NINCDS-ADRDA Criteria Research Articles

Statin Initiation and Risk of Incident Alzheimer Disease and Cognitive Decline in Genetically Susceptible Older Adults.

The association of statin initiation with incident Alzheimer disease (AD) dementia and cognitive decline by the APOE ε4 allele is unknown. Our objective was to examine whether the association of statin initiation with incident AD dementia and cognitive decline differs by the APOE ε4 allele. This population-based longitudinal cohort study was conducted in 4 urban communities in Chicago, IL, United States, consisting of 4,807 participants. Statin initiation is based on the inspection of medications during home assessments. Clinical diagnosis for incident AD used the NINCDS-ADRDA criteria, and longitudinal measurements of global cognition consisted of episodic memory, perceptual speed, and the Mini-Mental State Examination tests. The study participants had a mean age of 72 years, consisting of 63% female individuals and 61% non-Hispanic Black individuals. During the study period, 1,470 (31%) participants reported statin initiation. In a covariate-adjusted competing risk model, statin initiation was associated with a reduced risk of incident clinical AD [hazard ratio (HR) 0.81 (95% CI 0.70-0.94)] compared with nonusers. This association was statistically significantly lower (p interaction = 0.015) among participants with the APOE ε4 allele [HR 0.60 (95% CI 0.49-0.74)] compared with those without the APOE ε4 allele [HR 0.96 (95% CI 0.82-1.12)]. The annual decline in global cognition (β = 0.021, 95% CI 0.007-0.034) and episodic memory (β = 0.020, 95% CI 0.007-0.033) was also substantially slower among participants with the APOE ε4 allele after statin initiation compared with nonusers. However, the association of statin initiation with cognitive decline was not significant among those without the APOE ε4 allele. Our findings suggest that statins might be associated with a lower risk of incident AD among individuals with the APOE ε4 allele. The benefits of statin therapy need further consideration in randomized clinical trials, especially among those with the APOE ε4 allele. This study provides Class II evidence that among those aged 65 years or older, statin initiation was associated with a reduced risk of Alzheimer disease, especially in the presence of an APOE-e4 allele.

Serum NfL in Alzheimer Dementia: Results of the Prospective Dementia Registry Austria.

Background and Objectives: The neurofilament light chain (NfL) is a biomarker for neuro-axonal injury in various acute and chronic neurological disorders, including Alzheimer’s disease (AD). We here investigated the cross-sectional and longitudinal associations between baseline serum NfL (sNfL) levels and cognitive, behavioural as well as MR volumetric findings in the Prospective Dementia Registry Austria (PRODEM-Austria). Materials and Methods: All participants were clinically diagnosed with AD according to NINCDS-ADRDA criteria and underwent a detailed clinical assessment, cognitive testing (including the Mini Mental State Examination (MMSE) and the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD)), the neuropsychiatric inventory (NPI) and laboratory evaluation. A total of 237 patients were included in the study. Follow-up examinations were done at 6 months, 1 year and 2 years with 93.3% of patients undergoing at least one follow-up. We quantified sNfL by a single molecule array (Simoa). In a subgroup of 125 subjects, brain imaging data (1.5 or 3T MRI, with 1 mm isotropic resolution) were available. Brain volumetry was assessed using the FreeSurfer image analysis suite (v6.0). Results: Higher sNfL concentrations were associated with worse performance in cognitive tests at baseline, including CERAD (B = −10.084, SE = 2.999, p < 0.001) and MMSE (B = −3.014, SE = 1.293, p = 0.021). The sNfL levels also correlated with the presence of neuropsychiatric symptoms (NPI total score: r = 0.138, p = 0.041) and with smaller volumes of the temporal lobe (B = −0.012, SE = 0.003, p = 0.001), the hippocampus (B = −0.001, SE = 0.000201, p = 0.013), the entorhinal (B = −0.000308, SE = 0.000124, p = 0.014), and the parahippocampal cortex (B = −0.000316, SE = 0.000113, p = 0.006). The sNfL values predicted more pronounced cognitive decline over the mean follow-up period of 22 months, but there were no significant associations with respect to change in neuropsychiatric symptoms and brain volumetric measures. Conclusions: the sNfL levels relate to cognitive, behavioural, and imaging hallmarks of AD and predicts short term cognitive decline.

Alzheimer's Disease THErapy With NEuroaid (ATHENE): ARandomized Double-Blind Delayed-Start Trial.

Preclinical and clinical studies indicate a role for MLC901 (NeuroAiD II) in Alzheimer's disease (AD). The primary aim was to investigate its safety as add-on therapy to standard treatment and the secondary aims its effect on cognition and slowing disease progression. Randomized double-blind placebo-controlled delayed-start study. Patients with mild to moderate probable AD by NINCDS-ADRDA criteria, stable on acetylcholinesterase inhibitors or memantine (n= 125), were randomized to receive MLC901 (early starters) or placebo (delayed starters) for 6months, followed by a further 6months when all patients received MLC901, in a delayed-start design (clinical trial registration: ClinicalTrials.gov, NCT03038035). The primary outcome measure was occurrence of serious adverse events (SAEs) at 6months. Secondary outcomes included the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and other assessment scales. There was no significant difference in the risk of SAEs between early and delayed starters at month (M) 6 (22.6% vs 27.0%, risk difference-4.4%, 90% CI -16.9% to 8.3%). Similarly, there was no significant difference in the risk of adverse events and the occurrence of stroke or vascular events between early and delayed starters throughout the 12-month study period. Early starters did not differ significantly on ADAS-Cog from delayed starters at M6 [mean difference (MD)-1.0, 95% CI -3.3 to 1.3] and M12 (MD -2.35, 95% CI -5.45 to 0.74) on intention-to-treat analysis. Other cognitive assessment scales did not show significant differences. This study of 125 persons with dementia found no evidence of a significant increase in adverse events between MLC901 and placebo, thus providing support for further studies on both efficacy and safety. Analyses suggest the potential of MLC901 in slowing down AD progression, but this requires further confirmation in larger and longer studies using biomarkers for AD.

The efficacy and safety of zolpidem and zopiclone to treat insomnia in Alzheimer's disease: a randomized, triple-blind, placebo-controlled trial.

No prior studies have evaluated the efficacy and safety of zolpidem and zopiclone to treat insomnia of demented patients. This randomized, triple-blind, placebo-controlled clinical trial used these drugs to treat patients with probable, late onset Alzheimer's dementia (AD) (DSM V and NINCDS-ADRDA criteria) exhibiting insomnia (DSM V criteria and nocturnal NPI scores ≥ 2). Actigraphic records were performed for 7 days at baseline and for 14 days during the treatment period in 62 patients aged 80.5 years in average and randomized at a 1:1:1 ratio for administration of zolpidem 10 mg/day, zopiclone 7.5 mg/day or placebo. Primary endpoint was the main nocturnal sleep duration (MNSD), whereas secondary outcomes were the proportion of the night time slept, awake time after sleep onset (WASO), nocturnal awakenings, total daytime sleep time and daytime naps. Cognitive and functional domains were tested before and after drug/placebo use. Three participants under zopiclone use had intervention interrupted due to intense daytime sedation and worsened agitation with wandering. Zopiclone produced an 81 min increase in MNSD (95% confidence interval (CI): -0.8, 163.2), a 26 min reduction in WASO (95% CI: -56.2, 4.8) and a 2-episode decrease in awakening per night (95% CI: -4.0, 0.4) in average compared to placebo. Zolpidem yielded no significant difference in MNSD despite a significant 22 min reduction in WASO (95% CI: -52.5, 8.3) and a reduction of 1 awakening each night (95% CI: -3.4, 1.2) in relation to placebo. There was a 1-point reduction in mean performance in the symbols search test among zolpidem users (95% CI: -4.1, 1.5) and an almost eight-point reduction in average scores in the digit-symbol coding test among zopiclone users (95% CI: -21.7, 6.2). In summary, short-term use of zolpidem or zopiclone by older insomniacs with AD appears to be clinically helpful, even though safety and tolerance remain issues to be personalized in healthcare settings and further investigated in subsequent trials. This trial was registered in ClinicalTrials.gov Identifier: NCT03075241.

IS THYROID ASSOCIATED WITH DEMENTIA? A CASE CONTROL STUDY

Objectives: The present study was undertaken with an objective to explore if thyroid is related to dementia among participants aged 45 years and above. Design: Participants aged more than 45 years of age, giving written informed consent and meeting the selection criteria were enrolled in the study. The participants were administered with a series of paper pencil tests. The data was further analyzed for any association using the Statistical Package for Social Sciences, version 22 (SPSS 22). Setting: Participants attending the Outpatient Department (OPD) at Institute of Human Behaviour and Allied sciences (IHBAS), a tertiary care neuropsychiatric hospital and normal elderly controls from local community. Participants: A sample size of at least 40 cases of Dementia of Alzheimer type and at least 40 cases of vascular/ mixed dementia and 60 normal controls were recruited. Measurements: Semi-structured Performa for demographic and clinical variables; Hindi mental status examination (HMSE) for cognitive functions was applied as screening tools for both case and control groups;Tools for patients with dementia: NINCDS-ADRDA criteria for Probable Alzheimer's disease (McKhann et al), NINDS /AIREN criteria for diagnosis of probable vascular dementia (VaD), NINDS-AIREN diagnostic criteria for “Alzheimer's disease with Cerebro-Vascular Disease” (mixed dementia), Clinical Dementia Rating Scale (Morris et al 1997), and 5 ml blood sample collection and analysis through vein puncture. Results: The results of the study indicate that subclinical hypothyroidism is associated with dementia of Alzheimer type. Conclusion: When considered in light with varied ndings of prior studies, it may be implied that subclinical thyroid dysfunction not especially hypo or hyperthyroidism is a risk for DAT.

Author Response: Biological Subtypes of Alzheimer Disease: A Systematic Review and Meta-analysis.

We read the comment by Uleman and colleagues on our article1 with interest. The details on the AD criteria of the individual studies can be seen in supplementary table e-6 of our publication. Briefly, most neuroimaging studies diagnosed their AD patients with the NINCDS-ADRDA and DSM-IV criteria. Only Risacher et al.2 performed biomarker-based diagnosis. Postmortem studies relied on neuropathologic diagnosis of AD. We thus believe that this issue may only make a minimal contribution to the heterogeneity found. Instead, our recent study shows that a major source of heterogeneity is variability across studies in subtyping methods.3 We agree that the link between resilience/resistance and risk factors and comorbidity is through complex pathways. In our study, we did not elaborate on whether the severity and typicality axes are linear or nonlinear. Indeed, we believe that all—if not most—of the factors included in our model relate with each other in intricate associations, not only resilience and resistance. The next step is to empirically test and expand this conceptual model. Methods such as the ones mentioned by Uleman and colleagues will be important to understand associations among multiple factors in our conceptual model, helping to unravel the heterogeneity within AD.

Association Serum S100B Protein in Alzheimer's Disease: A Case Control Study from South India.

Recent evidence points to a possible link between the inflammatory modulatory protein S100B protein and the pathogenesis of Alzheimer's disease (AD). To investigate the elevated levels of serum S100B protein among AD in a South Indian cohort and its correlation with severity of cognitive impairment. A cross-sectional study was conducted with 100 AD patients and 100 age and sex matched healthy controls. Diagnosis of AD was made by a qualified neurologist using NINCDS ADRDA criteria. Measurement of serum S100B protein was performed using solid phase sandwich ELISA method in both cases and controls. Significantly higher prevalence of elevated serum S100B protein 44(44%) (p<0.0001), hypertension 52(52%) (p=0.02), diabetes mellitus 58(58%) (p=0.002), thyroid dysfunction 28(28%) (p=0.009), positive CRP 46(46%) (p<0.0001) and lower mean Mini-Mental State Examination (MMSE) values 20.4±5.1 (p<0.0001) were seen in AD patients compared to controls. Elevated S100B protein levels were significantly associated with Clinical dementia rating (CDR) score 2(34%) (p=0,05) and score 3 (61.3%) (p=0.03) compared to normal levels. After multivariable logistic regression analysis positive C-Reactive Protein (odds: 3.2; 95%CI: 2.8-9.8)(p=0.001), elevated S100B protein (odds: 9.0;95%CI:2.2-35.8) and diabetes mellitus (odd:1.2;95%CI:1.0-4.9)(p<0.0001), were significantly associated with AD. In our study, we established an independent association of elevated serum S100B protein levels with AD. Elevated S100B protein levels higher in CDR score 3.

Kidney function and dementia risk in community-dwelling older adults: the Shanghai Aging Study

BackgroundAssociation between kidney dysfunction and dementia has been studied in western cohorts, but with inconsistent conclusions which may be due to the different measurements of kidney function. We aim to verify the hypothesis that lower levels of kidney function would be associated with increased risk of incident dementia in Chinese elderly.MethodsOne thousand four hundred twelve dementia-free participants aged 60 years or older from the Shanghai Aging Study were enrolled and followed up for 5.3 years on average. Glomerular filtration rate (GFR) was calculated by using combined creatinine–cystatin C CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation. Diagnoses of incident dementia and Alzheimer’s disease (AD) were established using DSM-IV and NINCDS-ADRDA criteria based on medical, neurological, and neuropsychological examinations to each participant. Cox proportional regression was used to analyze the association of baseline GFRcrcys levels with incident dementia/AD, adjusting age, gender, education years, APOE-ε4, diabetes, hypertension, baseline Mini-Mental State Examination score, and proteinuria.ResultsA total of 113 (8%) and 84 (7%) participants developed dementia and AD. Comparing to participants with high GFRcrcys (≥ 80 ml/min/1.73 m2), participants with low (< 67 ml/min/1.73 m2) and moderate GFRcrcys (67 ≤ GFR < 80 ml/min/1.73 m2) had increased risk of incident dementia with hazard ratios (HRs) of 1.87 (95% CI 1.02–3.44) and 2.19 (95% CI 1.21–3.95) after adjustment for confounders, respectively. Low (HR = 2.27 [95%CI 1.10–4.68]) and moderate (HR = 2.14 [95% CI 1.04–4.40]) GFRcrcys at baseline was also independently associated with incident AD after adjustments when comparing to high GFRcrcys. The significant association between GFRcrcys and dementia risk was observed in female but not in male participants.ConclusionsGFRcrcys may be considered as a marker of an individual’s vulnerability to the increased risk of cognitive decline.

Low-Dose Whole Brain Radiation Therapy For Early Alzheimer’s Dementia: Early Results From A Phase IIa Trial

Report neurocognitive, imaging, and safety outcomes from a phase IIa trial of low-dose whole brain RT (LD-WBRT) for early Alzheimer’s dementia (eAD) in 5 patients who completed all study assessments. Based on improvements in amyloid burden and cognition in murine models and favorable outcomes with low-dose RT for systemic amyloidosis, we launched a human trial for eAD, defined by NINCDS-ADRDA criteria with confirmatory Florbetapir and FDG PET findings. The capacity to complete neurocognitive function (NCF), psychological function (PF), and quality of life (QOL) assessments was requisite. NCF was measured via a battery of validated assessments (WTAR, MMSE-2, HVLT-R, BVMT-R, WAIS-IV Digit Span and Coding, Trailmaking Parts A+B, COWAT, Semantic Fluency, Grooved Pegboard, BNT and JLO), PF via PHQ-9 and GAD-7, and QOL per QOL-AD and QUALID. Participant and informant ratings of cognition consisted of ECOG questionnaires. Participants underwent screening physical examination, screening as well as pre-treatment NCF, PF and QOL assessments, and screening Florbetapir and FDG PET imaging. Each received LD-WBRT (2Gyx5). Post-treatment evaluations included 6wk, 3mo, 9mo, and 12mo physical exams, NCF, PF, and QOL assessments (with BNT and JLO only at baseline and 12mo), 6mo FDG and Florbetapir PET, and Data Safety and Monitoring Committee (DSMC) toxicity evaluation. 5 patients were treated with LD-WBRT and completed all study assessments. Mean age was 73.2 (range 69-77) yrs, 3 female and 2 male. Comparing pre-treatment and 12mo MMSE-2 T-scores, 3 improved, 1 remained stable, and 1 declined. Skills expected to wane in early AD (naming, learning and memory) remained broadly stable at 1 year in 4 of 5, with trends for improved verbal learning in 3. The participant who declined in these measures and on Grooved Pegboard and Semantic Fluency, met the lowest-end inclusion criteria and was the eldest. Processing speed (Grooved Pegboard, WAIS-IV Coding, Trailmaking A), attention (WAIS-IV Digit Span), visuospatial skills (JLO, BVMT-R Copy), executive functions (Trailmaking A+B, lexical fluency), mood (PHQ-9, GAD-7) and QOL (QOL-AD, QUALID, ECOG) assessments remained stable, with exception of some declines in semantic fluency suggestive of temporal lobe dysfunction. However, there were improvements in several domains at 9 to 12mo. PET imaging remained stable with possible modest improvements in hippocampal amyloid and parietotemporal FDG. Results were independently reviewed by the Data Safety monitoring committee, and no safety issues encountered except transient epilation. 4 of the initial 5 patients with eAD treated with LD-WBRT experienced overall stability in NCF, PF, and QOL, with trends for improved verbal learning, and stability to possible improvement in PET imaging. The trial will continue to 15 patients at 2Gy x 5, then 15 at 2Gy x 10. Longer follow up is now planned to evaluate whether improvements in several domains at 9 to 12 months are confirmed.

The Brain Metabolic Correlates of the Main Indices of Neuropsychological Assessment in Alzheimer's Disease.

Background: The study aimed to investigate the relationships between F-18 fluorodeoxyglucose (18F)FDG uptake and neuropsychological assessment in Alzheimer’s disease (AD). Methods: We evaluated 116 subjects with AD according to the NINCDS-ADRDA criteria. All the subjects underwent a brain PET/CT with (18F)FDG, cerebrospinal fluid (CSF) assay, mini-mental state examination (MMSE) and further neuropsychological tests: Rey auditory verbal learning test, immediate recall (RAVLT immediate); Rey auditory verbal learning test, delayed recall (RAVLT, delayed); Rey complex figure test, copy (RCFT, copy); Rey complex figure test, delayed recall (RCFT, delayed); Raven’s colored progressive matrices (RCPM); phonological word fluency test (PWF) and Stroop test. We performed the statistical analysis by using statistical parametric mapping (SPM12; Wellcome Department of Cognitive Neurology, London, UK). Results: A significant relationship has been reported between (18F)FDG uptake and RAVLT immediate test in Brodmann area (BA)37 and BA22 and with RCFT, copy in BA40, and BA7. We did not find any significant relationships with other tests. Conclusion: In the AD population, brain (18F)FDG uptake is moderately related to the neuropsychological assessment, suggesting a limited impact on statistical data analysis of glucose brain metabolism.

The role of epsilon phenotype in brain glucose consumption in Alzheimer's disease.

The aim of our study was to investigate the impact of the epsilon phenotype in brain glucose consumption in a population with Alzheimer's disease. Statistical Parametric Mapping (SPM8) was used to investigate differences in brain glucose consumption (as detectable by means of 18F FDG-PET/CT) in the population examined. A total of 129 patients (72 females and 57 males) with a diagnosis of probable AD according to the NINCDS-ADRDA criteria underwent the PET/CT examination. The mean (SD) age of the patients was 70 (± 7) years; the mean Mini-Mental State Examination was 19(± 5.6). 59 expressed epsilon 4 phenotype (E4) and 70 expressed the epsilon 3 phenotype (E3). Cerebral spinal fluid amyloid, tau, and t-tau have been measured resulting equal to 367.4 (± 149.1), 584.7 (± 312.1), and 79.2(± 45.9) pg/ml, respectively. Patients with confirmed amyloid and Tau changes were classified as AD. Patients with amyloid changes but negative Tau, considered as high risk of AD, were classified as IAD. Age, sex, MMSE, scholarship, and CSF parameters were used as a covariate in the SPM analyses. We did not find significant differences in age, gender, and MMSE and CSF parameters among groups. In the analysis of the AD group as compared to AD-E3, AD-E4 subjects show a significant reduction of brain glucose consumption in inferior frontal gyrus bilaterally (BA 45, BA 47). In the analysis of the IAD group as compared to IAD-E3, IAD-E4 subjects show a significant reduction of brain glucose consumption in right in medial, middle, and superior frontal gyrus (BA10, BA11), and in left medial and middle frontal gyrus (BA10, BA11). The differences between IAD-E3 and AD-E3 and between IAD-E4 and AD-E4 (and vice versa analysis) resulted not significant. APO-e4 is related to a major involvement of the frontal cortex confirming its role of risk factor in AD, while APO-3 seems not related to a specific pattern, supporting the hypothesis of neutral/protective role in AD.

Torque teno virus viral load is related to age, CMV infection and HLA type but not to Alzheimer's disease.

Torque teno virus (TTV) is an unenveloped, circular, single stranded DNA virus with a genome size of approximately 3.8 kb. Previous studies have demonstrated varying grades of association between TTV DNA levels and immune deficiencies related to age, chronic infections and cancer. Alzheimer's disease (AD) has been related to persistent viral infections such as HSV-1 and CMV, but it is not known whether TTV viral load could serve as a functional biomarker of cellular immunity in this setting. Therefore, the objective of this study was to investigate whether TTV infection and viral load is related to AD status, CMV immunity, systemic inflammation or HLA types connected to anti-viral immunity. A total of 50 AD subjects and 51 non-demented controls were included in the study. AD subjects were diagnosed according to NINCDS-ADRDA and DSM-IV criteria and neuroradiologic findings were consistent with the diagnosis. TTV viral load was analyzed in plasma samples using a quantitative real-time PCR. Using a cut-off for TTV status at 200 copies/ml, 88% (89/101) of the study subjects were classified as TTV positive. TTV viral load significantly increased with age (beta 0.049 per year, p<0.001) but significantly decreased in relation to CMV IgG levels (beta -0.022 per 1000 units, p = 0.005) and HLA-B27 positivity (beta -0.53, p = 0.023). In conclusion, TTV immune control is not significantly affected by AD status, but appears related to age, CMV humoral immune response and HLA type.

LOWER PLATELET COUNT AND DECREASED MEAN PLATELET VOLUME IN PATIENTS WITH ALZHEIMER’S DISEASE

Platelets are the major players in hemostasis, but are also involved in thrombosis, inflammation and tissue repair. Platelets are generally accepted as a suitable model for Alzheimer's disease (AD). In the present study serum platelet count, mean platelet volume (MPV), platelet distribution width (PDW) and plateletcrit (PCT) in patients with Alzheimer disease were analyzed and compared with controls. Platelet count and indices were evaluated in 130 patients with AD (Mean age 71.3±7.7 years, range 55–85 years, 65 women), (DSM-IV; NINCDS-ADRDA criteria); recruited in a community elderly in Skikda-Algeria (2016-2018); and in 130 elderly controls, (Mean age 69.8±7.8 years, range 55–85 years, 65 women). We assessed the relation between these platelet parameters and the odds ratio (OR) for AD. Correlation with dementia severity (Clinical dementia rating-global score, and mini mental status examination), was also examined. The mean serum platelet count was 220.5±44.7x109/L (Range 148x109-354x109) among cases, and 240.1±49.9x109/L (Range 155x109-396x109) among controls, (p= 0.0009). By gender, the difference between cases and controls was significant both in men 218.3±50.2x 109/L vs. 236.8±52.4x109/L respectively, p=0.041; and in women 222.7±38.7x109/L vs. 243.4±47.4x109/L, p= 0.007. The odds ratio [95 percent confidence interval] of AD for the highest tertile of platelet count compared to the lowest tertile was 0.428 [0.234–0.782], p= 0.006. This association was significant both in men OR: 0.3175 [0.1316–0.7659], p=0.017, and in women OR: 0.2663 [0.1102–0.6440], p=0.003. MPV was significantly lower in men cases compared to controls 9.04±0.8 femtoliter (Range 7.3-11.4) vs.9.34±0.9 femtoliter (Range 7.8-11.6) respectively; p=0.045. Mean plateletcrit was decreased in AD group compared to control 0.202±0.03% (Range 0.120-0.324) vs. 0.216±0.05% (Range 0.129-0.360), p=0.003. PDW was similar, AD: 13.2±1.2%, control: 13.4±1.5%. Platelet count and indices did not correlate significantly with dementia severity. These findings show that Alzheimer's disease patients have lower platelet count and lower plateletcrit (Within normal range) compared to controls. Subjects in the low normal range of platelet count have an increased risk for developing Alzheimer's disease. Furthermore a lower MPV (within normal range) was also found in AD men. Taken together, these data suggest a key role for circulating platelets in Alzheimer's disease.

Brain metabolic patterns in patients with suspected non-Alzheimer's pathophysiology (SNAP) and Alzheimer's disease (AD): is [18F] FDG a specific biomarker in these patients?

The present study was conducted to compare the pattern of brain [18F] FDG uptake in suspected non-Alzheimer's pathophysiology (SNAP), AD, and healthy controls using 2-deoxy-2-[18F]fluoroglucose ([18F] FDG) positron emission tomography imaging. Cerebrospinal fluid (CSF) biomarkers amyloid-β1-42 peptide (Aβ1-42) and tau were used in order to differentiate AD from SNAP. The study included 43 newly diagnosed AD patients (female = 23; male = 20) according to the NINCDS-ADRDA criteria, 15 SNAP patients (female = 12; male =3), and a group of 34 healthy subjects that served as the control group (CG), who were found to be normal at neurological evaluation (male = 20; female = 14). A battery of neuropsychological tests was administrated in AD and SNAP subjects; cerebrospinal fluid assay was conducted in both AD and SNAP as well. Brain PET/CT acquisition was started 30 ± 5min after [18F] FDG injection in all subjects. SPM12 [statistical parametric mapping] implemented in MATLAB 2018a was used for the analysis of PET scans in this study. As compared to SNAP, AD subjects showed significant hypometabolism in a wide cortical area involving the right frontal, parietal, and temporal lobes. As compared to CG, AD subjects showed a significant reduction in [18F] FDG uptake in the parietal, limbic, and frontal cortex, while a more limited reduction in [18F] FDG uptake in the same areas was found when comparing SNAP to CG. SNAP subjects show milder impairment of brain [18F] FDG uptake as compared to AD. The partial overlap of the metabolic pattern between SNAP and AD limits the use of [18F] FDG PET/CT in effectively discriminating these clinical entities.

Brain Amyloid-β Deposition and Blood Biomarkers in Patients with Clinically Diagnosed Alzheimer's Disease.

Brain amyloid-β (Aβ) deposition is a hallmark to define Alzheimer's disease (AD). We investigated the positive rate of brain amyloid deposition assessed with 11C-Pittsburgh compound (PiB)-PET and blood Aβ levels in a cohort of probable AD patients who were diagnosed according to the 1984 NINCDS-ADRDA criteria. Eighty-four subjects with a clinical diagnosis of probable AD dementia, amnestic mild cognitive impairment (MCI), and cognitively normal (CN) status were subjected to PiB-PET and 18F-fluorodeoxyglucose (FDG)-PET scans. Plasma biomarkers of Aβ42, Aβ40, and T-tau were measured using single molecule array technology. The positive rate of PiB-PET, the associations between PiB-PET status and FDG-PET, plasma biomarkers, and clinical manifestations were analyzed. PiB-PET was positive in 77.36% of probable AD patients, 31.80% of MCI patients, and 0 of NC. Plasma Aβ42/Aβ40 ratio was associated with PiB-PET, the ROC curve analysis revealing an AUC of 0.77 (95% CI: 0.66-0.87), with a sensitivity of 82% and specificity of 64%. Some clinical manifestations were associated with PiB-PET imaging. Our findings indicate that only three-fourths of patients diagnosed with probable AD fit the pathological criteria, suggesting that we should be cautious regarding the accuracy of AD diagnosis when no biomarker evidence is available in our clinical practice.

Systemic Inflammatory Markers in Age-Associated Cognitive Impairment and Alzheimer’s Disease

Objectives. A set of immune markers reflecting different branches of multicomponent inflammatory reactions were assessed in mild cognitive impairment syndrome of the amnestic type (aMCI) in comparison with patients with Alzheimer’s disease (AD). A total of 67 patients aged 72 [63; 77] years with aMCI and 91 patients aged 74 [68; 79] years with AD were investigated. aMCI was diagnosed in accordance with the Petersen et al. (1999) criteria and the Dubois et al. (2014) criteria. Diagnoses of AD were made on the basis of ICD-10 and NINCDS-ADRDA criteria. The severity of dementia was determined on the basis of clinical signs using the CDR (Clinical Dementia Rating) scales and total Mini Mental State Examination (MMSE) scores. The control group consisted of 38 subjects with age and gender comparable to those of the study groups. Immunobiochemical investigations were performed using plasma. Leukocyte elastase (LE) and α1-proteinase inhibitor (α1-PI) activities were estimated spectrophotometrically and interleukin-6 (IL-6) and C-reactive protein (CRP) levels were measured using an immunoenzyme method. Results. A significant decrease in LE activity was seen in the AD group (p < 0.0001), along with increases in the activity/ levels of acute-phase proteins (α1-PI and CRP) and IL-6 (p < 0.0001, p < 0.05, and p < 0.01, respectively). Clinical-biochemical correlations were found between CDR, MMSE, and LE activity (r = –0.38, r = 0.31, p < 0.05), i.e., the more severe the cognitive decline in the state of dementia, as reflected in the MMSE and clinical symptoms, the lower the level of LE activity. Among patients with aMCI, there were significant increases in the activity/levels of α1-PI and IL-6 (p < 0.0001, p < 0.01), while only 30% of patients showed the spectrum of inflammatory markers typical of patients with AD. Conclusions. The results of this comparative analysis of the spectrum of inflammatory markers in patients with aMCI and AD suggest that about a third of aMCI patients constitute a group at extremely high risk of developing AD and require follow-up with regular assessment of the state of cognitive functions and, perhaps, of preventive therapy.

Borrelia burgdorferi as a risk factor for Alzheimer's dementia and mild cognitive impairment.

To determine the association of Borrelia burgdorferi infection with Alzheimer's disease or mild cognitive impairment (MCI) in older adults. Case-control study. Patients older than 60years, both sexes, were included. Three groups were created: with probable Alzheimer's disease cases with NINCDS-ADRDA criteria, MCI cases in those not meeting NINCDS-ADRDA criteria for dementia, but who had an abnormal cognitive evaluation and independence in instrumental activities of daily living (IADL), cognitively healthy controls were diagnosed with normal cognitive evaluation and independence in IADL were identified in the community. Western blot IgG against B. burgdorferi in serum was done in all the participants. Non-conditional logistic regression was applied to estimate the association of Alzheimer's disease or MCI and seropositive to B. burgdorferi. Thirty-eight patients with Alzheimer's disease, mean age of 75.6 ± 3.4years, 69% were females, education 8.3 ± 4.8years. 39 patients with MCI, mean age of 72.2 ± 6.8years, 85% were females, education 11.2 ± 4.2years. A total of 11/38 (29%) were positive to B. burgdorferi with Alzheimer's disease, 9/39 (23%) with MCI, and 11/108 (10%) of controls. In patients with Alzheimer's disease, an adjusted odds ratio (aOR) = 3.65 (95% CI 1.2-11.1) adjusted for education and a history of cerebrovascular disease (CVD) was estimated, and in patients with MCI an aOR = 3.2 (95% CI 1.1-9.1) for a history of diabetes mellitus and CVD was estimated. In our study, there was an increased risk of Alzheimer's disease and MCI in seropositive IgG patients to B. burgdorferi.

Shift in Hospitalizations for Alzheimer's Disease to Related Dementias in France between 2007 and 2017.

Alzheimer's disease (AD) is the first cause of dementia. Diagnostic criteria have evolved: proposals to revise the NINCDS-ADRDA criteria were published in 2007. Our aim was to analyze the evolution in the coding of AD in the French nationwide exhaustive hospital discharge database (PMSI) between 2007 and 2017. We analyzed evolution of International Classification of Diseases and Related Health Problems, 10th edition (ICD-10) coding for AD and AD dementia in the PMSI database from 2008 to 2017 (285,748,938 inpatient stays). We observed a 44% decrease in the number of inpatient stays with a principal diagnosis of AD or AD dementia from 2007 (46,313 inpatient stays) to 2017 (25,856 inpatient stays) in France. Over the same period, we observed a 49% increase in the number of inpatient stays with a principal diagnosis of related dementias (other organic mental disorders or other degenerative disorders). Overall, the number of inpatient stays for dementia remained stable despite the increase in the total number of inpatient stays: 95,377 in 2007 (0.409% of inpatient stays) and 99,190 in 2017 (0.344%). We therefore note a shift from AD and AD dementia to other dementia diagnoses since 2007. This study suggests a more accurate use of AD related ICD-10 codes since the revised criteria in 2007.

Validation of the Thai version of the short Boston Naming Test (T-BNT) in patients with Alzheimer’s dementia and mild cognitive impairment: clinical and biomarker correlates.

Objectives: Impairments in the Boston Naming Test (BNT), which measures confrontational word retrieval, frequently accompanies Alzheimer’s dementia (AD) and may predict a more rapid progression of illness. This study aims to validate the Thai version of the 15-item BNT (T-BNT) in participants with AD and amnestic mild cognitive impairment (aMCI) and to externally validate the T-BNT using clinical and biomarker measurements.Methods: This cross-sectional study recruited patients with AD, diagnosed according to NINCDS-ADRDA criteria (n = 60), aMCI, diagnosed using the Petersen criteria (n = 60), and healthy controls (n = 62). We examined the internal consistency, concurrent and discriminant reliability of the T-BNT. We also assessed the Mini Mental State Examination (MMSE), the Verbal Fluency Test (VFT) and the Word List Memory (WLM) tests and measured apolipoprotein E polymorphism and serum levels of folic acid, high-density lipoprotein cholesterol (HDL) and triglycerides.Results: This study validated a 10-item T-BNT (10T-BNT), which yielded good internal consistency (0.92), a one-factor unidimensional structure, and adequate concurrent and discriminant validity. Lower scores on the 10T-BNT highly significantly predict AD, but not aMCI, and are positively associated with VFT and WLM test scores. Furthermore, lowered 10T-BNT scores are significantly associated with the ApoE4 allele, lower folate levels and an increased triglyceride/HDL-cholesterol ratio.Conclusions: This study validated the 10T-BNT and the total score on this scale is strongly associated with AD, impairments in semantic and episodic memory and biomarkers, which are known to modify memory via different mechanisms.

Validity and reliability of the Spanish Version of the Montreal Cognitive Assessment (MoCA) for the detection of cognitive impairment in Mexico

ObjectiveTo establish the validity and reliability of the Montreal Cognitive Assessment in Spanish (MoCA-S) to identify mild cognitive impairment (MCI) and dementia in the Mexican elderly population. Material and methods168 participants from a memory clinic in Mexico City were enrolled and divided into 3 groups: 59 cognitively healthy (CHG), 52 with mild cognitive impairment (MCI) (DSM-5 criteria) and 57 with dementia (NINCDS-ADRDA criteria). The MoCA-S and Mini-Mental State Evaluation (MMSE) were applied at baseline and during the last months to establish intra-observer reliability. ROC curves and a multinomial regression model were constructed to evaluate the effect of age and education on MoCA-S performance. ResultsThe mean age of the participants was 76±8.1 years and the education rate was 10.7±5.2. The MoCA-S scores by group were: CHG, 27.3±1.9; MCI, 22.9±2.9; and dementia, 13.7±4.9 (p<0.001). The reliability of the MoCA-S was 0.89 and the intraclass correlation coefficient was 0.955. Sensitivity was 80% and specificity was 75%, with a cut-off point of 26 points for MCI (area under the curve, 0.886; p<0.001). For the dementia group, the sensitivity was 98% and specificity was 93%, with a cut-off point of 24 points (area under the curve, 0.998; p<0.001). The multinomial regression showed no association with education and age for both the MCI and dementia groups. ConclusionsThe MoCA-S is a valid and reliable instrument for MCI and dementia screening in the Mexican population, even after adjusting for age and education.