Early disease-specific characteristics for identifying Mixed Vascular-Alzheimer's Dementia in geriatric patients

doi:10.21203/rs.3.rs-3573907/v1

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Early disease-specific characteristics for identifying Mixed Vascular-Alzheimer's Dementia in geriatric patients

https://doi.org/10.21203/rs.3.rs-3573907/v1

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Purpose

Mixed Vascular-Alzheimer's Dementia (MVAD) is coexistence of both Alzheimer's disease and cerebrovascular disease (CVD) in the same patient. Thus, the current investigation focused on retrospectively classifying and diagnosing older geriatric patients at risk for dementia with both vascular risk factors and neuro-atrophy factors in Alzheimer's disease (AD)versus patients with nonvascular-AD etiology.

Methods

The study evaluated demographic and clinical data collected from a cohort of 192 geriatric out-patients (age range = 60–97 years) admitted for one baseline and one follow-up clinical consultations within a period of three years. Mini Mental State Examination (MMSE) scores and cardiovascular risk factors were reevaluated and utilized in the assessment of basic cognitive functioning and clinical diagnosis of MVAD and AD dementia subgroups during follow-up visits.

Results

A relatively high prevalence of MVAD diagnosis was found across the entire sample (36%). MVAD diagnosis was significantly higher in men with 59% prevalence, while AD diagnosis without vascular etiology was significantly higher in women with 69% prevalence. MVAD diagnosis was more pronounced under the age of 85, while AD diagnosis without vascular history was significantly higher in ages 85 years or older. Importantly, non-palpations of peripheral pulse and atrial fibrillation-type arrhythmia were found to be significant early risk factors related to prospective MVAD diagnosis (p < .008, OR = 30, p < .009, OR = .005).

Conclusion

Early comprehensive clinical evaluation of specific vascular risk factors prior to dementia onset could putatively predict the onset of MVAD.

Aging

Mixed Vascular-Alzheimer Dementia (MVAD)

Cerebral and Cardio Vascular risk factors

Peripheral pulse

Atrial fibrillation

The significant rise in relative number of older adults with multiple diseases, frailty, and physical disabilities due to different neurologic impairments raises the need for ongoing geriatric consultation to monitor or predict the onset of pre-dementia systemic and cognitive symptoms across ages 50 to 90 [1]. Particularly in older people at higher risk for entering prodromal dementia state [2]. Mixed dementia, the coexistence of Alzheimer's disease (AD) and cerebrovascular disease (CVD) is called Mixed Vascular-Alzheimer Dementia (MVAD). Mixed dementia remains a challenge for clinician and practitioners because the distinction between AD and MVAD might be complex requiring the detection of subtle differences in phenotypic expression and their clinical presentation can overlap. The problem of differential diagnosis is complicated by the fact that concomitant AD and cardio and cerebral vascular risk factors are often diagnosed as mixed dementia [3]. Studies indicate that the diagnosis of MVAD is very common with prevalence of 22% in the elderly [4].

In recent years, new research findings seem to support the connection between uncommon or novel cardio-vascular risk factors (CVRF) and cognitive decline observed in early prodromal or mild dementia stages [5–8]. In light of these findings, it is necessary to re-evaluate preceding cerebrovascular risk factors in elderly pre-dementia geriatric patients that may distinguish a unique pre-MVAD prodromal-dementia population that can be treated early to suppress the severity or delay the onset of pervasive dementia symptoms. For example, in cases of atrial fibrillation, such arrhythmia resulting in shower of emboli to brain induces immediate cognitive impairments. Currently, clinicians can apply atrial ablation procedures and induce a return to sinus rhythm and no formation of emboli. The same with correction of aortic stenosis or stiffness and discontinuing of antihypertensive class medication that reduce cardiac index [5–8].

Interestingly, the accurate and etiology-specific diagnosis of mixed dementia is inconsistent, neglecting significant symptomatic vascular components that could be directly evaluated and treated. Therefore, in most cases no attempt is made to optimally treat the vascular pathophysiology and related symptoms [9]. The clinician in the community could potentially utilize reliable clinical tools that detect etiological or physiological cardiovascular variables associated with MVAD onset and progression. In the clinical research setting, AD diagnosis requires evidence of amyloid and tau CSF biomarkers (or confirmed via autopsy indicating atrophy in the cerebrum). Clinical diagnosis of MVAD relies on the appearance of recent memory loss and identifying basic learning impairments related to vascular dementia. Importantly, the comprehensive clinical diagnosis of MVAD is directly related to the patients' medical history highlighting specific risk factors such as past occurrence of cardio-vascular and neuro-vascular events. More so, this could be validated using anatomical brain imaging (CT or MRI) displaying subcortical ischemic and white matter damage confirming MVAD etiology in dementia patients [3]. Unfortunately, patients in pre-dementia stages are not regularly referred to neuroimaging assessments to decipher the etiology of pre-dementia symptoms, brain-based evaluations are applied sporadically.

Therefore, the current investigation retrospectively examined early disease-specific indicators and behaviors in a sample of geriatric patients to identify early cardio-vascular risk factors (CVRF) significantly related with later MVAD diagnosis. The purpose of the current study was to retrospectively characterize referred elderly outpatients and to examine which early CVRF variables independently predicted the later diagnosis of MVAD. We aimed to identify certain variables that are significantly associated with MVAD onset in the geriatric population, by utilizing a multilevel clinical-approach to evaluate CVRF and cognitive-function variables as possible early predictors of a specific neurodegenerative disorder diagnosis, such as MVAD versus AD, in geriatric outpatients evaluated at pre and post dementia onset visits over a three-year period.

Design

The current study represents a retrospective observational investigation describing mainly clinical and cognitive parameters observed in MVAD versus AD patients, including etiology parameters (e.g., cardio and cerebral-vascular history, diabetes and hyperlipidemia ect) over a period of three years. The patients included in the current study were initially in a pre-dementia state, referred from their attending physician with complaints not necessarily related to salient cognitive decline (e.g sleeping disorder, weight loss, fall and instability). The attained list of diagnoses usually did not include dementia but tended to focus more on physical problems related to skeletal and joint pathological processes, or to cardiovascular or other systemic diseases. After consultation, patients return to the family physician with a recommendation to treat ongoing symptoms, including suggested prognosis based on the attempt to possibly delay or prevent dementia symptom-manifestation. The multilevel diagnostic approach applied in the current investigation aimed to examine the patient in the areas of physical, mental, cognitive and social functioning and provide informative feedback to the patient, the referring clinician, and to the immediate family [1]. The patient's disease etiology was assigned by a geriatric physician according to their medical history, disease-specific symptom severity (e.g., cardiovascular symptoms), and specific cognitive impairment criteria in prodromal dementia patients, prior to their MVAD versus AD formal diagnosis. The follow-up visits were used for diagnosis confirmation of early assessed diagnostic predictors.

Participants

The current retrospective investigation analyzed data collected from a cohort of 192 geriatric out-patients with mean age of 83.04 years (SD = 7.161, range = 60–97 years) referred for further clinical consultation by their family physician (GP) regarding their medical condition and diagnosis, prior to classification to specific dementia group. Later diagnostic dementia classification was inspected at follow-up visits in the same participants. Baseline-visit demographic data of MVAD group versus AD group can be viewed in Table 1. Baseline data was drawn from patients' pre-dementia visit and their post three-year follow-up visit during which they were diagnosed with dementia by the same geriatrician. The study was approved by the Herzog Medical Center ethics committee under the guidelines of the declaration of Helsinki. The study was approved without the requirement for obtaining informed consent.

Primary demographic, clinical, and/or medical background-variables included in the statistical risk-analyses considered the prevalence of socio-demographic characteristics (age, gender family status), ongoing diseases (diabetes background, high blood pressure, Ischemic heart disease, hyperlipidemia and brain strokes ) in MVAD versus AD. Secondary disease-specific and systemic medical-history baseline variables included were the prevalence of obesity, functional capacity level (bound to bed, bound to home), repetitive behavioral problems, gait-instability, arrhythmias such as Atrial fibrillation and detecting no palpation during assessment of peripheral pulses. The diagnostic inclusion in Alzheimer's disease (AD) group or mixed dementia (MVAD) subgroups group occurred within the period of the study (follow-up visits in the clinic) and was the predicted nominal variable.

To support MVAD classification, the current study utilized ≥ 2 of the five known cardio -vascular risk factors (CVRF) such as; diabetes mellitus adult type 2, high blood pressure, Ischemic heart disease, hyperlipidemia, and stroke history. The clinical criteria of Hachinski Ischemic Score (HIS ≥ 7) which represents a standard diagnostic examination for identifying vascular dementia with high inter-rater reliability [10–11] was also utilized for MVAD diagnosis in the current study. Age inclusion criteria for of target dementia-sample were older geriatric outpatients over the age of 60.

Data analysis

Descriptive and categorical distribution statistics (chi-square tests), examining differences in the prevalence predictors in MVAD (Yes/No) or AD population following retrospective-study analyses are presented for the 108 dementia participants included in the final analyses. Logistic regression models were used to estimate the Odds Ratio (OR) and 95% confidence intervals (CI) of significant association between potential baseline risk factors with later MVAD or AD classification. Primary and secondary risk factors entered to the multinomial logistic regression model included gender, age, and behavioral disturbances. Functional ADL, gait-instability, peripheral pulse, AF or arrhythmia and Obesity were also entered as predictors in the regression models. All data were organized and analyzed with SPSS software (version 20). All statistical tests were two-sided. A p value below 0.05 was considered significant.

Dementia patients

The preliminary retrospective descriptive analysis identified 108 (54%) dementia patients out of 192 baseline elderly patients. The prevalence of MVAD was higher in men with 59.4%, while the prevalence of AD was higher in women with 69.2% -prevalence (p = 0.004), see Table 1 for further details. The association with MVAD was more pronounced in patients under the age of 85 with 56.3% prevalence, while association with AD was found to be significant in the older ages, 85 years or older (p = 0.037).

In a univariate analysis peripheral pulse was found to be a significantly associated (P = 0.001 OR = 14) with the MVAD group. Atrial fibrillation-type arrhythmia was also a significantly associated with MVAD diagnosis (p < .087 OR = 0.38). Behavioral disturbances were also significantly associated with MVAD diagnosis group versus AD diagnosis group (P < 0.027 OR = 0.4), see Table 2. In a multivariate analysis peripheral pulse and atrial fibrillation-type arrhythmia were found to be significantly related with MVAD (P < 0.008 OR = 30, P < 0.009 OR = 0.005), see Table 3.

Although behavioral disturbances were more pronounced in MVAD, an independent samples t-test showed that patients with a diagnosis of MVAD displayed significantly higher MMSE scores compared to those with a diagnosis of AD (MVAD, Mean = 15.89, SD = 4.609) (AD, Mean = 12.95, SD = 5.208), DF = 109 t = 3.075, p < 0.01]. Unlike Gender and age, demographic and clinical parameters such as family status, obesity and functional capacity were not significantly related to either AD or MVAD diagnoses.

In the current study we retrospectively assessed early cardiovascular risk factors (CVRF) related to acquiring MVAD versus AD, such as arrhythmia, lack of peripheral pulses, lower cardiac index, aortic stenosis and medication. The assessment took into consideration concurrent known cardiovascular risk factors. Our findings indicated that these factors can be identified early, and suggest that CVRF could be treated at pre-dementia stages in order to delay vascular and neurodegenerative progression. In support of examining early CVRF parameters as pre-dementia risk factors, earlier studies have shown that low cardiac index (low blood pressure or low pulse) followed by cardiac lesion or antihypertensive drugs is associated with increased incidents of vascular dementia and Alzheimer disease [5, 12]. In addition, Diabetes mellitus adult type 2 (poorly controlled blood sugar) increases the risk of developing Alzheimer’s disease. This relationship seems to be consistent, a proportion of clinicians refer to it as Alzheimer’s “diabetes of the brain” or “type 3 diabetes (T3D)” [13]. In the current research the findings show that 10% of the total patients had low cardiac index (low blood pressure or low pulse) and 26% were diabetic.

The most prominent finding in the current study is the lower prevalence of AD versus MVAD prevalence in geriatric outpatient population over the age of 60. The results support the theoretical perspective suggesting that MVAD represents a geriatric syndrome [1]. MVAD-based geriatric syndromes seem to represent a final pathway affected by a multi factorial pathophysiological process (e.g., such as thrombosis, emboli, atherosclerosis and cardiac arrhythmias), which can lead to abnormal blood perfusion and limited oxygen-levels in the brain. These pathophysiological conditions can be observed in vascular cognitive impairment (VCI) patients and represent primary precursor stages leading to onset of dementia [14]. However, unlike the current findings, previous clinical research literature examining AD versus MVAD diagnosis consistently highlight a higher prevalence of AD patients in people over the age of 65 [14]. Mixed findings suggest that excessive AD diagnoses may stem from the lack of standardized objective measures examining specific critical risk-factors, and the scarcity of empirical clinical findings associated with different etiologies in elderly patients with disease-specific, pre-dementia, accelerated cognitive decline symptoms. For instance, rapid cognitive decline can occur in situations of delirium (involving disorientation) occurring in geriatric patients following surgery (with general anesthesia), or after falls and head trauma, or as a result of taking new medications (anticholinergic), brain tumors (meningioma), or normal pressure hydrocephalus (NPH). Unfortunately, in substantial portions of these high-risk patients, dementia symptoms are likely to follow [15–16]. The potential for reliably diagnosing MVAD versus other dementias is important because it may affect the course of treatment and prevent rapid neuro-deterioration [7, 12, 17]. In cases of atrial fibrillation, such as arrhythmia resulting in shower of emboli, clinicians can apply atrial ablation procedures and induce a return to sinus rhythm. Aortic valve stenosis can be applied within valve replacement procedures. In conjunction, interventions such as stent placement or bypassing carotid artery stenosis, and avoiding fatal arrhythmias (ventricular fibrillation) by cardioversion pacing could prevent further cognitive deterioration and disease progression. These conditions, if untreated, can lead to reduced blood-flow and lower oxygen levels in the brain [9, 18]. Recommended behavioral interventions to slow down the cognitive decline such as targeting problematic lifestyle habits (weight loss, reduction in carbohydrate, salt and sugar consumption, and taking medication to reduce excessive hypertension, hyperglycemia and high cholesterol) and recommending behavioral strategies to change them following the initial clinical evaluation. Additional clinical risk factors that can be assessed and treated could involve reducing excessive use of pharmacological treatments (i.e. polypharmacy) for hypertension and diabetes (resulting in hypotension, hypoglycemia low sugar level and lower heart rate (bradycardia) [5, 19].

The current findings suggest that the medical history and meticulous clinical functional assessments are important to distinguish AD from MVAD in the geriatric pre-dementia population. For instance, testing procedures to assess postural hypotension, noting blood pressure while sitting and standing, excessive bradycardia, murmurs in the heart or on carotid artery, no palpitation of peripheral pulses in the feet (related to stenosis), and assessing stability of gait while walking could all be informative in detecting MVAD versus AD [8]. The geriatrician also notes the physical history and a detailed medical background that includes medications that may affect the brain (anticholinergics, antihistamines, narcotics, antidepressants, etc.) [16]. Pre-dementia risk factors associated with cardiovascular disease promote the development of accelerated processes of atherosclerosis, thrombosis and shower of blood clots into arteries of the brain, all of which should be examined during routine geriatric assessments of prodromal vascular dementia [18]. Importantly, over 50% of patients included in the current investigation were diagnosed with dementia, implying a 50% risk probability for being diagnosed with dementia in the geriatric outpatient population, particularly from age 60 or higher. However, more systematic observational studies are needed to confirm this finding in a larger population, as well as expanding current findings by utilizing brain-imaging data reflecting progression of MVAD-specific pathophysiology in brain morphology [20]. Importantly, men were at greater risk for MVAD while women were in greater risk for AD. Patients within the lower age range were found to be at higher risk for MVAD while patients at the older age-range (85 years and older) were at greater risk for AD. These findings are consistent with the medical scientific literature [21–22]. Furthermore, predominant early cardiovascular MVAD risk factors were identified, including non-palpations of peripheral pulse in legs and atrial fibrillation, both are likely to reflect signs of chronic vascular problems such as atherosclerosis, increased risk of lacunar stroke, and risk for brain-embolism episodes [6].

In light of the current findings, geriatric counseling can represent a preventive-treatment approach that focuses on everyday functioning, providing clinical diagnoses based on the phenotypic expression of their brain state (e.g., mild cognitive impairment), and "making order" with prescribed medications, and by doing so, downsizing undesired medication side- effects [16, 23]. Research in clinical geriatric populations indicates that diagnostic models of comprehensive geriatric assessment (CGA) emphasize individual disease-specific needs and may prevent institutionalizations and is likely to reduce disability and adverse effects following exposure to multiple drugs [24]. CGA was found to be one of the most reliable standard methods of diagnosis and prognosis for the elderly patients with multiple diseases, frailties, and disabilities. The current retrospective research findings support this approach in putatively distinguishing prodromal MVAD from AD patients, which can have a significant impact on their quality of life, course of treatment, and prognosis [25]. To support these risk factors and clinical signs as reflective of early prodromal biomarkers identifying MVAD versus AD, we suggest employment of longitudinal functional and anatomical neuroimaging (e.g., PET, CT, fMRI and ERP parameters of brain reactivity to specific stimuli) studies in large samples of geriatric population including reliable cardiovascular risk factors as baseline predictors of MVAD versus AD, and versus healthy controls ages 60 to 90.

In the current investigation, we retrospectively distinguished between two dementia target subgroups, AD patients versus MVAD patients. The surprising and relatively novel finding was a high prevalence of MVAD within the sample diagnosed with dementia. Thus, it may be clinically prudent to repeatedly and routinely examine the risk factors and clinical signs highlighted in the current study that are likely to predict disease-specific cognitive decline in older people. Therefore, the diagnosis of AD disease should not be based on cognitive tests alone, but rather on systematic examination and evaluation of the medical background risk factors and clinical signs by multifunctional clinical evaluations as indicated by the CGA diagnostic approach. Since we observed that most referrals to the clinic were not necessarily based on cognitive symptom domains, the geriatrician should apply an array of cognitive and clinical testing procedures in the differential diagnosis of dementia and look for several risk factors associated with specific clinical-state outcomes, such as the onset of MVAD versus AD. Thus, geriatric consultation in an outpatient clinic setting that includes comprehensive assessments over time, and a multidimensional broad view of the physical, cognitive, mental, and social functions, could be critical in the identification of MVAD versus AD patients in their prodromal stages. This comprehensive assessment approach may allow the investigation of novel treatments for suppressing accelerated cognitive decline in early stages of dementia or significantly delaying progression of neurodegenerative processes in high-risk populations within the elderly community.

Table 1

Prevalence of study population among individuals with MVAD and with AD.
		MVAD (N = 69)		AD (N = 39)			P-value
		N	%	N	%		P-value
Gender	Female	28	40.6	27	69.2	8.184	0.004
Gender	male	41	59.4	12	30.8	8.184	0.004
Age	84-	40	56.3	16	36.4	4.338	0.037
Age	85+	31	43.7	28	63.6	4.338	0.037
Family Status	Widower	29	46.8	21	55.3	3.767	0.288
	Unmarried	1	1.6	2	5.3
	Married	31	50	13	34.2
	Divorced	1	1.6	2	5.3

Table 2

The Odds Ratios of MVAD tested using univariate logistic regression
Factors	OR	95% CI	P- value
Gender	3.295		0.004
Age	2.258	1.043–4.891	0.036
Behavioral Problems	0.392	0.168–0.918	0.027
Functional Bedbound	1.467	0.562–3.827	0.434
Functional Homebound	1.200	0.310–4.651	0.792
Gait Instability	0.542	0.217–1.352	0.191
Peripheral Pulse	13.983	5.226–37.415	0.001
AF or Arrhythmia	0.379	0.116–1.238	0.087
Obesity	0.753	0.261–2.177	0.598

Table 3

The Odds Ratios of MVAD tested using multivariate logistic regression.
Factors	OR	95% CI	P- value
Gender	1.182	0.143–9.759	0.877
Age	1.153	0.017–1.387	0.095
Behavioral Problem	0.826	0.057–12.036	0.889
Bedbound Functional	1.514	0.035–27.108	0.778
Functional Homebound	4.189	0.000–0	0.999
Gait Instability	1.193	0.119–11.990	0.881
Peripheral Pulse	29.990	2.384-377.228	0.008
AF or Arrhythmia	0.005	0.000-0.266	0.009
Obesity	0.531	0.068–4.163	0.547

Authors declare no conflicts of interest.

Ethics approval and consent to participate

The study was approved by the Herzog Medical Center ethics committee under the guidelines of the declaration of Helsinki. The study was approved without the requirement for obtaining informed consent.

Consent for publication

Not applicable

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request

Competing interests

The authors declare that they have no competing interests

Funding

None

Authors' contributions

E.F. and O.M. wrote and edited the manuscript. H.F. was responsible for data analysis and manuscript editing.

All authors reviewed the manuscript.

Acknowledgements

None

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No competing interests reported.

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Early disease-specific characteristics for identifying Mixed Vascular-Alzheimer's Dementia in geriatric patients

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