor at identifying which scenes contained altered landmarks, whether the modification was to the landmarks' relative size, internal features, or relation to surrounding context. To determine whether an indirect measure would prove more sensitive, we tracked eye movements during viewing. Changes in overall visual exploration, but not to specific regions of change, were related to participants' explicit endorsement of scenes as modified. These results support the contention that very familiar landmarks are represented at a global or gist level, but not local or fine-grained, level. These findings offer a unified view of memory for gist across verbal and spatial domains, and across recent and remote memory, with implications for hippocampal-neocortical interactions.

Anemia in sleep-deprived rats receiving anticoagulants.

Independent groups of rats were deprived of sleep and treated with the anticoagulant drugs phenylindanedione or dicoumarol for 1 to 8 days. These animals developed an extremely severe anemia which was accelerated by p-chlorophenylalanine. The red cell count and amount of hemoglobin decreased to half of normal values. No decrease occurred in animals subjected to any one single treatment. Histological examination indicated hemolysis, hypoplasia of hemopoietic organs, slight hemorrhage, but no evidence of stress. The severity of the anemia was inversely related to the amount of sleep permitted during sleep deprivation. This new syndrome demonstrates marked effects of sleep deprivation on both maturation and destruction of red blood cells. Depletion of serotonin by injection of parachlorophenylalanine blocked the increase in amount of brain waves of the type commonly seen in slow wave sleep but did not eliminate the production of these waves. This result is at variance with the theory that serotonin is the neurochemical responsible for the "priming" of slow wave sleep.

Anterograde and retrograde amnesia after lesions to frontal cortex in rats.

A socially acquired food-preference test was used to assess effects of lesions to the frontal cortex on anterograde and retrograde memory in rats. In Experiment 1, there was no effect of lesion when rats were administered a two-choice test in which the target food was to be selected in the presence of a single distractor. In Experiment 2, a three-choice memory test was administered in which the target food was presented along with two equally palatable alternatives. In the latter test, lesioned groups displayed anterograde amnesia that increased with the length of the interval between postoperative acquisition and test, and a severe retrograde amnesia that extended equally over the entire range of intervals between preoperative acquisition and test. This outcome, which contrasted with the pattern of memory loss previously observed in rats with hippocampal lesions on this test, was interpreted as evidence for the strategic role of the frontal lobes in directing response selection and retrieval processes in memory.

Ill-defined problem solving in amnestic mild cognitive impairment: linking episodic memory to effective solution generation.

It is well accepted that the medial temporal lobes (MTL), and the hippocampus specifically, support episodic memory processes. Emerging evidence suggests that these processes also support the ability to effectively solve ill-defined problems which are those that do not have a set routine or solution. To test the relation between episodic memory and problem solving, we examined the ability of individuals with single domain amnestic mild cognitive impairment (aMCI), a condition characterized by episodic memory impairment, to solve ill-defined social problems. Participants with aMCI and age and education matched controls were given a battery of tests that included standardized neuropsychological measures, the Autobiographical Interview (Levine et al., 2002) that scored for episodic content in descriptions of past personal events, and a measure of ill-defined social problem solving. Corroborating previous findings, the aMCI group generated less episodically rich narratives when describing past events. Individuals with aMCI also generated less effective solutions when solving ill-defined problems compared to the control participants. Correlation analyses demonstrated that the ability to recall episodic elements from autobiographical memories was positively related to the ability to effectively solve ill-defined problems. The ability to solve these ill-defined problems was related to measures of activities of daily living. In conjunction with previous reports, the results of the present study point to a new functional role of episodic memory in ill-defined goal-directed behavior and other non-memory tasks that require flexible thinking. Our findings also have implications for the cognitive and behavioural profile of aMCI by suggesting that the ability to effectively solve ill-defined problems is related to sustained functional independence.

Environmental influences on cognitive decline in aged rats.

Two experiments are reported in which young and old rats, housed in an impoverished (IE), enriched (EE), or standard (SE), environment, were tested on a series of complex, blind-alley mazes. In Experiment 1, 3-months exposure to IE exacerbated age differences in maze performance, relative to the differences between young and old rats in EE and SE. Old rats in the EE and SE conditions did not differ from each other. In Experiment 2, rats were raised for an additional 3 months in either IE or EE before further maze testing. The main findings were that the maze performance of old rats, transferred from IE to EE, improved significantly, whereas the performance of old rats, transferred from SE or EE to IE, declined. These results indicated that the deleterious effects of an impoverished environment on learning and memory are, at least partly, reversible, and that experience in a stimulating environment can protect old rats from the adverse effects of relocation to a deprived environment. Taken together, the results highlight the impact of environmental influences on cognitive function in old age, and emphasize the need to consider nonbiological factors in understanding the process of cognitive aging.

A neuropsychological analysis of memory loss with age.

This paper reports a series of experiments that assessed learning and memory performance in aged rats from a neuropsychological perspective. Relative to young adults, old rats displayed rapid rates of forgetting, increased susceptibility to interference, and poor long-term recall of specific experiences. There were no age differences on tests of short-term memory. In general, the performance of aged rats paralleled that of young rats with restricted lesions to the hippocampus, thereby supporting the conclusion that normal memory loss with age is related to progressive hippocampal dysfunction.

Conditional learning in aged rats: evidence of hippocampal and prefrontal cortex impairment.

Groups of normal old rats and young adult rats were administered a test of conditional discrimination learning in which different visual stimuli were associated with responses to different levers. Initially, rats were tested in a zero-delay condition in which they selected their responses in the presence of the conditional stimuli. They were later tested at 5- and 15-s delays between stimulus presentation and the appearance of the levers. Old rats were impaired in learning the basic conditional discrimination, a test thought to be sensitive to frontal lobe dysfunction. Age differences increased with the length of the interval, revealing a time-dependent memory loss that was attributed to impaired hippocampal function.

Glucose treatment attenuates spatial learning and memory deficits of aged rats on tests of hippocampal function.

Groups of old and young rats were administered three tests of spatial learning and memory that are known to be sensitive to hippocampal dysfunction: the radial arm maze (RAM), spatial non-matching-to-sample (SNMTS), and a spatial vs. local cue-preference task. Old rats performed worse than young rats on the RAM and SNMTS tasks; on the cue-preference task, young rats were biased to use spatial cues, whereas old rats exhibited strong preferences for distinct, local cues. Peripheral injections of glucose (100 mg/kg) improved performance by old rats on the RAM and SNMTS, which correlated with measures of glucose metabolism. Glucose treatment did not affect old rats performance on the cue-preference task. There was evidence that glucose-treatment improved performance of young rats in the RAM test, but not the other tests. The results extend the range of tasks on which glucose-induced cognitive enhancement has been demonstrated in aged rats, and provides further evidence that memory loss resulting from hippocampal dysfunction is especially amenable to glucose treatment.

Dietary protein, carbohydrate, and fat enhance memory performance in the healthy elderly.

BACKGROUND: Dietary carbohydrates can improve memory. Whether these effects are related to elevations in blood glucose or to energy ingestion is unknown. OBJECTIVES: Our objectives were to determine 1) the influence of isoenergetic protein-, carbohydrate-, and fat-containing drinks on cognitive performance and 2) whether the time period after ingestion affects cognition. DESIGN: After fasting overnight, 11 men and 11 women aged 61-79 y consumed either a 300-mL drink containing 774 kJ as pure protein (whey), carbohydrate (glucose), or fat (safflower oil) or a nonenergy placebo on 4 separate mornings. Cognitive tests were administered 15 and 60 min after ingestion of the drinks. Plasma glucose and serum insulin concentrations were measured. RESULTS: Only the carbohydrate drink increased blood glucose (P < 0.0001). Compared with the placebo, all 3 macronutrients improved delayed paragraph recall (PR) (P < 0.001) and improved or tended to improve immediate PR (P < 0.04) 15 min after ingestion. Beneficial effects on other cognitive tests were confined to one or more of the macronutrients: carbohydrate improved Trail Making Test (Trails) performance at 60 min (P = 0.02) and tended to improve Trails at 15 min (P = 0.04) and PR at 60 min in men, carbohydrate and fat improved or tended to improve performance on Trails at 15 and 60 min in subjects with poor baseline scores (r > -0.41, P < 0.03), fat tended to improve attention at 60 min (P < 0.05), and protein reduced the rate of forgetting on the PR at 15 min (P = 0.002). CONCLUSIONS: Energy intake from protein, carbohydrate, or fat can enhance memory independently of elevations in blood glucose. Each macronutrient may also exert unique effects on cognition.

Cognitive performance is associated with glucose regulation in healthy elderly persons and can be enhanced with glucose and dietary carbohydrates.

BACKGROUND: A glucose drink has been shown to improve memory in persons with poor glucose regulation and poor cognition. OBJECTIVE: The objective of this study was to determine 1) whether an association between cognition and glucose regulation is apparent in healthy seniors and 2) the effects of dietary carbohydrates on cognition. DESIGN: After an overnight fast, 10 men and 10 women (aged 60-82 y) consumed 50 g carbohydrate as glucose, potatoes, or barley or a placebo on 4 separate mornings. Cognitive tests were administered 15, 60, and 105 min after ingestion of the carbohydrate. Plasma glucose and serum insulin were measured. RESULTS: In a multiple regression analysis, poor baseline (placebo) verbal declarative memory (immediate and 20-min delayed paragraph recall and word list recall) and visuomotor task performance were predicted by poor beta cell function, high incremental area under the glucose curve, low insulin resistance, and low body mass index. The difference in plasma glucose after food consumption [glucose > potatoes > barley > placebo (P: < 0.03)] did not predict performance. Although overall performance did not differ with consumption of the different test foods, baseline score and beta cell function correlated with improvements in immediate and delayed paragraph recall for all 3 carbohydrates (compared with placebo); the poorer the baseline memory or beta cell function, the greater the improvement (correlation between beta cell function and improvement in delayed paragraph recall: r > -0.50, P: < 0.03). Poor beta cell function correlated with improvement for all carbohydrates in visuomotor task performance but not on an attention task. CONCLUSIONS: Glucose regulation was associated with cognitive performance in elderly subjects with normal glucose tolerance. Dietary carbohydrates (potatoes and barley) enhanced cognition in subjects with poor memories or beta cell function independently of plasma glucose.

A comparison of normal old rats and young adult rats with lesions to the hippocampus or prefrontal cortex on a test of matching-to-sample.

Rats with lesions to the dorsal hippocampus (HPC) or prefrontal cortex (PFC), normal old rats, and young adult controls were compared on a test of matching-to-sample. Subjects were presented with two lights in succession and were trained to press a lever when the lights were the same brightness and withhold a lever-press when they were different. The PFC and aged groups, but not the HPC group, were impaired when the comparison stimulus was presented immediately after the sample stimulus. When delays of 5 and 15 sec were introduced between the stimuli, the HPC and aged groups' performance deteriorated to chance levels. The PFC group's performance was not differentially affected by the delays. The results were consistent with previous findings that implicated the HPC in episodic memory and the PFC in working memory. The aged group was impaired on both types of memory, revealing signs of HPC and PFC dysfunction.

Networks of domain-specific and general regions involved in episodic memory for spatial location and object identity.

Positron emission tomography (PET) was used to investigate human episodic memory for spatial location and object identity. We measured regional cerebral bloodflow (rCBF) while subjects engaged in perceptual matching of the location or the identity of line drawings of objects. Perceptual matching also involved incidental encoding of the presented information. Subsequently, rCBF was measured when subjects retrieved the location or the identity of these objects from memory. Using the multivariate partial least squares image analysis, we identified three patterns of activity across the brain that allowed us to distinguish structures that are differentially involved in processing spatial location and object identity from structures that are differentially involved in encoding and retrieval but operate across both domains. Domain-specificity was evident by increased rCBF during the processing of spatial location in the right middle occipital gyrus, supramarginal gyrus, and superior temporal sulcus, and by increased rCBF during the processing of object identity in portions of bilateral lingual and fusiform gyri. There was a nearly complete overlap between domain-specific dorsal and ventral extrastriate cortex activations during perceptual matching and memory retrieval. Evidence of domain-specificity was also found in the prefrontal cortex and the left hippocampus, but the effect interacted with encoding and retrieval. Domain-general structures included bilateral superior temporal cortex regions, which were preferentially activated during encoding, and portions of bilateral middle and inferior frontal gyri, which were preferentially activated during retrieval. Together, our data suggest that encoding and retrieval in episodic memory depend on the interplay between domain-specific structures, most of which are involved in memory as well as perception, and domain-general structures, some of which operate more at encoding and others more at retrieval.

Amnesia in a patient with bilateral lesions to the thalamus.

A case of anterograde amnesia is described in a 38-yr-old man with bilateral thalamic lesions. The patient appeared to have suffered no general intellectual loss and performed normally on standard memory tasks involving immediate recall of new material. There was, however, consistent impairment in recalling material, verbal and non-verbal, over delays as brief as a few seconds. Impairment was especially marked on tests involving free recall and partial cueing procedures; recognition memory was also impaired. Premorbid memory tested normally and susceptibility to interference was less than in other organic amnesics. Various interpretations of the patient's amnesia were considered but a deficit at the initial stages of information processing appeared to be indicated.

Clustering and switching on verbal fluency: the effects of focal frontal- and temporal-lobe lesions.

We examined the hypothesis that, on verbal fluency, clustering (i.e. generating words within subcategories) is related to temporal-lobe functioning, whereas switching (i.e. shifting between subcategories) is related to frontal-lobe functioning. Tests of phonemic and semantic fluency were administered to 53 patients with focal frontal-lobe lesions (FL), 23 patients with unilateral temporal-lobe lesions (TL) and 55 matched controls. Performance by FL patients was consistent with our hypothesis: in comparison to controls, patients with left-dorsolateral or superior-medial frontal lesions switched less frequently and produced normal cluster sizes on both phonemic and semantic fluency. Performance by TL patients was not consistent across fluency tasks and provided partial support for our hypothesis. On phonemic fluency, TL patients were unimpaired on both switching and clustering. On semantic fluency, TL patients were impaired on switching in comparison to controls and left TL patients produced smaller clusters than right TL patients. The best indices for discriminating the patient groups, therefore, were phonemic-fluency switching (impaired only with frontal lesions) and semantic-fluency clustering (impaired only with temporal-lobe lesions).

Memory as assessed by recognition and reading time in normal and memory-impaired people with Alzheimer's disease and other neurological disorders.

Three experiments are reported that examine the dissociations in performance on two tests of retention, speeded reading and recognition in young people, home-dwelling and institutionalized elderly people, and people with severe memory disorders. In Experiment 1, subjects read sentences in normal and in geometrically transformed script at initial presentation, 1-2 hr later, and again 4-14 days later. On the latter two occasions, they were required to distinguish old sentences that they had read previously from new ones. In general, the young and elderly subjects could distinguish old from new sentences at the short delay, and all but the institutionalized elderly people could do so at the long delay. Retention as measured by reading speed typically paralleled recognition performance in that those items that were recognized best were read most quickly. The dissociation between these two tests of retention is seen only in people with memory disorders. Although these people could not distinguish old from new items even at short delays (most could not even remember having seen any sentences), their retention as assessed by reading time was similar to that of the other groups. Old sentences were read most quickly, indicating retention of item-specific information, and reading time of new sentences improved, indicating the acquisition and retention of a general skill. Experiment 2 examined what type of item-specific information was retained. Young, elderly, and memory-disordered subjects studied weakly associated word pairs and sentences. A few minutes later they were tested on both recognition and speeded reading of old, new, and recombined pairs and sentences, the last being those in which words from a studied pair or sentence were recombined with words from other such pairs or sentences. The results of both retention tests indicated that young and elderly people could distinguish old from new and recombined items. People with memory disorders, however, again failed on recognition but performed normally on speeded reading. Like the other two groups, they read old items faster than either recombined or new items. In Experiment 3, similar results were obtained even when the word pairs were constructed using randomly associated items. The results of all three experiments suggest that on implicit tests of memory, such as speeded reading, people with memory disorders can be shown to have formed and retained new associations despite failing utterly on explicit tests, such as recognition, that require conscious recollection of a previous episode.(ABSTRACT TRUNCATED AT 400 WORDS)

Prefrontal cortex and caudate nucleus in conditional associative learning: dissociated effects of selective brain lesions in rats.

Rats with lesions to prefrontal cortex (PFC) or caudate nucleus (CN) were compared on tests of conditional associative learning (CAL) that placed varying demands on conditional rule learning and working-with-memory operations that are essential for response selection. Damage to either structure impaired performance, but the respective deficits resulted from disruption of different processes. CN lesions produced a consistent learning deficit that was thought to reflect a basic impairment in forming stimulus-response (S-R) associations. The behavior of PFC rats was more variable and depended on task requirements. When S-R learning or response selection was relatively easy, the PFC was not critical. However, when either component was made more difficult, thus requiring the contribution of strategic processes, PFC damage produced profound impairments. In addition to clarifying the roles of the PFC and CN in CAL, the results provide further evidence that multiple brain regions participate in relatively simple behavioral tasks and that their respective contributions can be dissociated.

Aging and time-of-day effects on cognition in rats.

This study used an animal model to investigate the importance of the time at which testing occurs for age differences in learning and memory. Groups of old and young rats were entrained to a 12-hr light-dark schedule and administered tests of delayed alternation and inhibitory avoidance conditioning at the beginning or end of their high-activity cycle. Apart from normal age differences in test performance, the behavioral results demonstrated that old but not young rats were affected by the time of testing. In both tasks, old rats tested late in the activity cycle performed significantly worse than did old rats tested early in the cycle, under conditions that challenged memory processes that are known to involve the hippocampus. The results indicate that circadian disruption in old age can adversely affect memory and related cognitive function, with important implications for inhibitory control.

Hippocampal and prefrontal cortex contributions to learning and memory: analysis of lesion and aging effects on maze learning in rats.

Young adult rats with bilateral lesions to the hippocampus or prefrontal cortex, young operated controls, and normal old rats were tested on two complex mazes in the Hebb-Williams series. Approximately half the animals were previously trained on one of the mazes; the remainder received no previous training. The trained hippocampal rats showed sparing of memory for the general skill of maze learning but poor recall of the specific maze on which they had been previously trained. The opposite pattern was observed in trained prefrontal rats. In contrast, the aged rats' memory for maze-specific and maze-general information was impaired. The results confirmed the importance of the hippocampus for recalling highly specific information and pointed to a possible role for the frontal lobes in learning and remembering nonspecific skill-related information. The generalized deficit of the aged rats indicates that both types of memory were compromised and offers further evidence of frontal lobe and hippocampal dysfunction in normal aging.

Cognitive impairment in rats fed high-fat diets: a specific effect of saturated fatty-acid intake.

One-month-old rats were fed 1 of 4 high-fat diets (20% fat) or chow (4.5% fat) for 3 months. Dietary saturated (SFA), monounsaturated (MUFA), or polyunsaturated (PUFA) fatty acids varied such that their independent effects on cognitive performance could be tested. Rats were tested on a variable-interval delayed-alternation task. Impairment in both the ability to learn the basic alternation rule and remembering trial-specific information over time was observed in rats fed the experimental diets relative to those fed chow. The degree of impairment was highly associated with the level of SFAs fed and independent of the MUFAs or PUFAs. Dietary fat altered brain phosphatidylcholine fatty-acid profile, but the membrane changes did not correlate with cognitive impairment. The results demonstrate that cognitive impairment is directly associated with SFA intake but suggest that the mechanism is independent of bulk brain membrane compositional changes.