Dementia and Geriatric Cognitive Disorders

<i>Background/Aims:</i> Mobility impairment in older adults has been suggested to be a marker of subclinical structural and functional brain abnormalities. We investigated a possible association between static postural instability and brain abnormalities and cognitive decline. <i>Methods:</i> The study subjects were 390 community residents without definitive dementia (67 ± 7 years old) and 21 patients with Alzheimer’s disease (AD). Brain atrophy was measured by MRI. <i>Results:</i> The mobility of the posturography-measured center of gravity (COG) was positively associated with the temporal horn area (THA; r = 0.260; p < 0.001). Subjects who could not stand on one leg for >40 s (n = 102) showed a significantly larger THA (22 ± 18 vs. 14 ± 11 × 10^–2 cm²; p < 0.001). Multiple regression analysis identified COG path length (β = 0.118; p = 0.032) and one-leg standing time (β = 0.176; p = 0.001) as independent determinants of THA. Mild cognitive impairment (MCI) subjects (n = 61) had a significantly enlarged THA compared to that of normal cognitive subjects (22 ± 16 vs. 16 ± 13 × 10^–2 cm²; p = 0.002). AD patients showed a more enlarged THA (78 ± 55 × 10^–2 cm²). Subjects with cognitive decline showed a significantly shorter one-leg standing time (normal: 50 ± 17 s; MCI: 42 ± 21 s; AD: 18 ± 20s; p < 0.001). <i>Conclusion:</i> Reduced postural stability was an independent marker of brain atrophy and pathological cognitive decline in the elderly.

<i>Background and Purpose:</i> Patients with mild cognitive impairment and subcortical cerebrovascular disease (svMCI) can be isolated using criteria modified from those of Erkinjuntti et al. for subcortical vascular dementia and have poorer outcomes (cognitive deterioration, disability, institutionalization, and mortality). The aim of this study was to test which of the core (dysexecutive syndrome with relative sparing of memory, gait disorders and extrapyramidal signs) and supporting (urinary and behavioral symptoms) clinical features are most useful to recognize patients with svMCI and discriminate them from those with amnestic MCI (aMCI). <i>Methods:</i> Twenty-nine svMCI and 14 aMCI patients were seen in a memory clinic. Tests and scales assessing core and supporting features that independently contributed to the discrimination between svMCI and aMCI were identified with stepwise logistic regression analysis. The accuracy of the discrimination was estimated with area under the receiver operating characteristic curve and 95% confidence intervals (CIs). <i>Results:</i> The most accurate scales were the extrapyramidal sign scale by Richards et al. (0.75, 95% CI 0.61–0.89), letter fluency (0.75, 95% CI 0.61–0.90), irritability of the Neuropsychiatric Inventory and urinary dependence (0.66, 95% CI 0.49–0.82 for both), and digit span forward (0.59, 95% CI 0.41–0.77). The overall accuracy of a model compounding information from main and supporting features was 0.98, 95% CI 0.94–1.0. <i>Conclusions:</i> All the domains that are included in the clinical criteria for svMCI independently contribute to the identification of the condition. These criteria can be useful to recognize svMCI patients in clinical settings.

<i>Background:</i> An early and accurate diagnosis of Alzheimer’s disease (AD) is important in order to initiate symptomatic treatment with currently approved drugs and will be of even greater importance with the advent of disease-modifying compounds. <i>Methods:</i> Protein profiles of human cerebrospinal fluid samples from patients with AD (n = 85), frontotemporal dementia (n = 20), and healthy controls (n = 32) were analyzed by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry to verify previously discovered biomarkers. <i>Results:</i> We verified 15 protein biomarkers that were able to differentiate between AD and controls, and 7 of these 15 markers also differentiated AD from FTD. <i>Conclusion:</i> A panel of cerebrospinal fluid protein markers was verified by a proteomics technology which may potentially improve the accuracy of the AD diagnosis.

<i>Background/Aims:</i> The aim of this study was to investigate the role of cerebrospinal fluid β-amyloid(1–42) levels and auditory event-related potentials (AERPs) in the progress of mild cognitive impairment (MCI) to Alzheimer’s disease (AD). <i>Methods:</i> In 53 MCI patients, lumbar puncture was performed and β-amyloid(1–42) levels were determined. Twenty patients were reexamined after 11 months. During this period, 5 of them progressed to AD. Neuropsychological and ERP analyses were performed on all patients during both baseline and endpoint examinations. <i>Results:</i> Compared to stable MCI patients, those that progressed to AD had significantly lower β-amyloid(1–42) levels (Mann-Whitney test, Z = –2.952, p = 0.003; effect size r = –0.41) and significantly prolonged N200 latencies (Mann-Whitney test, Z = –3.561, p < 0.001, effect size r = –0.49). From ERP variables, only the N200 latency significantly correlated with β-amyloid(1–42) levels (baseline examination: r_s = –0.421, p = 0.002; follow-up examination: r_s = –0.574, p = 0.008). <i>Conclusions:</i> The combined use of these two parameters enabled discrimination of stable MCI patients from those who developed AD, with 100% sensitivity and specificity. Therefore, this method could be of high diagnostic value for the early diagnosis of AD.

<i>Background:</i> Serum amyloid P component (SAP), present in amyloid-β (Aβ) plaques in Alzheimer’s disease (AD), may protect Aβ deposits against proteolysis, thereby promoting plaque formation. The aim was to investigate if SAP levels in cerebrospinal fluid (CSF) and serum can be used to discriminate controls, AD and mild cognitive impairment (MCI) patients, and to identify incipient AD among MCI patients. <i>Methods:</i> SAP levels in CSF and serum were determined in 30 controls, 67 MCI and 144 AD patients. At follow-up, 39 MCI patients had progressed to dementia, while 25 had remained stable (mean follow-up time: 2.6 ± 1.0 and 2.1 ± 0.8 years). <i>Results:</i> Cross-sectionally no differences were found in SAP levels in CSF and serum between the groups. MCI patients that had progressed to dementia at follow-up had lower CSF SAP levels (13 mg/l, range 3.3–199.3 mg/l) than MCI nonprogressors (20.2 mg/l, range 7.0–127.7 mg/l; p < 0.05). A low CSF SAP level was associated with a 2-fold increased risk of progression to AD (hazard ratio = 2.2; 95% confidence interval = 0.9–5.4). <i>Conclusion:</i> Our data suggest that measurement of CSF SAP levels can aid in the identification of incipient AD among MCI patients.

<i>Background:</i> The cerebrospinal fluid (CSF) proteins β-amyloid 42 (Aβ42) and Tau are believed to indirectly reflect some core pathological features of Alzheimer’s disease (AD). Their topographic origin and their association with synaptic dysfunction are still not well understood. <i>Aim:</i> The present study aimed to explore possible associations between cerebral glucose metabolism and CSF Aβ42 as well as Tau protein levels in AD. <i>Methods:</i> CSF analyses and ¹⁸F-FDG PET scans were conducted on 32 patients with mild-to-moderate AD. Voxel-based statistical parametric correlations were computed for CSF protein levels and cerebral glucose metabolism. <i>Results:</i> After correction for multiple comparisons, a strong positive association between CSF Aβ42 levels and glucose metabolism was identified for 2 extensive clusters located in the right temporal, prefrontal and anterior cingulate cortices. For CSF Tau protein, no association was observed for any brain region. <i>Conclusions:</i> These findings point to a significant association between synaptic dysfunction as measured with ¹⁸F-FDG PET and CSF Aβ42 levels, but do not suggest a correlation between synaptic function and CSF Tau levels.

Cerebrospinal fluid (CSF) biological markers may be of valuable help in the diagnosis of dementia. The aim of the present study was to evaluate CSF levels of 13 potential biomarkers in patients with Alzheimer’s disease (AD), frontotemporal lobe dementia, alcohol dementia, major depression and control patients without any neuropsychiatric disease. The study was performed using β-amyloid 1–42 (Aβ42), total tau and phosphorylated tau-181 (P-tau181) as core markers. The ratio P-tau181/Aβ42 could significantly distinguish AD patients from all other diagnostic subgroups. CSF levels of 5 growth factors (HGF, GDNF, VEGF, BDNF, FGF-2) and 3 cytokines/chemokines (TNF-α, TGF-β₁, MIP-1α) did not significantly differentiate between the studied groups. However, depending on the degree of neurodegeneration (as expressed by the ratio P-tau181/Aβ42), patients with AD displayed significantly increased CSF levels of nerve growth factor (NGF) as compared to healthy controls. CSF levels of monocyte chemoattractant protein 1 (MCP-1) were found to be significantly increased with age in all groups but did not distinguish AD patients from healthy controls. The results confirmed the suitability of the ratio P-tau181/Aβ42 for the diagnosis of AD, while CSF levels of NGF and MCP-1 are less specific and reliable for AD. It is suggested that the increase in NGF depends on the extent of neurodegeneration of the AD type and the increase in MCP-1 on age.

<i>Background:</i> In mild cognitive impairment (MCI), Alzheimer’s disease (AD)-type cerebrospinal fluid (CSF) biomarker profiles predict rapid progression and conversion to AD. An increased brain amyloid burden in AD and MCI has been demonstrated with PET using [¹¹C]PIB (Pittsburgh compound B). Little is known about the relationship between these biomarkers in MCI. <i>Methods:</i> We studied 15 patients with amnestic MCI and 22 controls with PET using [¹¹C]PIB. In MCI patients, CSF levels of Aβ42, pTAU, totalTAU and the Aβ42/pTAU ratio were measured. <i>Results:</i> In MCI patients, CSF Aβ42 was abnormal in 53% of patients, totalTAU in 67%, pTAU in 64% and the Aβ42/pTAU ratio in 64%. A composite neocortical [¹¹C]PIB uptake score was increased in 87% of the MCI patients. Only 54% of [¹¹C]PIB-positive subjects showed AD-type Aβ42 values. During a 2-year follow-up, 6 MCI patients converted to AD, all of them had increased neocortical PIB scores at the MCI stage. Abnormal CSF Aβ42 was found in 3 patients, pTAU in 3 patients and Aβ42/pTAU ratio in 4 patients. <i>Conclusion:</i> Follow-up studies are needed to confirm whether [¹¹C]PIB uptake might be more sensitive than CSF Aβ42 concentration in detecting increased amyloid burden in MCI, as suggested by the results of this study.

<i>Background/Aims:</i> Increased cerebrospinal fluid (CSF) tau, decreased CSF amyloid-β42 (Aβ42) and the apolipoprotein E gene <i>(APOE) </i>ε<i>4</i> allele predict progression from mild cognitive impairment (MCI) to Alzheimer’s disease (AD). Here, we investigated these markers to assess their predictive value and influence on the rate of disease progression. <i>Methods:</i> Using ELISA, we measured the CSF biomarkers in 47 AD patients, 58 patients with MCI and 35 healthy control subjects. Twenty-eight MCI patients revisited the clinic and half of them progressed to AD during a period of 3–12 years. <i>Results:</i> The expected changes in CSF total (T)-tau, phosphorylated (P)-tau and Aβ42 levels were found in AD, confirming the diagnostic value of these biomarkers. We were also able to corroborate an increased risk for progression from MCI to AD with elevated CSF T-tau and P-tau and with the presence of the <i>APOE </i>ε<i>4/</i>ε<i>4</i> genotype, but not with decreased Aβ42. Finally, for the first time we demonstrated that MCI subjects with high CSF T-tau or P-tau and <i>APOE </i>ε<i>4</i> homozygosity progressed faster from MCI to AD. <i>Conclusions:</i> CSF T-tau and P-tau as well as the <i>APOE </i>ε<i>4/</i>ε<i>4</i> genotype are robust predictors of AD and are also associated with a more rapid progression from MCI to AD.

There are various anticholinesterase inhibitors (AChEIs) for the symptomatic treatment of mild to moderate Alzheimer’s disease (AD). All AChEIs have shown greater efficacy than placebo in randomized, double-blind, parallel-group clinical trials. No differential studies have yet been made of the efficacy between all AChEIs. The study aims to determine the differential efficacy of the AChEIs with respect to a historical sample of patients with AD that were not treated with AChEIs. An open-label, prospective, observational study with a retrospective control group was undertaken to examine the evolution of the cognitive function over a 6-month period. The patients were assessed with the Mini-Mental State Examination (MMSE) at study entry and at 6 months. A general linear model was applied for repeated measurements with the MMSE score as the dependent variable, treatment type as an independent variable and the severity of the deterioration, age and the MMSE baseline score as covariables. Of the sample of 147 patients, 40 initiated treatment with donepezil, 32 with galantamine, 30 with rivastigmine and 45 were part of a historical sample of the memory clinic patients between 1991 and 1996 that had not been treated with AChEIs. The average age was 73.7 years (SD = 6.9; range = 52–86), 67.3% were women, 78.2% of the cases were mild and the MMSE baseline score was 18.1 points (range = 11–27). No significant intergroup differences were observed in these variables. The average doses of donepezil, galantamine and rivastigmine were 5.87 mg/day (SD = 1.92), 14.81 mg/day (SD = 6.25) and 6.41 mg/day (SD = 1.82), respectively. At 6 months, the difference in the MMSE score with respect to the untreated group was 1.6 points for donepezil (95% CI 0.79–2.37; p < 0.001), 0.99 points for galantamine (95% CI 0.14–1.85; p = 0.01) and 0.90 points for rivastigmine (95% CI 0.05–1.74; p = 0.03). No significant differences were observed in the efficacy among the groups treated with AChEIs (p > 0.05). Treatment with AChEIs significantly delays the global cognitive impairment associated with AD for at least 6 months. Our study found no significant differences in efficacy between donepezil, galantamine and rivastigmine. Further studies in the context of daily clinical practice will determine the clinical significance of the changes observed. An important variability of the response to the treatment was observed in treated patients.