Global cerebrovascular burden and long-term clinical outcomes in Asian elderly across the spectrum of cognitive impairment.

ABSTRACTBackground/Aim:To investigate the predictive ability of the previously established global cerebrovascular disease (CeVD) burden scale on long-term clinical outcomes in a longitudinal study of Asian elderly participants across the spectrum of cognitive impairment. METHODS: A case-control study was conducted over a 2-year period involving participants with no cognitive impairment, cognitive impairment-no dementia (CIND), and Alzheimer's disease (AD). Annually, cognitive function was assessed with a comprehensive neuropsychological battery and the clinical dementia rating (CDR) scale was used to stage disease severity. RESULTS: Of 314 participants, 102 had none/very mild CeVD, 31 mild CeVD, 94 moderate CeVD, and 87 severe CeVD at baseline. There was a 1.14 and 1.42 units decline per year on global cognitive z-scores in moderate and severe CeVD groups, respectively, compared to none/very mild CeVD. Moderate-severe CeVD predicted significant functional deterioration at year 2 (HR = 2.0, 95% CI = 1.2-3.4), and conversion to AD (HR = 6.3, 95% CI = 1.7-22.5), independent of medial temporal atrophy. CONCLUSION: The global CeVD burden scale predicts poor long-term clinical outcome independent of neurodegenerative markers. Furthermore, CeVD severity affects the rate of cognitive and functional deterioration. Hence, cerebrovascular burden, which is potentially preventable, is a strong prognostic indicator, both at preclinical and clinical stages of AD, independent of neurodegenerative processes.

Cerebral microbleeds and neuropsychiatric symptoms in an elderly Asian cohort.

OBJECTIVES: Neuropsychiatric symptoms (NPS) are commonly found in patients with cerebral small vessel disease such as white matter hyperintensities and lacunar infarcts. However, the association between cerebral microbleeds (CMBs) and NPS has not been examined. Hence the present study sought to investigate the relation between CMBs and NPS in an elderly population. METHODS: This is a cross-sectional study of elderly Asians living in the community, who were assessed on a comprehensive neuropsychological battery and underwent clinical examinations as well as brain MRI scans. The 12-item neuropsychiatric inventory (NPI) was administered to a reliable informant. Total scores for individual symptoms and for NPI global performance were calculated and compared across three groups: no CMB, presence of 1 CMB and presence of multiple CMBs, controlling for demographics, vascular risk factors and other MRI markers. RESULTS: A total of 802 participants were included in the analysis. Participants with multiple CMBs had higher NPI total score compared to those with no CMB (1.06 vs 2.66, p=0.03). On individual symptom scores, higher score on depression (0.16 vs 0.53, p=0.02) and disinhibition (0.01 vs 0.14, p=0.04) was found in those elderly with multiple CMBs, independent of demographic and vascular risk factors, history of stroke, and other small vessel and large vessel disease markers. CONCLUSIONS: The presence of multiple CMBs is associated with high global neuropsychiatric disorder burden, in particular symptoms of depression and disinhibition. Future studies are recommended to investigate the importance of CMBs in the pathogenesis and longitudinal progression of neuropsychiatric disorders in the general elderly population.

Cortical cerebral microinfarcts on 3T MRI: A novel marker of cerebrovascular disease.

OBJECTIVE: We examined the risk factors of cortical cerebral microinfarcts (CMIs) on 3T MRI and their association with cognitive impairment. METHODS: Participants (aged 60 years and older) from the multiethnic Epidemiology of Dementia In Singapore Study underwent detailed neuropsychological testing and 3T brain MRI. Cortical CMIs were graded using a previously validated protocol. Cognitive impairment was categorized into cognitive impairment, no dementia (CIND)-mild, CIND-moderate, and dementia. Cognitive function was summarized as composite and domain-specific z scores. RESULTS: Among 861 participants, 54 (6.3%) had ≥1 cortical CMI. In multivariate-adjusted models, the risk factors of cortical CMIs were increasing age, Malay ethnicity, hypertension, diabetes, history of stroke, and markers of both large (cortical infarcts and intracranial stenosis) and small (lacunar infarcts, white matter hyperintensities, cerebral microbleeds) vessel disease. Presence of cortical CMIs was associated with CIND-moderate (odds ratio: 3.12; 95% confidence interval [CI]: 1.18-8.58), dementia (odds ratio: 16.92; 95% CI: 3.37-85.05), and poorer cognitive function (mean difference in composite z score: -0.42; 95% CI: -0.62 to -0.21). Additional adjustments for vascular risk factors and other MRI markers did not alter these associations. CONCLUSIONS: Cortical CMIs are a novel MRI marker of cerebrovascular disease and are independently associated with cognitive impairment and dementia. These findings provide new insights into the burden of cerebrovascular disease in cognitive impairment. Future research is needed to establish the additional etiologic and prognostic significance of cortical CMIs.

The Diagnostic Utility of the NINDS-CSN Neuropsychological Battery in Memory Clinics.

AIMS: To examine the diagnostic utility of the National Institute of Neurological Disorders and Stroke and the Canadian Stroke Network (NINDS-CSN) neuropsychological battery in memory clinics comparing controls with patients with no cognitive impairment (NCI), patients with cognitive impairment-no dementia (CIND) at varying severity levels (mild/moderate), and patients with dementia. METHODS: A total of 405 participants with NCI, CIND or dementia were assessed with the NINDS-CSN battery. The discriminatory properties of all three protocols (5, 30 and 60 min) before and after education stratification (none/primary vs. secondary/above) were examined by receiver operating characteristic curves. RESULTS: Overall, the shorter protocols are equivalent to the longer protocol in diagnosing dementia, regardless of education. To discriminate between nondementia groups, before education stratification, the 5-min protocol showed varied discriminatory properties between different diagnostic/severity groups. After stratification, the 5-min protocol was broadly equivalent to the longer protocols in lower-education groups [area under the curve (AUC) range: 0.77-0.87] but was less accurate in the higher-education groups (AUC range: 0.68-0.78). The 30- and 60-min protocol constantly showed moderate-to-excellent differentiating capacities regardless of education (AUC range: 0.80-0.90). CONCLUSION: The NINDS-CSN neuropsychological battery can be applied in memory clinics and effectively discriminate between cognitively intact individuals and those with cognitive impairments of varying severity. Furthermore, level of education should be taken into consideration when choosing protocols with different lengths for cognitive assessment.

Validation of the Total Cerebrovascular Disease Burden Scale in a Community Sample.

BACKGROUND: A total cerebrovascular disease (CeVD) burden scale was previously constructed and an inverse association of CeVD burden and cognition was found. However, the generalizability of the CeVD scale has not been examined. OBJECTIVE: The objective was to validate the previously constructed total CeVD burden scale by establishing its association with cognitive function and dementia diagnosis in a community sample. METHODS: Eligible participants were assessed on an extensive neuropsychological battery and underwent MRI scans. The total CeVD scale, comprising markers of both small- and large-vessel diseases, was derived according to previously described criteria. Association of total CeVD burden with global and domain-based cognitive performance and dementia diagnostic utility of the scale was established. RESULTS: A total of 863 participants were included in the analysis. A stepwise association of CeVD burden score with global and domain-specific cognitive function was found. Per score increase on the total CeVD burden scale was associated with 3.6 (95% CI = 2.1-6.4) times higher odds of dementia compared to dementia-free. DISCUSSION: The total CeVD burden scale is associated with cognition and dementia in a community sample. Longitudinal studies are required to establish the predictive ability of this scale.

The Combined Utility of a Brief Functional Measure and Performance-Based Screening Test for Case Finding of Cognitive Impairment in Primary Healthcare.

BACKGROUND: Use of a total risk score (TRS) based on vascular and sociodemographic risk factors has been recommended to identify patients at risk of cognitive impairment. Moreover, combining screening tests has been reported to improve positive predictive values (PPV) for case finding of cognitive impairment. OBJECTIVE: We investigated the utility of the conjunctive combination of the informant-based AD8 and the performance-based National Institute of Neurological Disorders and Stroke-Canadian Stroke Network (NINDS-CSN) 5-minute protocol for the detection of cognitive impairment, defined by a clinical dementia rating (CDR) score ≥0.5, in patients at risk of cognitive impairment (TRS ≥3). METHODS: Participants were recruited from 2 primary healthcare centers in Singapore and received the AD8, Montreal Cognitive Assessment, Mini-Mental State Examination, CDR, and a formal neuropsychological test battery. The scores for NINDS-CSN 5-minute protocol were extracted from the Montreal Cognitive Assessment items. Area under the receiver operating characteristics curve analyses were conducted to determine the discriminant indices of the screening instruments, the conjunctive combination (ie, screened positive on both tests), and the compensatory combination (ie, screened positive in either of or both tests). RESULTS: A total of 309 participants were recruited of whom 78.7% (n = 243) had CDR = 0 and 21.3% (n = 66) had CDR ≥0.5. The conjunctive combination of AD8 and NINDS-CSN 5-minute protocol achieved excellent PPV and acceptable sensitivity (PPV 91.7%, sensitivity 73.3%). CONCLUSIONS: The conjunctive combination of the AD8 and NINDS-CSN 5-minute protocol is brief and accurate, and hence, suitable for case finding of cognitive impairment (CDR ≥0.5) in patients screened positive on the TRS in primary healthcare centers.

Risk Factors of Cognitive Impairment and Brief Cognitive Tests to Predict Cognitive Performance Determined by a Formal Neuropsychological Evaluation of Primary Health Care Patients.

BACKGROUND: Case finding for cognitive impairment (CI) is recommended for all persons older than 70 years. OBJECTIVE: The present study identified additional risk factors of CI so as to operationalize a composite total risk score (TRS) for case finding. We then examined the additive effect of the TRS and brief cognitive tests to improve the diagnosis of CI. METHODS: The study was conducted in 2 primary health care centers in Singapore. A total of 1082 individuals (≥60 years old) were assessed for sociodemographic risk factors and their informants were administered the AD8; 309 individuals who agreed for further cognitive assessments completed the Mini-mental state examination (MMSE) and Montreal Cognitive Assessment (MoCA), and a neuropsychological battery at a research center. Primary health care medical records were accessed for data on vascular risk factors. RESULTS: Of the 309 individuals who underwent neuropsychological evaluation, 4 were excluded due to missing medical data; 167 (54.8%) individuals had CI and 138 (45.2%) had No Cognitive Impairment (NCI). The ß coefficients were standardized to calculate risk scores. CI was significantly predicted by age >70 years (odds ratio [OR] 5.99; score = 3), diabetes (OR 3.36; score = 2), stroke (OR 2.70; score = 1), female gender (OR 2.02; score = 1) and individual cognitive complaints (SCC) (OR 1.95; score = 1). The TRS had an optimal cutoff of ≥3 and explained considerable variance in global cognitive composite Z-scores (R(2) = 0.41, P < .001). The MoCA explained substantial variance compared with the MMSE and AD8 (R(2) changes of 0.474, 0.422, and 0.157, P < .001, respectively). CONCLUSION: The TRS is a reasonable measure to predict individuals at risk of CI. The addition of the MoCA, in persons with positive TRS scores, is a useful approach to improve the diagnosis of CI for at-risk patients attending primary health care.

Clinical utility of the informant AD8 as a dementia case finding instrument in primary healthcare.

The informant AD8 has excellent discriminant ability for dementia case finding in tertiary healthcare settings. However, its clinical utility for dementia case finding at the forefront of dementia management, primary healthcare, is unknown. Therefore, we recruited participants from two primary healthcare centers in Singapore and measured their performance on the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Clinical Dementia Rating (CDR), and a local formal neuropsychological battery, in addition to the AD8. Logistic regression was conducted to examine the associations between demographic factors and dementia. Area under the receiver operating characteristics (ROC) curve analysis was used to establish the optimal cut-off points for dementia case finding. Of the 309 participants recruited, 243 (78.7%) had CDR = 0, 22 (7.1%) CDR = 0.5, and 44 (14.2%) CDR ≥1. Age was strongly associated with dementia, and the optimal age for dementia case finding in primary healthcare settings was ≥75 years. In this age group, the AD8 has excellent dementia case finding capability and was superior to the MMSE and equivalent to the MoCA [AD8 AUC (95% CI): 0.95 (0.91-0.99), cut-off: ≥3, sensitivity: 0.90, specificity: 0.88, PPV: 0.79 and NPV: 0.94; MMSE AUC (95% CI): 0.87 (0.79-0.94), p = 0.04; MoCA AUC (95% CI): 0.88 (0.82-0.95), p = 0.06]. In conclusion, the AD8 is well suited for dementia case finding in primary healthcare settings.

The reliability and validity of the informant AD8 by comparison with a series of cognitive assessment tools in primary healthcare.

BACKGROUND: The validity and reliability of the informant AD8 in primary healthcare has not been established. Therefore, the present study examined the validity and reliability of the informant AD8 in government subsidized primary healthcare centers in Singapore. METHODS: Eligible patients (≥60 years old) were recruited from primary healthcare centers and their informants received the AD8. Patient-informant dyads who agreed for further cognitive assessments received the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Clinical Dementia Rating (CDR), and a locally validated formal neuropsychological battery at a research center in a tertiary hospital. RESULTS: 1,082 informants completed AD8 assessment at two primary healthcare centers. Of these, 309 patients-informant dyads were further assessed, of whom 243 (78.6%) were CDR = 0; 22 (7.1%) were CDR = 0.5; and 44 (14.2%) were CDR≥1. The mean administration time of the informant AD8 was 2.3 ± 1.0 minutes. The informant AD8 demonstrated good internal consistency (Cronbach's α = 0.85); inter-rater reliability (Intraclass Correlation Coefficient (ICC) = 0.85); and test-retest reliability (weighted κ = 0.80). Concurrent validity, as measured by the correlation between total AD8 scores and CDR global (R = 0.65, p < 0.001), CDR sum of boxes (R = 0.60, p < 0.001), MMSE (R = -0.39, p < 0.001), MoCA (R = -0.41, p < 0.001), as well as the formal neuropsychological battery (R = -0.46, p < 0.001), was good and consistent with previous studies. Construct validity, as measured by convergent validity (R ≥ 0.4) between individual items of AD8 with CDR and neuropsychological domains was acceptable. CONCLUSIONS: The informant AD8 demonstrated good concurrent and construct validity and is a reliable measure to detect cognitive dysfunction in primary healthcare.

Association of neuropsychiatric symptoms and sub-syndromes with cognitive impairment in community-dwelling Asian elderly.

OBJECTIVES: To investigate the presence of neuropsychiatric symptoms (NPS) and sub-syndromes in elderly community-dwelling Asians with varying severity of cognitive impairment. METHODS: Chinese and Malay participants (n = 613) from the Epidemiology of Dementia in Singapore (EDIS) Study aged ≥ 60 years underwent clinical examination, neuropsychological testing, and NPS assessment using the Neuropsychiatric Inventory (NPI). Diagnosis of no cognitive impairment (NCI), cognitive impairment-no dementia (CIND), including CIND-mild and CIND-moderate, and dementia were made using established criteria. RESULTS: A significant increase in the numbers of NPS was observed accompanying with increasing severity of cognitive impairment (p < 0.001). Compared to those with NCI/CIND-mild, participants with CIND-moderate [Odds ratio (OR): 4.2, 95% confidence interval (CI): 1.8-10.0] or dementia [OR: 9.2, 95% CI: 2.3-36.0] were more likely to have two or more neuropsychiatric sub-syndromes. Participants with CIND-moderate were more likely to have hyperactivity [OR: 2.0, 95% CI: 1.0-3.8] and apathy [OR: 2.9, 95% CI: 1.0-8.4] sub-syndromes, whereas patients with dementia were more likely to have psychosis [OR: 6.9, 95% CI: 2.4-20.1], affective (OR: 8.7, 95% CI: 1.8-42.9), and hyperactivity (OR: 5.4, 95% CI: 1.8-16.1). Furthermore, executive dysfunction and visual memory impairment were associated with the presence of three neuropsychiatric sub-syndromes; whist language and visuomotor speed impairment were related to the presence of two sub-syndromes. By contrast, impairment in attention, verbal memory, and visuoconstruction were not associated with any of the sub-syndromes. CONCLUSIONS: The presence of NPS and sub-syndromes increase with increasing severities of cognitive impairment, and different neuropsychiatric syndromes are associated with specific impairment on cognitive domains in community-dwelling Asian elderly.

Feasibility and acceptability of the informant AD8 for cognitive screening in primary healthcare: a pilot study.

OBJECTIVES: The utility of informant AD8 for case finding of cognitive impairment at primary healthcare settings is unknown and therefore its feasibility and acceptability for targeted screening at a primary healthcare clinic should be investigated. METHODS: The informants of older adult patients attending a primary healthcare clinic in Singapore were administered the AD8. Positive screening findings were provided to patients' primary care physicians for referrals to specialist memory clinics. The acceptability of AD8 was evaluated by collecting feedbacks from the informants and primary care physicians. RESULTS: 205 patients and their informants were recruited. However, 6 (2.9%) informants were uncontactable, while the majority of the remaining 199 patients with completed AD8 (96.5%, n=192) found it acceptable where 59 (29.6%) patients were deemed cognitively impaired (AD8≥2). Clinicians (100%, n=5) found the AD8 helpful in facilitating referrals to memory clinics. However, most referral recommendations (81.4%, n=48) were declined by patients and/or informant due to limited insight of implications of cognitive impairment. CONCLUSIONS: The AD8 can be easily administered and is well tolerated. It detected cognitive impairment in one-third of older adult patients and therefore may be useful for case finding of cognitive impairment in the primary healthcare.