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Dementia and CancerA Review of the Literature and Current PracticeLuke Solomons, Joyce Solomons, Margot GosneyAging Health.2013;9(3):307-319.Abstract and IntroductionAbstractAge is a risk factor for dementia, and also for most cancers. Surprisingly, rates of cancer appear to be lower in individuals with dementia and vice versa. Genetic mechanisms could underpin this inverse relationship and are outlined, but underdiagnosis must also be taken into account. Individuals with cancer and dementia pose unique challenges to healthcare professionals owing to the potential for impaired decision-making capacity, poor communication and difficulties following medication regimes. Mild cognitive impairment and 'chemo brain' should be differentiated from progressive neurodegeneration.IntroductionDementia is a progressive neurodegenerative condition that increases with age. An aging population has led to a rapid increase in the prevalence of dementia.[1] Age is a risk factor for most cancers and estimates suggest that by 2030, 70% of all cancers will occur in elderly people.[2] The increasing prevalence of these conditions has serious implications on healthcare provision and the healthcare economy. Economic data on the cost of dementia are available from the UK, USA, western Europe and developed countries, and less from developing ones we refer to economic data from the UK in this review. According to the Global Burden of Disease estimates for the 2003 World Health Report,[3] dementia contributed 11.2% of years lived with disability in people aged 60 years and older, along with stroke (9.5%), musculoskeletal disorders (8.9%), cardiovascular disease (5.0%) and all forms of cancer (2.4%).Given that both cancer and dementia are seen as diseases of elderly people, the expectation is that there will be a significant overlap of the two conditions. However, there appears to be a disconnect between the prevalence rates of the two conditions occurring together. A small, but growing, body of evidence appears to show lower rates of cancer in patients diagnosed with dementia, especially Alzheimer's dementia, as compared with cognitively intact matched controls;[46] and a lower incidence of Alzheimer's dementia in cancer survivors.[7] Genetic links between neurodegeneration and cell proliferation have been suggested, but population-based studies also suggest that underdiagnosis might be responsible for some of the mismatch.The diagnosis and treatment of cancer is associated with high levels of psychological distress in patients and their families.[8,9] Many survivors display important symptoms of psychological distress that are related to the continuing effects of cancer and its treatment.[10] A diagnosis of cognitive impairment or dementia is a well-established component of frailty scores, which are helpful in determining prognosis and making treatment choices.[11] However, individuals with dementia who are diagnosed with cancer pose unique challenges in clinical practice owing to impairments in understanding, communication, capacity to consent and issues related to death and dying. Patients' relatives and carers are called on to make surrogate decisions for them when they lack the capacity to do so, and this can be distressing for both groups.In the first part of this review, we look at current evidence in the area of overlap between cancer and dementia. In the 'hands on' second section, the authors address common clinical considerations, such as the differential diagnosis of dementia, assessment of decision-making capacity and the management of pain and distress.Epidemiology of Dementia & CancerThe prevalence rates for dementia increase with age rates increase from 1.3% between the ages of 65 and 69 years to 32.5% in individuals over the age of 95 years in developed countries.[12] Rates in developing countries seem to be lower there are several possible explanations, including the possibility that early dementia is ignored, risk factors for dementia are lower and also, in very poor countries, fewer individuals survive to 65 years. With increasing age, rates of dementia are higher in women compared with men, but there do not appear to be racial differences in prevalence rates. Early-onset dementia (onset before the age of 65 years) is rarer, accounting for 2.2% of people with dementia.The prevalence rates of cancer increase with age as well 50% of all cancers occur in individuals over the age of 70 years, but for some specific tumors the rates are higher, for example, in colorectal cancer, where 65% of all tumors occur in individuals over the age of 70 years.Costs of Cancer & Dementia CareA report by the Alzheimer's Research Trust estimated that in 2008, the cost to the UK economy from dementia was 19.7 billion, of which 6% was spent on healthcare, 46% on social care and 48% on informal care. The same report estimated that cancer cost 12 billion, of which 33% was on healthcare, 5% on social care and 11% on informal care, and 51% of total costs was accounted for by productivity losses.[13] The larger proportion of social care costs relative to healthcare costs incurred by dementia serve to highlight the significant impact that dementia has on a person's quality of life (QoL) and psychosocial environment. These need to be considered early in the process of management of the small, but increasing, proportion of patients who have been diagnosed with cancer and dementia.Given the inherent difficulties with measuring outcomes to evaluate the effectiveness of treatment plans, health-related QoL measures can be used to record changes. There are several QoL instruments, such as the QL-index and Euroqol,[14,15] that have been developed for patients with cancer that are used extensively in clinical trials[16] these are mainly based on self-report scales and cognitive impairment could impact on the individual's ability to complete these scales. Several QoL scales in dementia have been developed for example, the DEMQOL, which has a linked 'proxy' version filled out by carers (DEMQOL Proxy) that provides complimentary perspectives and information[17] and such measures might be more appropriate for use in patients in the overlap group.Cancer & Dementia: Diagnostic Uncertainties Leading to Underdiagnosis?Population-based cohort studies report lower rates of dementia in cancer survivors. Studies on rates of cancer in individuals with dementia have found that the converse is also true, with lower rates of cancer in people with dementia.[47] There are several explanations put forward to explain this disconnect.Underdiagnosis of cancer is one possible explanation one study reported that individuals with prevalent Alzheimer's disease had a 69% lower risk of being admitted to hospital for cancer.[5] Individuals with dementia tend to under-report symptoms, such as gastrointestinal discomfort, joint pain and vision problems, which leads to delays in medical attention being sought.[18] Thus, they are diagnosed with more advanced stages of cancer, often too late to be treated. One study on individuals with colon cancer found that those with dementia were twice as likely to be diagnosed without tissue sampling and that they were half as likely to receive surgical resection or adjuvant treatment.[19] A study on individuals with breast cancer reached similar conclusions women with dementia were likely to have a more advanced stage of cancer and less likely to have treatment.[20] A Dutch study on elderly care physicians found that advanced dementia was the leading cause for nonreferral of patients with suspected cancer.[21] A recent study found that approximately half of the population of individuals with dementia were accidentally discovered to have cancer (48%) or had unexpected unfolding of clinical signs (44%), whereas most cognitively intact patients (63%) voluntarily sought medical evaluation.[22] Cancer & Dementia: Possible Genetic LinksOverlapping biological pathways and genes could potentially explain the link between cancer and dementia. The fundamental biological basis of cancer is uncontrolled cell proliferation and/or prolonged cell survival, while dementia involves neuronal cell degeneration and death. Thus, it is not surprising that various pathways and genes involved in cell-cycle regulation have been considered to link these two major age-related diseases.Tumor suppressor genes (TSGs) are a group of genes that play an integral role in cell-cycle regulation. These genes act at different levels and are vital in preventing uncontrolled cell growth and inappropriate cell survival, thus acting as potent barriers to cancers. TP53 is a vital TSG that is activated by various stress inducers, such as hypoxia and DNA damage. p53 acts as a transcription factor for various pathways resulting in inhibition of cell-cycle progression, promotion of senescence or apoptosis. TP53 mutations resulting in impaired function of the p53 protein are noted in more than half of all human cancers.[23,24] In the tumors that retain wild-type p53, there is evidence that the activity of the p53 protein could be attenuated by various mechanisms, including augmentation of p53-negative regulators, such as Mdm2 and Mdm4.[25] Germline mutations of TP53 are known to cause LiFraumeni syndrome, a rare familial predisposing cancer condition, with individuals prone to a significantly increased risk of various cancers including breast cancers, sarcomas, leukemias and brain cancers. Inactivation of p53 as a major cause of cancer is irrefutable. Interestingly, transgenic mouse models with gain-of-function TP53 mutations resulting in augmented p53 activity were found to exhibit features of aging and reduced longevity ().[26] Box 1. Some of the genes implicated in cancer and dementia.Tumor suppressor genes TP53 BRCA1 P16 Retinoblastoma family of genes

Peptidyl-propyl cis/trans isomerase (PPIase) Pin1

DNA repair genes DNA Pol-

miRNA genes miR-29 family

Genes on chromosome 21 ERG ETS2 APP

-amyloid accumulation induced in transgenic mice, which leads to progressive neuronal degeneration and cell death, was correlated with increased activity of p53-mediated apoptosis.[27] Elevated levels of p53 have been noted in the CNS of patients diagnosed with neurodegenerative disorders[2831] and there have been reports of elevated p53 levels in the brains of patients with Alzheimer's dementia.[3234] Presenelin 1 and 2 mutations, which cause familial dementia, are shown to act through p53-mediated apoptosis.[35,36] This limited evidence suggests that p53 levels could have inverse effects in the pathogenesis of cancers and dementia, but further research in this area is warranted. Other TSGs implicated in the causation of human cancers and dementia include BRCA1, p16 and the Retinoblastoma family of genes.[3743] The Pin1 gene encodes a peptidyl-propyl cis/trans isomerase (PPIase) that specifically binds to phosphorylated ser/thr-pro motifs (pro-directed phosphorylation) and catalytically regulates the postphosphorylated key proteins, including various cell-cycle regulatory mitotic factors, transcription factors, apoptotic factors and the cytoskeletal tau protein.[44] Pin1 is reported to be overexpressed in various common cancers, such as breast, prostate, brain, cervical, lung and colon cancers.[4548] Dysregulation of the RbERF pathway in cancers is thought to cause overexpression of Pin1 in cancers.[49,50] The role of Pin1 in positive regulation of Cyclin D1 through C-jun interaction[46,47] and stabilization of catenin- molecule by preventing APC-mediated suppression indicates that overexpression of Pin1 in cancers could act by enhancing various oncogenic signals.[46] Furthermore, Pin1 is involved in regulating p53 activity by interacting with phosphorylated p53 formed following DNA damage, thus promoting DNA-binding and transactivation of p53.[51] Increased Pro-directed phosphorylation of tau and -amyloid protein is shown to be a precursor of tangle formation and neurodegeneration in Alzheimer's dementia.[52] Pin1 appears to have a protective role in age-related neurodegeneration by binding to the pro-directed phosphorylated tau protein, facilitating its dephosphorylation, and thus restoring its stable form.[53,54] Pin1 could inhibit Cdc25c, which activates mitotic cell-cycle kinases that induce apoptosis in neurons.[52] The protective nature of Pin1 is further supported by depletion of Pin1 reported in Alzheimer's dementia.[53] Loss of Pin1 in mouse models has been reported to cause age-dependent motor and behavioral phenotypes associated with tau hyperphosphorylation, filament formation and neurodegeneration.[55] Thus, Pin1 is a vital protein involved in the pathogenesis of both cancers and Alzheimer's dementia. While overexpression of Pin1 is associated with various oncogenic pathways, depletion of Pin1 appears to play a role in the causation of Alzheimer's dementia. Pin1 is, therefore, considered to be an important genetic link that further supports the biological connection between cancers and dementia.Germline mutations in certain DNA repair pathway genes are known to cause genetic conditions characterized by a combination of cancer predisposition and neurodegenerative phenotypes. Examples of such genetic conditions include xeroderma pigmentosa, a genetically heterogenous condition caused by mutations in the nucleotide excision DNA repair pathway genes, and ataxia telangiectasia caused by mutations in ATM, a gene that encodes a serine/threonine protein kinase involved in DNA repair or cell-cycle arrest and apoptosis response to DNA damage.Accumulation of DNA damage, genomic instability and the role of DNA repair pathway/genes in the pathogenesis of cancers are well established. There is growing evidence to suggest a potential role of DNA repair pathways/genes in neurodegenerative conditions including dementia. It has been proposed that specific DNA repair pathways may be less accessible to postmitotic neurons in comparison with mitotic cells, causing progressive accumulation of DNA damage, which could result in neuronal degeneration and death.[56,57] Biochemical assays on isolated nuclei have shown a twofold increase in the level of DNA strand breakage in patients with Alzheimer's dementia in comparison with controls.[58] DNA polymerase-, an important enzyme in the DNA repair complex, has been implicated in the pathogenesis of Alzheimer's dementia by loading in DNA replication forks in neurons with -amyloid accumulation.[59] miRNAs are noncoding RNAs of 1825 nucleotides in length. They are known to regulate gene expression, primarily through translational inhibition, by binding to imperfect complementary sequences in the 3' untranslated region of mRNA. miRNAs bind to protein effector complexes, acting as a guide strand to bring them to the target mRNA. This results in impairment of protein translation or mRNA degradation. Recent studies have shown that miRNAs regulating cell proliferation, differentiation and apoptosis could act through overlapping pathways linking cancer and dementia.It has been found that onco-miRNAs and suppressor miRNAs could be representing two forms of the same gene, functioning as an oncogene or TSG based on the tissue type and target site.[60] miRNAs belonging to the miR-29 family are underexpressed in certain lung cancers, causing upregulation of specific DNA methyltranferases and resulting in an aberrant DNA methylation pattern in these cancers.[60] Furthermore, miRNAs from the same family have also been shown to regulate a specific antiapoptic protein, MCL1.[61] These findings suggest that the miR-29 family could act as tumor suppressors through the regulation of specific methyltranferases and MCL1.Member miRNAs of the miR-29 family could have a potential role in the pathogenesis of Alzheimer's dementia. Specific miRNAs from this family are shown to regulate BACE1, which is implicated in the accumulation of -amyloid in patients with sporadic Alzheimer's dementia. The expression of specific miRNAs from the miR-29 family are shown to be suppressed in patients with Alzheimer's dementia, thus upregulating BACE1 activity, which could provide a potential explanation for the accumulation of -amyloid and the pathogenesis of the disease.[62] Finally, individuals with Down's syndrome (DS; trisomy 21) have a predisposition to developing certain hematological malignancies and early-onset dementia. DS has, therefore, been a platform for studies to investigate the possible candidate genes on chromosome 21 to explain the potential link between the malignancies and dementia in these patients.DS confers an approximately ten- to 50-fold increase in the risk of developing leukemias in children, the most common types being acute myeloid leukemia and acute lymphoid leukemia. Several genes on chromosome 21, including transcription factors, miRNAs, oncogenes and TSGs, have been implicated in tumorigenesis. The oncogenic candidate genes on chromosome 21 include ERG, ETS2, DYRK1A, TMPRSS2, TIFF1, SIM2, RUNX1, mir-125b2, -155 and let7c.[6372] Linkage analyses have identified the APP gene on chromosome 21 as a candidate gene in familial Alzheimer's dementia. APP, a precursor of -amyloid, has a tendency to form amyloid plaques, which are linked to Alzheimer's dementia.[73] Interestingly, APP has been found to be the most overexpressed gene in patients with acute myeloid leukemia with normal cytogenetics compared with controls. APP has been hypothesized to cause leukemogenesis along with ERG and EST2. However, the exact molecular basis is not clear.[74] In summary, there are various overlapping biological pathways and genes that link cancer and dementia these include TSG, DNA repair pathway genes, miRNAs and genes on chromosome 21. There are potentially other genes in these pathways that could link these two common conditions of aging. The limited evidence so far suggests links between cancer and neurodegeneration, and warrants further research.Cognitive Impairment That Is Not DementiaCognitive impairments in patients receiving treatment for cancer have been well documented, but the phrase 'cognitive impairment' encompasses a variable cluster of symptoms. Studies in the early 2000s reported prevalence rates of cognitive impairment following treatment for cancer of up to 75%; however, there were several methodological criticisms of these studies.[75,76] A study looking at pretreatment cognitive impairment in patients diagnosed with breast cancer found that up to a third of patients had some cognitive impairment prior to treatment[77] the mean age of participants in the study was 50.4 years. The authors suggest that stress and depression could affect performance on neuropsychological tests.'Chemo brain' or 'chemo fog' are terms found in the literature and on numerous cancer support websites that include a heterogenous cluster of cognitive symptoms in patients undergoing chemotherapy for cancer.[201] These include a spectrum of impairments including verbal and visuospatial memory deficits, language problems, frontal executive dysfunction, and disturbances of attention and concentration. Some reviewers suggest that the phrase 'cognitive disorders related to cancer or therapy' should be used to describe them.[78] Chemo brain might be classified under the Diagnostic and Statistical Manual of Mental Disorders (4th Edition) category of 'mild cognitive impairment either amnestic or nonamnestic' depending on the cognitive domains involved. A recent meta-analysis of the literature on mild cognitive impairment reported that the majority of individuals diagnosed with this condition did not progress to dementia over a 10-year follow-up period.[79] This is in contrast with more severe cognitive impairment that falls into the dementia spectrum, which is progressive, and hence it is important for the right diagnosis to be made.Delirium is a syndrome of acutely altered mental status characterized by inattention and a fluctuating course.[80,81] It is the most common complication in hospitalized older individuals[82] Increasing age is a risk factor for delirium, with individuals over the age of 65 years being more prone to delirium. Some literature on chemo brain suggests that the incidence increases with age,[83] but whether it is a potential marker for future dementia (as is the case with delirium) is unclear.The question about cancer treatment leading to dementia has been studied and the results in published literature have been mixed the association has not been borne out by a large population-based study,[83] while other studies seem to suggest that a group of women receiving chemotherapy were at a higher risk of severe cognitive changes.[84,85] In a study comparing cognitive function in cancer patients with their cancer-free twins, the authors reported an increased risk for long-term cognitive dysfunction in the cancer group, and that the cancer group were twice as likely to be diagnosed with dementia, but the odds ratio did not reach significance.[86] There is increasing evidence that most types of treatment for cancer, including systemic therapy, radiotherapy, immunotherapy and also adjuvant medication such as steroids, anticholinergic medication and pain relief, have a negative impact on cognition. Some data on the effect of cancer therapies on the symptom severity of an existing dementia are emerging, but the available evidence is anecdotal and in the form of single-case reports. Given that age is an important risk factor for cognitive impairment, older adults are much more likely to suffer cognitive impairments with treatment. Evidence from histopathological studies seem to support this a study comparing the brains of individuals diagnosed with vascular dementia (VaD) with Alzheimer's dementia also looked at the brains of patients given radiation for brain tumors and found very low microvascular densities.[87] Clinical ChallengesScreening & Diagnosing DementiaDementia is described in the Diagnostic and Statistical Manual of Mental Disorders (4th Edition) as a disorder with memory impairment and at least one other symptom from another cognitive domain[81] aphasia, apraxia, agnosia or disturbances in executive functioning accompanied by impairment in social and occupational function. The course is characterized by gradual onset and continuing cognitive decline.The symptoms of dementia can be clustered under three domains: neuropsychological, neuropsychiatric and executive function features ().Box 2. Three domains/clusters of symptoms of dementia. Neuropsychological: Problems with memory Problems with language Neuropsychiatric: Personality changes Psychiatric symptoms (e.g., anxiety, depression, hallucinations and delusions) Challenging behavior/restlessness/wandering Impaired executive function: Difficulty with basic activities of daily living (e.g., washing, dressing, feeding, grooming and walking)

Given the spectrum of cognitive impairments associated with cancer, some experts point out that no validated and practical tests are available for the assessment of cognitive function in cancer patients.[88] Age and the effects of cancer treatment have been pointed out as possible causes of decreases in cognitive function; in both instances, a strong possibility of a decrease in frontal lobe function exists.[89] This uncertainty should not preclude screening for cognitive impairments as these scores can provide useful baselines for future comparisons.Older adults are more prone to delirium due to underlying physical illnesses, and the treatment of the underlying delirium can lead to complete resolution of the cognitive impairments. Thus, a definitive diagnosis of dementia in physically unwell patients with a single assessment poses challenges and follow-up assessment should be arranged.The Mini-Mental State Examination (MMSE) is the most widely used screening tool for dementia,[90] but difficulties in detecting early stages of dementia and impairments in some cognitive domains have been highlighted, including in patients with cancer.[77] In clinical practice, it might be used as a screen for all individuals aged over 65 years, with scores under 27 triggering a referral for further screening, including neuropsychological testing. The Montreal Cognitive Assessment is another bedside cognitive screening tool. It encompasses more cognitive domains and appears to be more sensitive at detecting mild cognitive impairment.[91] Routine screening of all patients with the Montreal Cognitive Assessment and referral of those scoring