Epilepsy has a growing frequency, particularly in the elderly. Several triggers may cause late-onset epilepsy; however, more than 20% of epilepsies, manifesting in the elderly, has an unknown ...etiology. Although cognition is frequently altered in patients affected by epilepsy, there is a paucity of studies specifically evaluating cognition in patients affected by late-onset epilepsy. The aim of the present study was to assess the cognitive profile of patients affected by late-onset epilepsy with an unknown etiology and followed for 12 months.
Patients affected by diagnosed late-onset epilepsy with unknown etiology were included in this observation. All patients were evaluated at the time of diagnosis (baseline) and at follow-up (12 months later). We distributed patients in subgroups based on seizure type (focal seizures FS, secondarily generalized seizures SGS, primarily generalized seizures GS) and antiepileptic drug (AED) regimen (mono- vs. polytherapy). Cognition was evaluated through standardized neuropsychological testing.
Fifty-eight patients were included in this observation and distributed in three groups: 29 affected by FS, 14 affected by SGS, 15 affected by GS. Forty-five patients were in monotherapy, and 13 in polytherapy. The most frequent treatments were levetiracetam (n = 12), valproic acid (VPA) (n = 9), carbamazepine (n = 9), and oxcarbazepine (n = 7). We documented a significant decrease of Mini-Mental State Examination (MMSE) and memory scores at follow-up in the whole group. Verbal learning decreased exclusively in VPA users.
Patients affected by late-onset epilepsy with unknown etiology showed a significant decline of cognition at follow-up, independently from number and efficacy of AEDs received. These results deserve verification in larger longitudinal cohorts.
•Evidence of cognitive decline in patients with LOEU is scarce and limited to small samples.•LOEU shows a particular susceptibility to cognitive decline.•VPA seems to negatively influence cognition in patients with LOEU.
Background
Subtle deficits not fulfilling Mild Cognitive Impairment (MCI) can be associated with pathophysiological AD biomarkers positivity and higher risk of clinical progression (Parnetti et al., ...2019). Several attempts have been carried out in order to characterize neuropsychological features and Alzheimer’s disease (AD) biomarkers in pre‐MCI populations (Chipi et al., 2019). We aimed to explore, by applying the A/T/(N) classification scheme (Jack et al., 2018), the prevalence of cerebrospinal fluid (CSF) AD‐like profile (A+/T+) in a cohort of subjective cognitive decline (SCD), pre‐MCI and MCI subjects.
Method
Seventy‐six consecutive patients (34 M; 42F; mean age: 68.7 years; mean education: 10.7 years), referred to our Memory Clinic from 2016 to 2019, were defined as SCD (n.11) (Jessen et al., 2014), pre‐MCI (n. 28) (Duara et al., 2011) and MCI (n.37) (Albert et al., 2011) by means of an advance neuropsychological battery and underwent lumbar puncture for the analysis of CSF core AD biomarkers (Aβ42/Aβ40 ratio, total tau, phospho‐tau). According to the cut‐off used in our lab, we considered Aβ42/40 ratio <0.069 as A+, phospho‐tau >70 pg/mL as T+, total tau > 400 pg/mL as N+.
Result
No differences were found in age, gender and education among groups. AD‐like CSF profile (A+T+) was found in 10.7% of pre‐MCI and in 54.1% of MCI (p<0.001). None of SCD subjects showed AD‐like profile. Prevalence of A+ was found in 9.1% of SCD and 35.7% of pre‐MCI, compared to 73% of MCI (SCD vs MCI: p<0.001; pre‐MCI vs MCI: p=0.0049).
Conclusion
Consistent proportion (10.7%) of subjects with subtle cognitive deficits not fulfilling MCI (pre‐MCI) in our cohort showed evidence of AD‐like profile, while none of SCD resulted A+/T+. Amyloidosis was detectable in both SCD and pre‐MCI subjects. Accordingly, pre‐MCI with evidence of AD‐like biomarkers may be considered as the earliest clinical manifestation of AD, and may represent an important target for treatment with disease‐modifying drugs.
Abstract
Background
Subtle deficits not fulfilling Mild Cognitive Impairment (MCI) can be associated with pathophysiological AD biomarkers positivity and higher risk of clinical progression (Parnetti ...et al., 2019). Several attempts have been carried out in order to characterize neuropsychological features and Alzheimer’s disease (AD) biomarkers in pre‐MCI populations (Chipi et al., 2019). We aimed to explore, by applying the A/T/(N) classification scheme (Jack et al., 2018), the prevalence of cerebrospinal fluid (CSF) AD‐like profile (A+/T+) in a cohort of subjective cognitive decline (SCD), pre‐MCI and MCI subjects.
Method
Seventy‐six consecutive patients (34 M; 42F; mean age: 68.7 years; mean education: 10.7 years), referred to our Memory Clinic from 2016 to 2019, were defined as SCD (n.11) (Jessen et al., 2014), pre‐MCI (n. 28) (Duara et al., 2011) and MCI (n.37) (Albert et al., 2011) by means of an advance neuropsychological battery and underwent lumbar puncture for the analysis of CSF core AD biomarkers (Aβ42/Aβ40 ratio, total tau, phospho‐tau). According to the cut‐off used in our lab, we considered Aβ42/40 ratio <0.069 as A+, phospho‐tau >70 pg/mL as T+, total tau > 400 pg/mL as N+.
Result
No differences were found in age, gender and education among groups. AD‐like CSF profile (A+T+) was found in 10.7% of pre‐MCI and in 54.1% of MCI (p<0.001). None of SCD subjects showed AD‐like profile. Prevalence of A+ was found in 9.1% of SCD and 35.7% of pre‐MCI, compared to 73% of MCI (SCD vs MCI: p<0.001; pre‐MCI vs MCI: p=0.0049).
Conclusion
Consistent proportion (10.7%) of subjects with subtle cognitive deficits not fulfilling MCI (pre‐MCI) in our cohort showed evidence of AD‐like profile, while none of SCD resulted A+/T+. Amyloidosis was detectable in both SCD and pre‐MCI subjects. Accordingly, pre‐MCI with evidence of AD‐like biomarkers may be considered as the earliest clinical manifestation of AD, and may represent an important target for treatment with disease‐modifying drugs.
Previous evidence has shown different resting-state eyes-closed electroencephalographic delta (<4 Hz) and alpha (8–10.5 Hz) source connectivity in subjects with dementia due to Alzheimer's (ADD) and ...Lewy body (DLB) diseases. The present study tested if the same differences may be observed in the prodromal stages of mild cognitive impairment (MCI). Here, clinical and resting-state eyes-closed electroencephalographic data in age-, gender-, and education-matched 30 ADMCI, 23 DLBMCI, and 30 healthy elderly (Nold) subjects were available in our international archive. Mini-Mental State Evaluation (MMSE) score was matched in the ADMCI and DLBMCI groups. The eLORETA freeware estimated delta and alpha source connectivity by the tool called lagged linear connectivity (LLC). Area under receiver operating characteristic curve (AUROCC) indexed the classification accuracy among individuals. Results showed that widespread interhemispheric and intrahemispheric LLC solutions in alpha sources were abnormally lower in both MCI groups compared with the Nold group, but with no differences were found between the 2 MCI groups. AUROCCs of LLC solutions in alpha sources exhibited significant accuracies (0.72–0.75) in the discrimination of Nold versus ADMCI-DLBMCI individuals, but not between the 2 MCI groups. These findings disclose similar abnormalities in ADMCI and DLBMCI patients as revealed by alpha source connectivity. It can be speculated that source connectivity mostly reflects common cholinergic impairment in prodromal state of both AD and DLB, before a substantial dopaminergic derangement in the dementia stage of DLB.
•We evaluated the abnormalities in functional cortical connectivity computed in rsEEG sources in subjects with Mild Cognitive Impairment due to Alzheimer’s and Lewy Body disease.•At the group level, EEG markers of functional cortical connectivity were abnormally lower in in Alzheimer’s Disease (ADD) and Lewy Body Disease (DLB) patients compared to healthy elderly subjects (Nold).•At the group level, EEG markers of functional cortical connectivity were similar between in ADD and DLB patients compared to Nold subjects.•At the individual level, EEG marker of functional cortical connectivity exhibited better classification accuracies for the discrimination of ADD versus Nold, and DLB versus Nold, but not between ADD and DLB.
The variability of Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers undermines their full-fledged introduction into routine diagnostics and clinical trials. Automation may help to ...increase precision and decrease operator errors, eventually improving the diagnostic performance. Here we evaluated three new CSF immunoassays, EUROIMMUNtrademark amyloid-β 1-40 (Aβ1-40), amyloid-β 1-42 (Aβ1-42), and total tau (t-tau), in combination with automated analysis of the samples. The CSF biomarkers were measured in a cohort consisting of AD patients (n = 28), mild cognitive impairment (MCI, n = 77), and neurological controls (OND, n = 35). MCI patients were evaluated yearly and cognitive functions were assessed by Mini-Mental State Examination. The patients clinically diagnosed with AD and MCI were classified according to the CSF biomarkers profile following NIA-AA criteria and the Erlangen score. Technical evaluation of the immunoassays was performed together with the calculation of their diagnostic performance. Furthermore, the results for EUROIMMUN Aβ1-42 and t-tau were compared to standard immunoassay methods (INNOTESTtrademark). EUROIMMUN assays for Aβ1-42 and t-tau correlated with INNOTEST (r = 0.83, p < 0.001 for both) and allowed a similar interpretation of the CSF profiles. The Aβ1-42/Aβ1-40 ratio measured with EUROIMMUN was the best parameter for AD detection and improved the diagnostic accuracy of Aβ1-42 (area under the curve = 0.93). In MCI patients, the Aβ1-42/Aβ1-40 ratio was associated with cognitive decline and clinical progression to AD.The diagnostic performance of the EUROIMMUN assays with automation is comparable to other currently used methods. The variability of the method and the value of the Aβ1-42/Aβ1-40 ratio in AD diagnosis need to be validated in large multi-center studies.
Abstract The presence of abnormal levels of Aβ and neurodegeneration in individuals with mild cognitive impairment (MCI) may indicate prodromal Alzheimer’s disease (AD), while MCI with normal Aβ may ...reflect normal aging or some other neurodegenerative or psychiatric process. While this has important implications for the management of MCI patients, few studies have closely examined the relationship between CSF and structural biomarkers, and cognitive function in MCI. We aimed to examine the relationship between cognitive function, hippocampal volume and cerebrospinal fluid (CSF) biomarkers of Aβ and tau in a group of well characterized patients with mild cognitive impairment (MCI). MCI patients (n=145) were assessed on wide range of cognitive tasks from the Cambridge Neuropsychological Test Automated Battery (CANTAB) measuring memory, executive function, sustained attention and processing speed, Geriatric Depression Scale (GDS), Functional Activities Questionnaire (FAQ). Hippocampal volume was measured using magnetic resonance imaging (MRI), and CSF markers of Aβ42 , tau and p-tau181 were also measured. Worse performance on a wide range of memory and sustained attention tasks were associated with reduced hippocampal volume, higher CSF levels of tau and p-tau181 and increased tau/Aβ42 ratio. Memory tasks such as PAL and PRM that showed association with CSF and structural biomarkers were also associated with lower ability to conduct functional activities of daily living, thus providing a link between AD related biomarkers, memory performance and functional outcome. Further, when participants were classified into Aβ+ and Aβ- groups, Aβ+ MCIs showed additional impairments relative to the Aβ- MCIs on recognition and working memory tasks. Even at a single timepoint, there were significant associations between AD biomarkers (i.e., Aβ, tau and hippocampal volume loss) and cognitive performance on the CANTAB in individuals with MCI. These results suggest that biomarkers of Aβ and tau are strongly related to cognitive performance, and have implications for the early detection and characterisation of incipient AD.
We hypothesized that dopamine neuromodulation might affect cortical excitability in Parkinson's disease (PD) patients set in quiet wakefulness, as revealed by resting state eyes-closed ...electroencephalographic (rsEEG) rhythms at alpha frequencies (8–12 Hz). Clinical and rsEEG rhythms in PD with dementia (N = 35), PD with mild cognitive impairment (N = 50), PD with normal cognition (N = 35), and normal (N = 50) older adults were available from an international archive. Cortical rsEEG sources were estimated by exact low-resolution brain electromagnetic tomography. Compared with the normal older group, the PD groups showed reduced occipital alpha sources and increased widespread delta (<4 Hz) sources. Widespread frontal and temporal alpha sources exhibited an increase in PD with dementia compared with PD with mild cognitive impairment and PD with normal cognition groups, as function of dopamine depletion severity, typically greater in the former than the latter groups. A daily dose of levodopa induced a widespread reduction in cortical delta and alpha sources in a subgroup of 13 PD patients under standard chronic dopaminergic regimen. In PD patients in quiet wakefulness, alpha cortical source activations may reflect an excitatory effect of dopamine neuromodulation.
There is a great interest in developing cerebrospinal fluid (CSF) biomarkers for diagnosis and prognosis of Parkinson's disease (PD). CSF alpha synuclein (α-syn) species, namely total and oligomeric ...α-syn (t-α-syn and o-α-syn), have shown to be of help for PD diagnosis. Preliminary evidences show that the combination of CSF t-α-syn and classical Alzheimer's disease (AD) biomarkers-β-amyloid 1-42 (Aβ42), total tau (t-tau), phosphorylated tau (p-tau)-differentiate PD patients from controls, and that reduced levels of Aβ42 represent a predictive factor for development of cognitive deterioration in PD. In this prospective study carried out in 44 PD patients and 25 neurological controls we wanted to verify whether the combination of CSF α-synuclein species-t-α-syn and o-α-syn-and classical AD biomarkers may help in differentiating PD from neurological controls, and if these biomarkers may predict cognitive decline. The median of follow-up duration was 3 years (range: 2-6 years). Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were used for monitoring cognitive changes along time, being administered once a year. Oligo/total α-syn ratio (o/t-α-syn ratio) confirmed its diagnostic value, significantly contributing to the discrimination of PD from neurological controls. A greater diagnostic accuracy was reached when combining o/t-α-syn and Aβ42/tau ratios (Sens = 0.70, Spec = 0.84, AUC = 0.82; PPV = 0.89, NPV = 0.62, LR+ = 4.40, DOR = 12.52). Low CSF Aβ42 level was associated with a higher rate of MMSE and MoCA decline, confirming its role as independent predictive factor for cognitive decline in PD. None of the other biomarkers assessed (t-tau, p-tau, t-α-syn and o-α-syn) showed to have prognostic value. We conclude that combination of CSF o/t-α-syn and Aβ42/tau ratios improve the diagnostic accuracy of PD. PD patients showing low CSF Aβ42 levels at baseline are more prone to develop cognitive decline.
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