Comorbidity

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Comorbidity

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Comorbidity
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Pre-existing medical conditions related to Alzheimer’s disease
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The slide presents an overview of various pre-existing medical conditions that are associated with AD.

There is a good body of evidence to support an association between traumatic brain injury (TBI), diabetes, and depression with an increased risk of dementia.[Jiang et al., 2013] The pathogenesis of depression and AD, putatively, involve common molecular mechanisms, such as chronic inflammation, and hyperactivation of the hypothalamic–pituitary–adrenal axis.[Jiang et al., 2013]

Cerebrovascular events (e.g., stroke, cerebral embolism, microinfarct, white matter intensities) are associated with cognitive impairment and/or an increased risk of dementia, potentially caused by direct damage to the brain regions involved in cognitive function, increased amyloid β (Aβ) deposition (by promoting production and disrupting clearance mechanisms), or an enhanced inflammatory response.[Jiang et al., 2013] In contrast, cancer appears to have an inverse relationship with the development of AD, as studies have shown a decreased risk of AD in patients surviving cancer.[Jiang et al., 2013] This may be due to the common (often reciprocal) molecular mechanisms involved in cancer and in the development of AD (e.g., factors which regulate apoptosis, and the cell cycle).[Jiang et al., 2013]

Jiang T, Yu J-T, Tian Y, Tan L. Epidemiology and etiology of Alzheimer’s disease: from genetic to non-genetic factors. Curr Alzheimer Res 2013; 10 (8): 852–867.

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Modifiable lifestyle factors related to Alzheimer’s disease
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The slide presents an overview of the various modifiable lifestyle factors that are associated with AD.

There is evidence to suggest that moderate coffee consumption, physical activity, and cognitive activity, all play a preventative role in AD.[Jiang et al., 2013] Animal studies have shown that caffeine reduces oxidative stress, inhibits Aβ production, protects against disruptions of the blood–brain barrier, and improves cognitive performance.[Jiang et al., 2013] Physical activity can help to maintain normal brain function in the elderly, reducing the risk of developing AD, and there is evidence to suggest that physical activity may also prolong survival in people with AD.[Jiang et al., 2013] The protective effect of physical activity may be mediated by factors such as a reduction in Aβ levels, increased cerebral perfusion (blood flow to the brain), enhanced neurogenesis in the brain, and reduced oxidative stress, among other factors.[Jiang et al., 2013] Cognitive activity may protect against the progression of AD by preventing the deposition of Aβ and increasing cognitive reserve (i.e., the resilience to neuropathological damage).[Jiang et al., 2013]

There is a good body of evidence to support an association between smoking and the risk of developing AD, which appears to be influenced by ApoE status (increased risk of AD in ApoE e4 carriers).[Jiang et al., 2013]

Light-to-moderate alcohol consumption reduces the risk of AD, possibly more so in women than in men, due to effects such as elevated high-density lipoprotein cholesterol, reductions in fibrinogen (and other thrombotic factors), reduced insulin resistance, and improved endothelial function.[Jiang et al., 2013] In contrast, excessive alcohol intake has detrimental effects on the brain (possibly due to brain atrophy and to smaller brain volumes, or even due to secondary complications of excessive alcohol intake such as traumatic brain injury, stroke, etc.), and may predispose people to dementia.[Jiang et al., 2013]

The relationship between body weight and the risk of AD depends on the age at which the body weight is measured.[Jiang et al., 2013] Evidence suggests that a higher body mass index (BMI) or obesity in mid-life is associated with an increased risk of dementia, whereas in late-life an inverse association has been reported.[Jiang et al., 2013]

 

Jiang T, Yu J-T, Tian Y, Tan L. Epidemiology and etiology of Alzheimer’s disease: from genetic to non-genetic factors. Curr Alzheimer Res 2013; 10 (8): 852–867.

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Cumulative rates of comorbidities in patients with dementia
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This study a was population-based retrospective cohort study using the Clinical Practice Research Datalink, which provides anonymised data from the electronic health records of 674 primary care practices in the UK.[Browne et al., 2017] The study included a total of 4,999 patients from a sample of 5,609 incident cases of dementia between March 2008 and February 2009.[Browne et al., 2017] The rates of multimorbidity were high.[Browne et al., 2017]

A cross-sectional study of 72,815 Spanish patients with dementia in 2008 found that the average number of comorbidities was 3.69, significantly higher than the number of comorbidities (2.44) in the patients without dementia (p<0.001).[Poblador-Plou et al., 2014] These studies demonstrate the comorbidity burden AD places on the patient, as well as on the families of patients, and on society in general.[Browne et al., 2017; Poblador-Plou et al., 2014]

Browne J, Edwards DA, Thodes KM, et al. Association of comorbidity and health service usage among patients with dementia in the UK: a population-based study. BMJ Open 2017; 7: e012546.

Poblador-Plou B, Calderón-Larrañaga A, Marta-Moreno J, et al. Comorbidity of dementia: a cross-sectional study of primary care older patients. BMC Psychiatry 2014; 14: 84.

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The comorbidity burden of Alzheimer’s disease
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This study was a retrospective, nested case-control study, using a random sample of claims data from 2 million Taiwanese people between 2001–2011.[Wang et al., 2018] In order to establish whether the risks of certain comorbidities were greater than normal in patients with AD, a control group of individuals without a diagnosis of AD was constructed, to compare against.[Wang et al., 2018] Large-scale epidemiological projects have been undertaken in the past, showing the rates of various diseases in patients with AD,[Poblador-Plou et al., 2014; Bunn et al., 2014] but without a control group it is difficult to know whether the rates are actually higher than would be expected.

In the Taiwanese nested case-control study, 28,380 cases of dementia were identified, 2,618 of which met the criteria for AD.[Wang et al., 2018] The most common comorbidities among patients with AD were hypertension, osteoarthritis, depression, diabetes, and cerebrovascular disease, with diabetes, osteoporosis, depression, and cerebrovascular disease all being statistically significantly more prevalent in patients with AD compared with the control group.[Wang et al., 2018] The authors note that analysis of claims database data will never truly reflect the weight of some comorbidities; depression, for example, will not always be captured by diagnostic codes.[Wang et al., 2018] However, the strength of the association between depression and AD was the strongest among all the comorbidities identified in the study.[Wang et al., 2018]

 

Bunn F, Burn AM, Goodman C, et al. Comorbidity and dementia: a scoping review of the literature. BMC Med 2014; 12: 192.

Poblador-Plou B, Calderón-Larrañaga A, Marta-Moreno J, et al. Comorbidity of dementia: a cross-sectional study of primary care older patients. BMC Psychiatry 2014; 14: 84.

Wang JH, Wu YJ, Tee BL, Loc RY. Medical comorbidity in Alzheimer’s disease: a nested case-control study. J Alzheimers Dis 2018; 63 (2): 773–781.

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Costs associated with the comorbidities of AD
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The costs associated with the comorbidities of AD have been studied in various healthcare systems, including the additional caregiving costs.[Browne et al., 2017; Hill et al., 2002; Kuo et al., 2008; Leon et al., 1998]

It has long been recognised that Alzheimer’s disease, and other dementias, are associated with a host of hidden costs.[Fillit, 2000] Examples of the hidden costs of AD include patients making poor financial decisions, and being involved in car accidents that lead to higher insurance premiums.[Fillit, 2000] The costs to the family of patients with AD can be great, including lost productivity at work because of dealing with care-related telephone calls or emergencies, and treatment of stress-related conditions such as headaches and chronic back pain.[Fillit, 2000]

Browne J, Edwards DA, Thodes KM, et al. Association of comorbidity and health service usage among patients with dementia in the UK: a population-based study. BMJ Open 2017; 7: e012546.

Fillit HM. The pharmacoeconomics of Alzheimer’s disease. Am J Manag Care 2000; 6 (22 Suppl): S1139–1144.

Hill JW, Futterman R, Duttagupta S, et al. Alzheimer’s disease and related dementias increase costs of comorbidities in managed Medicare. Neurology 2002; 58 (1): 62–70.

Kuo TC, Zhao Y, Weir S, et al. Implications of comorbidity on costs for patients with Alzheimer disease. Med Care 2008; 46 (8): 839–846.

Leon J, Cheng CK, Neumann PJ. Alzheimer’s disease care: costs and potential savings. Health Aff (Millwood) 1998; 17 (6): 206–216.

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The psychiatric comorbidities of Alzheimer’s disease
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The psychiatric comorbidities of dementia
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The assessment of neuropsychiatric symptoms in patients with dementia is challenging.[Cerejeira et al., 2012] Assessment requires detailed information about a patient’s clinical history, their subjective experiences, and an objective rating of their behaviour.[Cerejeira et al., 2012] To this end, reliable family members, or caregivers of the individual may be interviewed to obtain a fuller picture of the patient’s symptoms.[Cerejeira et al., 2012] There are several established instruments that can be used to asses the neuropsychiatric symptoms of dementia, including the BEHAVE-AD scale, and the Neuropsychiatric Inventory (NPI).[Cerejeira et al., 2012]

The NPI assesses the frequency and severity of a patient’s behavioural disturbances, in 12 domains, based on a caregiver interview.[Cummings, 1997] For each domain, the NPI also assesses the subjective amount of caregiver burden.[Cummings, 1997] Each domain is scored for frequency, severity, and associated caregiver distress.[npiTEST.net] Frequency is rated on a 4-point scale, from 1 (rarely) to 4 (very often).[Cummings, 1997; npiTEST.net] Severity is rated on a 3-point scale, from 1 (mild) to 3 (severe).[Cummings, 1997; npiTEST.net] Frequency and severity scores are multiplied, such that each domain is scored from 1 to 12.[Cummings et al., 1994; Cummings, 1997] Caregiver distress, based on the response to the question “how emotionally distressing do you find this behaviour?”, is rated on a 6-point scale, from 0 (not at all) to 5 (very severely or extremely).[npiTEST.net] The NPI Total score for frequency and severity ratings is the sum of the 12 domain scores, ranging from 0 (lowest) to 144 (highest).[Cummings, 1997] The total score for caregiver distress ranges from 0 (lowest) to 60 (highest).[npiTEST.net]

Cerejeira J, Lagarto L, Mukaetova-Ladinska EB. Behavioral and psychological symptoms of dementia. Front Neurol 2012; 3: 73.

Cummings JL, Mega M, Gray K, et al. The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994; 44 (12): 2308–2314.

Cummings JL. The Neuropsychiatric Inventory: assessing psychopathology in dementia patients. Neurology 1997; 48 (Suppl 6): S10–S16.

npiTEST.net. What is the Neuropsychiatric Inventory? http://npitest.net/npi/about-npi.html. Accessed November 2018.

Other references used on slide:

Lyketsos CG, Steinberg M, Tschanz JT, et al. Mental and behavioral disturbances in dementia: findings from the Cache County Study on Memory in Aging. Am J Psychiatry 2000; 157: 708–714.

Lyketsos CG, Carrillo MC, Ryan JM, et al. Neuropsychiatric symptoms in Alzheimer’s disease. Alz Dement 2011; 7 (5): 532–539.

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Depression and Alzheimer’s disease
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AD and depression are thought to share some common risk factors, including inflammation.[Li et al., 2014] However, the direction of the risk is poorly understood.[Li et al., 2014] Does depression increase the risk of AD, or does dementia increase the risk of depression; is depression a part of the clinical syndrome of AD, or do they both simply share common causes?[Wint, 2011] It seems likely that depression seen in patients with AD is heterogeneous, but in some cases is caused by the neurodegenerative processes of AD.[Lee & Lyketsos, 2003]

As elaborated on the slide, patients with AD appear to be at a higher risk of developing depression than the general population.[Chi et al., 2015; Ferrari et al., 2013] However, conversely, patients with depression appear to be at a greater risk of developing AD and dementia.[Saczynski et al., 2010] In an analysis of the Framingham study, individuals with depression at baseline had a greater risk of developing dementia (risk ratio: 1.7).[Saczynski et al., 2010] The result remained significant after correction for age, sex, education, and biochemical factors.[Saczynski et al., 2010] The authors discuss the fact that several lifestyle factors associated with longstanding depression may be associated with dementia risk, including diet, social engagement, and physical activity.[Saczynski et al., 2010]

 

Chi S, Wang C, Jiang T, et al. The prevalence of depression in Alzheimer’s disease: a systematic review and meta-analysis. Curr Alzheimer Res 2015; 12 (2): 189–198.

Ferrari AJ, Charlson FJ, Norman RE, et al. The epidemiological modelling of major depressive disorder: application for the global burden of disease study 2010. PLoS One 2013; 8 (7): e69637.

Lee HB, Lyketsos CG. Depression in Aheleimer’s disease: heterogeneity and related issues. Biol Psychiatry 2003; 54 (3): 353–362.

Li XL, Hu N, Tan MS, et al. Behavioral and psychological symptoms in Alzheimer’s disease. Biomed Res Int 2014; 927804.

Saczynski JS, Beiser A, Seshadri S, et al. Depressive symptoms and risk of dementia: the Framingham Heart Study. Neurology 2010; 75 (1): 35–41.

Wint D. Depression: a shared risk factor for cardiovascular and Alzheimer disease. Cleve Clin J Med 2011; 78 (Suppl 1): S44–46.

Other reference used on slide

Ismail Z, Elbayoumi H, Fischer CE, et al. Prevalence of depression in patients with mild cognitive impairment a systematic review and meta-analysis. JAMA Psychiatry 2017; 74 (1): 58–67.

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Anxiety and Alzheimer’s disease
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Generalised anxiety disorder (GAD) is characterised by excessive anxiety and worry, about numerous events or activities.[APA, 2013] Examples include worrying about household chores, or being late for appointments.[APA, 2013]

Methodologically, the study of symptoms of anxiety in patients with AD is complicated.[Seignourel et al., 2008] In order to properly interrogate the relationship between AD and anxiety, a distinction must be made between the symptoms of AD and separate anxiety disorders, and the potential overlap between anxiety and depressive symptoms must be considered.[Seignourel et al., 2008]

Another of the difficulties of studying anxiety in patients with dementia relates to how the data should be collected.[Seignourel et al., 2008] In most studies of anxiety, the ideal source of information is the patient themselves.[Seignourel et al., 2008] However, this approach may not be appropriate when some patients may have difficulty communicating, or remembering their symptoms, as is likely to be the case in dementia.[Seignourel et al., 2008] One solution is to interview caregivers of the patients, but this risks missing important information about which the caregivers might not have been aware.[Seignourel et al., 2008] A fuller approach is to include several sources of information about the patient, including a patient interview, a caregiver interview, medical staff interviews, and medical records, from which a comprehensive view of anxiety symptoms can be assembled.[Seignourel et al., 2008]

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fifth Edition (DSM-5™). © American Psychiatric Association, 2013.

Seignourel JP, Kunik ME, Snow L, et al. Anxiety in dementia. Clin Psychol Rev 2008; 28 (7): 1071–1082.

Other references used on slide:

Calleo JS, Kunik ME, Reid D, et al. Characteristics of generalized anxiety disorder in patients with dementia. Am J Alzheimers Dis Other Demen 2011; 26 (6): 492–497.

Teri L, Ferretti LE, Gibbons LE, et al. Anxiety in Alzheimer’s disease: prevalence and comorbidity. J Gerontol A Biol Sci Med Sci 1999; 54 (7): M348–352.

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Agitation and Alzheimer’s disease
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Although agitation is a common feature of dementia,[Gauthier et al., 2010; Margallo-Lana et al., 2001] there was for a long time no consensus definition of agitation, and no widespread agreement on what elements should be included in the syndrome.[Cummings et al., 2015] The International Psychogeriatric Association (IPA) has produced a provisional definition of agitation in cognitive disorders:[Cummings et al., 2015]

  1. Patient meets criteria for cognitive impairment or dementia syndrome.
  2. One of the following behaviours associated with observed or inferred emotional distress; persistent or recurrent (at least 2 weeks); representing a change from premorbid behaviour:
    excessive motor activity
    verbal aggression
    physical aggression
  3. Severe enough to cause disability.
  4. Comorbid conditions or environmental circumstances do not entirely account for the behaviour.

However, despite the until-recent lack of a consensus definition, various interventions have been suggested for patients with agitation and dementia.[Livingston et al., 2014] One meta-analysis studied 33 randomised controlled trials of non-pharmacological treatments for agitation in dementia.[Livingston et al., 2014] Some interventions were linked to improvements in agitation, particularly person-centered care, communication skills training, adapted dementia care mapping, activities, and music therapy.[Livingston et al., 2014]

Cummings J, Mintzer J, Brodaty H, et al. Agitation in cognitive disorders: International Psychogeriatric Association provisional consensus clinical and research definition. Int Psychogeriatr 2015; 27 (1): 7–17.

Gauthier S, Cummings J, Ballard C, et al. Management of behavioral problems in Alzheimer’s disease. Int Psychogeriatr 2010; 22 (3): 346–372.

Livingston G, Kelly L, Lewis-Holmes E, et al. Non-pharmacological interventions for agitation in dementia: systematic review of randomised controlled trials. Br J Psychiatry 2014; 205 (6): 436–442.

Margallo-Lana M, Swann A, O’Brien J, et al. Prevalence and pharmacological management of behavioural and psychological symptoms amongst dementia sufferers living in care environments. Int J Geriatr Psychiatry 2001; 16: 39–44.

Other references used on slide

Banerjee S, Smith SC, Lamping DL, et al. Quality of life in dementia: more than just cognition. An analysis of associations with quality of life in dementia. J Neurol Neurosurg Psychiatry 2006; 77 (2): 146–148.

Borsje P, Wetzels RB, Lucassen PL, et al. The course of neuropsychiatric symptoms in community-dwelling patients with dementia: a systematic review. Int Psychogeriatr 2015; 27 (3): 385–405.

Knapp M, Chua KC, Broadbent M, et al. Predictors of care home and hospital admissions and their costs for older people with Alzheimer's disease: findings from a large London case register. BMJ Open 2016; 6 (11): e013591.

Peters ME, Schwartz S, Han D, et al. Neuropsychiatric symptoms as predictors of progression to severe Alzheimer's dementia and death: the Cache County Dementia Progression Study. Am J Psychiatry 2015; 172 (5): 460–465.

Selbæk G, Engedal K, Bergh S.The prevalence and course of neuropsychiatric symptoms in nursing home patients with dementia: a systematic review. J Am Med Dir Assoc 2013; 14 (3): 161–169.

Tariot P. Treatment of agitation in dementia. J Clin Psychiatry 1999; 60 (Suppl 8): 11–20.

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Bipolar disorder, schizophrenia, and Alzheimer’s disease
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A methodological challenge to studying the interaction of dementia and bipolar disease, is the fact that many studies of dementia and depression are poorly controlled for bipolar disorder – it is possible that, in many of the studies, the depression cohorts include patients with bipolar disorder.[da Silva et al., 2013] One approach that has been taken, is to ask whether the number of bipolar episodes increases the risk of developing dementia.[Kessing & Andersen, 2004] In one study taking this approach, the risk of developing dementia increased by 6% for each episode of bipolar disorder leading to hospital admission.[Kessing & Andersen, 2004]

da Silva J, Goncalves-Pereira M, Xavier M, Mukaetova-Ladinska EB. Affective disorders and risk of developing dementia: systematic review. Br J Psychiatr 2013; 202: 177–186.

Kessing LV, Andersen PK. Does the risk of developing dementia increase with the number of episodes in patients with depressive disorder and in patients with bipolar disorder? J Neurol Neurosurg Psychiatry 2004; 75: 1662–1666.

Other references used on slide

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fifth Edition (DSM-5™). © American Psychiatric Association, 2013.

Cai L, Huang J. Schizophrenia and the risk of dementia: a meta-analysis study. Neurosci Dis Treat 2018; 14: 2047–2055.

Chen MH, Li CT, Tsai CF, et al. Risk of subsequent dementia among patients with bipolar disorder or major depression: a nationwide longitudinal study in Taiwan. JAMDA 2015; 16: 504–508.

Garcez ML, Falchetti ACB, Mina F, Budni J. Alzheimer’s disease associated with psychiatric comorbidities. An Acad Bras Cienc 2015; 87 (2 Suppl): 1461–1473.

Zilkens RR, Bruce DG, Duke J, et al. Severe psychiatric disorders in mid-life and risk of dementia in late-life (age 65–84 years): a population based case-control study. Curr Alz Res 2014; 11: 681–693.

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Sleep disturbances and Alzheimer’s disease
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The study of sleep disturbances in AD is complicated by the still incomplete understanding of the normal functions of sleep in a non-pathological context.[Cipriani et al., 2015] The aetiology of the sleep disorders seen in dementia appears to be driven by several factors, including some potentially shared pathological brain changes, as well as environmental factors and medication side effects.[Cipriani et al., 2015] It is clear, though, that the sleep disturbances of AD negatively impact on an individual’s quality of life and functioning, as well as the well-being of their caregivers.[Cipriani et al., 2018; Tractenberg et al., 2005]

Cipriani G, Lucetti C, Danti S, Nuti A. Sleep disturbances and dementia. Psychogeriatrics 2015; 15 (1): 65–74.

Tractenberg RE, Singer CM, Kaye JA. Symptoms of sleep disturbance in persons with Alzheimer’s disease and normal elderly. J Sleep Res 2005; 14 (2): 177–185.

Other references used on slide:

Brzecka A, Leszek J, Ashraf GM, et al. Sleep disorders associated with Alzheimer’s disease: a perspective. Front Neurosci 2018; 12: 330.

Guarnieri B, Adorni F, Musicco M, et al. Prevalence of sleep disturbances in mild cognitive impairment and dementing disorders: a multicenter Italian clinical cross-sectional study on 431 patients. Dement Geriatr Cogn Disord 2012; 33 (1): 50–58.

Shin HY, Han HJ, Shin DJ, et al. Sleep problems associated with behavioral and psychological symptoms as well as cognitive functions in Alzheimer’s disease. J Clin Neurol 2014; 10 (3): 203–209.

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The impact of the psychiatric comorbidities of Alzheimer’s disease
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A large scale anonymous survey of the carers of patients with dementia in Germany, Poland, France, and the UK was published in 2008, questioning people about the burden of caring for individuals with dementia.[Georges et al., 2008] In total, 1,181 carers responded to the questionnaire; 47% were caring for a spouse or partner, whilst 37% were caring for a parent.[Georges et al., 2008] The symptoms that carers reported having the most difficulty dealing with were difficulties with activities of daily living (ADL), such as using the lavatory.[Georges et al., 2008] Memory problems and confusion in patients with dementia caused difficulties for 32% of carers.[Georges et al., 2008]

Another survey sampled patients with dementia and their caregivers, using the Neuropsychiatric Inventory (NPI) scale to assess the correlation between the level of neuropsychiatric symptomatology and scores on the caregiver distress subscale.[Mukherjee et al., 2017] A total of 107 patients with dementia and their caregivers were included in the analysis.[Mukherjee et al., 2017] Almost all (99.1%) had at least one neuropsychiatric symptom, according to the NPI.[Mukherjee et al., 2017] Interestingly, there appeared to be differences between different subtypes of dementia; the total burden of neuropsychiatric symptoms appeared to be greatest in patients with frontotemporal dementia, and lowest amongst patients with vascular dementia.[Mukherjee et al., 2017] The predominant symptoms in patients with AD were apathy, agitation, irritability, depression, sleep disorders, and anxiety.[Mukherjee et al., 2017] Crucially, the level of caregiver distress significantly increased with increasing number, and severity, of the neuropsychiatric symptoms (both p<0.001).[Mukherjee et al., 2017]

Georges J, Jansen S, Jackson J, et al. Alzheimer’s disease in real life – the dementia carer’s survey. Int J Geriatr Psychiatry 2008; 23 (5): 546–551.

Mukherjee A, Biswas A, Roy A, et al. Behavioural and psychological symptoms of dementia: correlates and impact on caregiver distress. Dement Geriatr Cogn Dis Extra 2017; 7 (3): 354–365.

Other references used on slide

Küçükgüçlü Ö, Söylemez BA, Yener G, et al. Examining factors affecting caregiver burden: a comparison of frontotemporal dementia and Alzheimer’s disease. Am J Alzheimers Dis Other Demen 2017; 32 (4): 200–206.

Zahodne LB, Ornstein K, Cosentino S, et al. Longitudinal relationships between Alzheimer disease progression and psychosis, depressed mood, and agitation/aggression. Am J Geriatr Psychiatry 2015; 23 (2): 130–140.

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The physical comorbidities of Alzheimer’s disease
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The physical comorbidities of Alzheimer’s disease
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References

The burden of physical disease is greater in patients with AD than that observed in age-matched control individuals.[Duthie et al., 2011; Poblador-Plou et al., 2014] The range of physical disease seen in patients with AD includes cerebrovascular disease, thyroid problems, and eye problems.[Duthie et al., 2011; Poblador-Plou et al., 2014]

One study, which investigated the stage-specific comorbidity-burden in 679 patients with AD, found that the burden of physical disease increased as AD progresses (according to MMSE [the Mini-Mental State Examination] scores).[Doraiswamy et al., 2002] Furthermore, a higher medical comorbidity burden was associated with lower (worse) MMSE scores (p<0.001).[Doraiswamy et al., 2002] The study also found that medical comorbidity was associated with impaired mobility and incontinence, likely due to the prevalence of musculoskeletal problems and urinary disorders.[Doraiswamy et al., 2002] The authors highlight the impact that the physical disease burden of AD will have on healthcare systems, adding to the already costly nature of the condition.[Doraiswamy et al., 2002] Physical comorbidities are important for healthcare providers to consider, because the medical comorbidities of AD make a significant contribution to the cognitive and functional decline seen in patients with AD.[Duthie et al., 2011]

Doraiswamy PM, Leon J, Cummings JL, et al. Prevalence and impact of medical comorbidity in Alzheimer’s disease. J Gerontol Med Sci 2002; 52A (3): M173–177.

Duthie A, Chew D, Soize RL. Non-psychiatric comorbidities associated with Alzheimer’s disease. QJM 2011; 104 (11): 913–920.

Poblador-Plou B, Calderón-Larrañaga A, Marta-Moreno J, et al. Comorbidity of dementia: a cross-sectional study of primary care older patients. BMC Psychiatry 2014; 14: 84.

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Vascular disease and Alzheimer’s disease
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It is becoming increasingly recognised that cardiac and brain health are intertwined; leading some to coin the phrase: ‘what’s good for the heart is good for the brain’.[Breitner & Galasko, 2015] A wide-ranging review of the literature identified several shared risks between vascular disease and AD, as shown on the slide, and identified some areas of possible neuropathological overlap:[Santos et al., 2017]

  • reduction in cerebral blood flow
  • deposition of amyloid-beta (Aβ)
  • larger scale morphological changes in vasculature
  • changes to the permeability of the blood–brain barrier
  • modulations to cholinergic neurotransmission.

Breitner JCS, Galasko D. Encouraging trends toward reduced risk of Alzheimer disease: what’s good for the heart is good for the brain. Neurol Clin Pract 2015; 5 (3): 190–192.

Santos CY, Snyder PJ, Wu WC, et al. Pathophysiologic relationship between Alzheimer’s disease, cerebrovascular disease, and cardiovascular risk: a review and synthesis. Alzheimers Dement (Amst) 2017; 7: 69–87.

Other reference used on slide

Gottesman RF, Schneider AL, Zhou Y, et al. Association between midlife vascular risk factors and estimated brain amyloid deposition. JAMA 2017; 317 (14): 1443–1450.

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Cardiovascular disease and Alzheimer’s disease
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It is difficult to establish the directionality of the risk between AD and cardiovascular disease (CVD) – do they share common risk factors, does CVD indirectly increase the risk of AD, or is there a direct link between the two?[Stampfer, 2006] Further clouding the investigation of the relationship between the risk factors for AD and CVD is the difference in the age of onset of the two conditions.[Stampfer, 2006] Cognitive impairment probably takes years to develop; early-life shared risk factors could, therefore, have a greater influence on the disease course of AD than late-life risk factors, which become evident once the disease process is underway.[Stampfer, 2006] This logic applies less to the CVD process, which can be evident at an earlier stage in life than is typically observed for AD.[Stampfer, 2006]

Although still poorly understood, it is increasingly being realised that AD and cardiovascular disease share common pathology.[Stampfer, 2006] But, a full understanding of the direct relationship is not necessary to explore the possible therapeutic potential of improving vascular health in patients with AD, or indeed those at risk of developing AD.[Marlatt et al., 2008]

Marlatt M, Lucassena PJ, Perry G. Alzheimer’s disease: cerebrovascular dysfunction, oxidative stress, and advanced clinical therapies. J Alzheimers Dis 2008; 15 (2): 199–210.

Stampfer MJ. Cardiovascular disease and Alzheimer’s disease: common links. J Intern Med 2006; 260 (3): 211–223.

Other references used on slide

Poblador-Plou B, Calderón-Larrañaga A, Marta-Moreno J, et al. Comorbidity of dementia: a cross-sectional study of primary care older patients. BMC Psychiatry 2014; 14: 84.

Stewart R. Cardiovascular factors in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 1998; 65: 143–147.

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Thyroid function and Alzheimer’s disease
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As shown on the slide, the thyroid gland is controlled by the interactions of the hypothalamic–pituitary–thyroid axis.[Medscape] Hypothyroidism (an under-active thyroid gland) usually manifests as symptoms of slowing mental and physical ability, but it can be asymptomatic.[Medscape] The physiological effects of an under-active thyroid can include depression, fatigue, decreased appetite, intolerance to cold, forgetfulness and impaired memory, and muscle and joint pain.[Medscape]

Whilst there is evidence that supports an association between thyroid function and AD, the link is not completely understood.[Tan et al., 2008; Tan & Vasan, 2009] Some have theorised that the neurodegeneration of AD leads to a loss of thyroid function, as explained on the slide, others have suggested that changes in thyroid function may have a direct effect on the AD process, whilst an alternative explanation is that both AD and thyroid disorders are mediated by similar vascular risk factors.[Tan et al., 2009] More research is needed to fully elucidate the connections between AD and thyroid function, to establish whether either one is a modifiable risk factor for the other.[Tan et al., 2009]

Medscape website. Hypothyroidism. Available at: https://emedicine.medscape.com/article/122393-overview. Accessed November 2018.

Tan ZS, Beiser A, Vasan RS, et al. Thyroid function and the risk of Alzheimer’s disease: the Framingham study. Arch Intern Med 2008; 168 (14): 1514–1520.

Tan ZS, Vasan RS. Thyroid function and Alzheimer’s disease. J Alzheimers Dis 2009; 16 (3): 503–507.

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Diabetes and Alzheimer’s disease
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References

As stated on the slide, the cooccurrence of diabetes and AD is likely to increase; treatment, and prevention, of conditions such as diabetes in patients with AD should be a concern to the attending physician.[Scrutton & Brancati, 2016] Such treatment is likely to be confounded by the changes sometimes seen in patients with AD, some of whom are observed to favour sweet and snack foods,[Ikeda et al., 2002] and be less capable of adhering to a diet.[Feil et al., 2012]

Feil DG, Zhu CW, Sultzer DL. The relationship between cognitive impairment and diabetes self-management in a population-based community sample of older adults with Type 2 diabetes. J Behav Med 2012; 35 (2): 190–199.

Ikeda M, Brown J, Holland AJ, et al. Changes in appetite, food preference, and eating habits in frontotemporal dementia and Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2002; 73 (4): 371–376.

Scrutton J, Brancati CU. Dementia and comorbidities. Ensuring parity of care. International Longevity Centre, 2016.

Other reference used on slide

Cheng G, Huang C, Deng H, Wang H. Diabetes as a risk factor for dementia and mild cognitive impairment: a meta-analysis of longitudinal studies. Intern Med J 2012; 42 (5): 484–491.

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Osteoporosis and Alzheimer’s disease
Slide information
References

Because bone mineral density can be a predictor of fractures, it has been used to measure risk of fractures in patients with AD in a meta-analysis study – specifically hip bone mineral density.[Zhao et al., 2012] The meta-analysis identified a total of nine studies, some that report odds ratios and risk of hip fracture, and others that report values for hip bone mineral density in patients with AD, compared with controls.[Zhao et al., 2012] From the analysis, the risk of hip fracture was 1.8 times greater in patients with AD compared with controls (95% CI [confidence interval]: 1.54, 2.11).[Zhao et al., 2012] Furthermore, the standardised mean difference in hip bone mineral density between patients with AD and controls was -1.12 (95% CI: -1.34, -0.90).[Zhao et al., 2012] The authors discuss the role that factors such as Vitamin D, calcium, and PTH (parathyroid hormone) might play in the mechanics of osteoporosis in AD.[Zhao et al., 2012] Indeed, there are many potential pathophysiological links between AD and osteoporosis, including the connection with Vitamin D, which is itself being explored as a risk factor for AD.[Chen & Lo, 2017]

Chen YH, Lo RY. Alzheimer’s disease and osteoporosis. Tzu Chi Med J 2017; 29 (3): 138–142.

Zhao Y, Shen L, Ji HF. Alzheimer’s disease and risk of hip fracture: a meta-analysis study. Scientific World Journal 2012; 2012: 872173.

Other references used on slide

Bednarski J, Gasińska K, Rucińska M, Turżańska K. Alzheimer’s disease and osteoporosis – correlation increasing the risk of life-threatening fractures? MEDtube Sci 2014; (2) 1: 32–38.

Downey CL, Young A, Burton EF, et al. Dementia and osteoporosis in a geriatric population: is there a common link? World J Orthop 2017; 8 (5): 412–423.

Wang HK, Hung CM, Lin SH, et al. Increased risk of hip fractures in patients with dementia: a nationwide population-based study. BMC Neurol 2014; 14: 175.

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Urinary tract infections and Alzheimer’s disease
Slide information
References

Urinary tract infections (UTIs) occur when an infectious agent enters the urinary tract, via the urethra, and moves upwards towards the bladder or kidneys.[Alzheimer’s society] Although usually treatable with antibiotics, UTIs can have serious complications, including kidney damage and blood poisoning.[Alzheimer’s society] There are several practical things that can be done to reduce the risk of a UTI.[Alzheimer’s society] These include staying well hydrated, using the toilet regularly, maintaining a healthy diet, and maintaining good hygiene.[Alzheimer’s society]

Alzheimer’s Society. Urinary tract infections (UTIs) and dementia. Factsheet 528LP. April 2015.

Other references used on slide

Hodgson NA, Gitlin LN, Winter L, Czekanski K. Undiagnosed illness and neuropsychiatric behaviors in community residing older adults with dementia. Alzheimer Dis Assoc Disord 2011; 25 (2): 109–115.

Sampson EL, Blanchard MR, Jones L, et al. Dementia in the acute hospital: prospective cohort study of prevalence and mortality. Br J Psychiatry 2009; 195 (1): 61–66.

Scrutton J, Brancati CU. Dementia and comorbidities. Ensuring parity of care. International Longevity Centre, 2016.

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Glaucoma and Alzheimer’s disease
Slide information
References

Glaucoma is a leading cause of irreversible blindness across the globe, and has an estimated prevalence of 3.5% in people aged 40–80, meaning an estimated 64.3 million people globally have the condition.[Tham et al., 2014] This global value is predicted to rise to 111.8 million people by the year 2040.[Tham et al., 2014]

Although there is still disagreement in the literature, some argue that glaucoma is a manifestation of the neurodegeneration that underlies AD.[Cesareo et al., 2015; Lai et al., 2017; Mancino et al., 2018] There are many hypotheses that have been proposed to explain the connection: similarities in changes to fluid pressures in the brain and eyes, possible infectious agents, the genetics of the two conditions, and mechanisms of autophagy.[Mancino et al., 2018] Ultimately, more research is needed to fully understand the pathological intersection of AD and glaucoma.[Mancino et al., 2018]

Cesareo M, Martucci A, Ciuffoletti E, et al. Association between Alzheimer’s disease and glaucoma: a study based on Heidelberg retinal tomography and frequency doubling technology perimetry. Front Neurosci 2015; 9: 479.

Lai SW, Lin CL, Liao KF. Glaucoma may be a non-memory manifestation of Alzheimer’s disease in older people. Int Psychogeriatr 2017; 29 (9): 1535–1541.

Mancino R, Martucci A, Cesareo M, et al. Glaucoma and Alzheimer disease: one age-related neurodegenerative disease of the brain. Curr Neuropharmacol 2018; 16 (7): 971–977.

Tham YC, Li X, Wong TY, et al. Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis. Ophthalmology 2014; 121 (11): 2081–2090.

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Seizures, epilepsy, and Alzheimer’s disease
Slide information
References

Epilepsy is a condition whereby an individual is predisposed for some reason to epileptic seizures.[Medscape] These seizures can be debilitating, and potentially harmful.[Medscape]

As outlined on the slide, patients with AD appear to be at a greater risk of experiencing seizures than control individuals, although the exact mechanisms behind this association are not well understood.[Irizarry et al., 2012; Sherzai et al., 2014] There is some argument about the best therapeutic approach, given that the seizures seen in patients with AD are typically sparse (although possibly under-estimated), and appear to respond well to anti-epileptic therapy.[Abou-Khalil, 2010] Indeed, physicians should consider the pro-epileptic potential of some therapies used in the treatment of AD when assessing patients with seizures.[Abou-Khalil et al., 2010]

Abou-Khalil BW. How important is Alzheimer’s disease as a risk factor for unprovoked seizures and epilepsy in the elderly? Epilepsy Curr 2010; 10 (2): 36–37.

Irizarry MC, Jin S, He F, et al. Incidence of new-onset seizures in mild to moderate Alzheimer disease. Arch Neurol 2012; 69 (3): 368–372.

Medscape website. Epilepsy and Seizures. https://emedicine.medscape.com/article/1184846-overview. Accessed November 2018.

Sherzai D, Losey T, Vega S, Sherzai A. Seizures and dementia in the elderly: Nationwide Inpatient Sample 1999–2008. Epilepsy Behav 2014; 36: 53–56.

Other reference used on slide

Høgh P, Smith SJ, Scahill RI, et al. Epilepsy presenting as AD: neuroimaging, electroclinical features, and response to treatment. Neurology 2002; 58 (2): 298–301.

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Clinical guidelines and older patients with dementia
Slide information
References

Despite the wealth of clinical guidelines available for dementia, and AD, they generally deal poorly with the comorbidity burden in older patients, as outlined on the slide.[Damiani et al., 2014] The authors of the meta-analysis discuss the difficulties that treating the comorbidities of dementia often bring, where treatments that can be prescribed for the comorbidity may actually interfere with the treatment regimen for dementia, or vice versa.[Damiani et al., 2014] This highlights the need for treatment guidelines that discuss the many comorbidities of dementia, rank the treatments available, and consider the potential interactions of possible treatments.[Damiani et al., 2014]

Damiani G, Silvestrini D, Trozzi L, et al. Quality of dementia clinical guidelines and relevance to the care of older people with comorbidity: evidence from the literature. Clin Interv Aging 2014; 9: 1399–1407.

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While dementia...
References

Scrutton J, Brancati CU. Dementia and comorbidities. Ensuring parity of care. International Longevity Centre, 2016.

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