<i>Background:</i> Patients with Alzheimer’s disease (AD) and amnestic mild cognitive impairment (MCI) have difficulties with spatial orientation. <i>Objective:</i> To test hypothesis that spatial navigation is impaired early in MCI patients representing the presymptomatic stage of AD. <i>Methods:</i> We tested patients with probable AD (n = 21), MCI, further classified according to Petersen’s criteria as amnestic MCI (aMCI) single domain (n = 11), aMCI multiple domain (n = 31), or nonamnestic MCI (n = 7). The aMCI group was also stratified using cued recall according to Dubois’ criteria into memory impairment of the hippocampal type (n = 10) and isolated memory retrieval impairment-nonhippocampal (n = 32) and also according to ApoE4 status into E4+ (n = 12) and E4– (n = 30). These patients and controls (n = 28) were tested in the human variant of the Morris water maze. Depending on the subtest, the subjects could use the egocentric or allocentric (hippocampus-dependent) navigation. <i>Results:</i> The AD and aMCI multiple domain groups were impaired in all subtests. The aMCI single domain group was impaired in allocentric subtests. The hippocampal MCI group performed poorer than the nonhippocampal MCI group and similarly to the AD group. The ApoE4+ group was as bad as the AD group when compared with the E4– group. <i>Conclusion:</i> aMCI subjects represent a very heterogeneous population, and spatial memory or cued recall examination can add more value to aMCI classification. ApoE4+ patients are more impaired than ApoE4– patients.
A poly-T length polymorphisms at rs10524523 ('523') of the TOMM40 gene influence the age of onset in Alzheimer's disease (AD). The individuals with very long (VL) poly-T variants have earlier disease onset than individuals with short (S) poly-T variants. We aimed to assess the association of TOMM40 ('523') poly-T variants with cognitive functions, especially with hippocampus-specific visual memory binding in subjects with amnestic mild cognitive impairment (aMCI). Since aMCI population may have various risk of AD even if similar on conventional neuropsychological tests, we challenged our subjects to novel visual memory binding test and hypothesized that aMCI patients with VL poly-T variants would have poorer performance than those with S poly-T variants. Eighty patients with aMCI were stratified according to poly-T length polymorphisms at '523' into homozygous for S (S/S; n=27), homozygous for VL (VL/VL;n=23) and heterozygous (S/VL;n=30) TOMM40 poly-T variant groups. We recruited only APOE ε3/ε3 homozygotes to eliminate variance associated with various risk of AD due to APOE status. All subjects underwent neurological, internal, and laboratory evaluations, brain MRI, neuropsychological examination and computer test of visual memory binding (Episodic-like Memory Test, EMT) which required subjects to remember spatial positions and temporal orders of series of pictures in three successive levels of difficulty (3, 5 and 7 items). The one-way analysis of variance with post-hoc Tukey's HSD test was used. The groups did not differ in demographic characteristics and MMSE. The VL/VL group had lower total EMT score (sum of three levels of difficulty) (p=.008) and score in EMT 5-item (p=.014) and EMT 7-item (p=.036) subtests compared to the S/S group. Further, the VL/VL group had lower total EMT score (p=.030) and score in EMT 7-item subtest (p=.041) compared to the S/VL group. The differences between the S/S and S/VL groups were not significant. The groups also did not differ in other neuropsychological tests. Visual memory binding deficits among APOE ε3/ε3 aMCI patients are more pronounced in TOMM40 '523' VL/VL carriers than in those with S/S poly-T variants. These findings indicate the association between the TOMM40 '523' polymorphism and cognitive performance.
Abstract Background The ability to understand emotions is often disturbed in patients with cognitive impairments. Right temporal lobe structures play a crucial role in emotional processing, especially the amygdala, temporal pole (TP), superior temporal sulcus (STS), and anterior cingulate (AC). Those regions are affected in early stages of Alzheimer´s disease (AD). The aim of our study was to evaluate emotional prosody recognition (EPR) in participants with amnestic mild cognitive impairment (aMCI) due to AD, AD dementia patients, and cognitively healthy controls and to measure volumes or thickness of the brain structures involved in this process. In addition, we correlated EPR score to cognitive impairment as measured by MMSE. The receiver operating characteristic (ROC) analysis was used to assess the ability of EPR tests to differentiate the control group from the aMCI and dementia groups. Methods Eighty-nine participants from the Czech Brain Aging Study: 43 aMCI due to AD, 36 AD dementia, and 23 controls, underwent Prosody Emotional Recognition Test. This experimental test included the playback of 25 sentences with neutral meaning each recorded with different emotional prosody (happiness, sadness, fear, disgust, anger). Volume of the amygdala and thickness of the TP, STS, and rostral and caudal parts of AC (RAC and CAC) were measured using FreeSurfer algorithm software. ANCOVA was used to evaluate EPR score differences. ROC analysis was used to assess the ability of EPR test to differentiate the control group from the aMCI and dementia groups. The Pearson’s correlation coefficients were calculated to explore relationships between EPR scores, structural brain measures, and MMSE. Results EPR was lower in the dementia and aMCI groups compared with controls. EPR total score had high sensitivity in distinguishing between not only controls and patients, but also controls and aMCI, controls and dementia, and aMCI and dementia. EPR decreased with disease severity as it correlated with MMSE. There was a significant positive correlation of EPR and thickness of the right TP, STS, and bilateral RAC. Conclusions EPR is impaired in AD dementia and aMCI due to AD. These data suggest that the broad range of AD symptoms may include specific deficits in the emotional sphere which further complicate the patient’s quality of life.
Abstract Background Spatial navigation deficits are present early in Alzheimer´s disease (AD) and could thus serve as an early cognitive marker of the disease. AD patients were shown to have altered scene exploration during spatial navigation as they overlook objects of interest. We aimed to evaluate the potential of a virtual spatial navigation task and eye‐tracking assessment to identify individuals with early AD and to differentiate them from those with cognitive deficit of other etiology. Methods 48 participants: amnestic mild cognitive impairment (aMCI) with positive AD‐biomarkers (aMCI due to AD, n=14), aMCI with negative biomarkers (aMCI AD‐negative, n=8), mild AD dementia (n=9) and cognitively normal (CN) older adults (n=17) underwent clinical and neuropsychological evaluation, MRI brain scan, amyloid PET imaging, cerebrospinal fluid biomarker assessment and spatial navigation testing in a virtual realistic‐looking “Intersections” test. The test consisted of three tasks: i) egocentric “route repetition”, where participants repeated the route through a virtual city, ii) allocentric “route retracing”, where participants indicated their way back, and iii) allocentric “different approach direction” combined with eye‐tracking, where participants indicated their original position from a different perspective at each intersection with two same and two unique houses. Number of fixations and length of fixation of unique houses were analyzed. Results The aMCI due to AD and mild AD dementia groups had lower scores in the egocentric “route repetition” and allocentric “route retracing” tasks compared to the CN (p<0.012) and aMCI AD‐negative (p<0.007) groups. There were no differences between the CN and aMCI AD‐negative groups in these tasks. The AD dementia group had lower scores in the allocentric “different approach direction” task compared to the CN group (p=0.027). Duration and number of fixations of unique landmarks in the “different approach direction” was similar across all groups that demonstrated higher number and longer duration of fixations regardless of the task performance (p<0.001). Conclusion The egocentric and allocentric tasks from the virtual “Intersection” test reliably detect spatial navigation impairment typical for early stages of AD. Spatial navigation unlike scene exploration can differentiate individuals with aMCI due to AD from those with non‐AD etiology.
10Neurologicke odděleni, Pardubicka krajska nemocnice, Pardubice
11Centrum klinických neurověd, Neurologicka klinika 1. LF UK a VFN, Praha
12Neurologicka klinika, LF UK a FN Hradec Kralove
13Výzkumna skupina Aplikovane neurovědy, CEITEC MU, Brno
14Psychiatricka lecebna Dobřany
Průzkum mezi 150 ambulantnimi neurology, psychiatry a geriatry zjisťoval aktualni zvyklosti v diagnostice a lecbě kognitivnich poruch
v CR. Vice než polovina pacientů s kognitivni poruchou byla diagnostikovana až ve středně pokrocilem a pozdnim stadiu. Výsledky ukazuji
nedostatecne uživani zobrazovacich metod v diagnostice. Větsina pacientů s diagnozou Alzheimerovy choroby je lecena kognitivy.
Potvrzuje se siroke uživani neucinných nootropik.
Lumbar puncture (LP) is increasingly used as ancillary investigation in memory clinics. The invasive nature of this procedure is however hampering widespread implementation. We aimed to investigate patient-acceptance of LP, and the incidence of and risk factors for post-LP complications in memory clinic populations across Europe. All patients presenting at the memory clinic were prospectively included, whenever an LP was considered. Patients were included from November 2010 until March 2014 in twenty-three memory clinics across Europe. We included 3868 patients (50% women, mean age 66±11 years, mean MMSE 25±5). Three hundred ten patients (8%) refused to undergo LP and 102 patients (3%) could not be contacted for follow-up. Prior to LP various patient and LP procedure characteristics were recorded. Within two weeks after LP patients were asked about their complaints. Main outcome measures were typical post-LP headache (PLPH) and local back pain. Logistic regression analysis using generalized estimated equations was used to investigate risk factors for post-LP complications. In total, 1065 patients (31%) reported complaints of any kind after the LP; 589 patients (17%) reported back pain, 649 (19%) headache, of which 296 (9%) reported typical PLPH. There were only few complications needing medical intervention; 11 patients (0.3%) received a blood patch, 23 (0.7%) were hospitalized. The most important risk factor for PLPH was history of headache (OR [95%CI] 1.8 [1.2-2.6] for mild headache; 2.7 [1.9-3.7] for chronic/severe headache). An atraumatic needle (OR [95%CI] 0.4 [0.2-0.8]) and age >65 years (OR [95%CI] 0.7 [0.5-1.0]) were preventive. A small needle diameter was associated with less severe headache (OR [95%CI] 0·6 [0·4-0·9]). The most important risk factor for post-LP back pain was number of LP attempts (OR [95%CI] 2.1 [1.7-2.7] for 2-4 attempts; 5.4 [2.9-10.2] for >4 attempts). There was no effect of gender, rest after LP or volume of CSF withdrawn. LPs can be safely performed in memory clinics. Complaints were mostly mild in nature; complications needing medical intervention were rare. Risk factors should be taken into account and if possible modified when performing LPs.
Abstract Due to methodological reasons, the X-chromosome has not been featured in the major genome-wide association studies on Alzheimer’s Disease (AD). To address this and better characterize the genetic landscape of AD, we performed an in-depth X-Chromosome-Wide Association Study (XWAS) in 115,841 AD cases or AD proxy cases, including 52,214 clinically-diagnosed AD cases, and 613,671 controls. We considered three approaches to account for the different X-chromosome inactivation (XCI) states in females, i.e. random XCI, skewed XCI, and escape XCI. We did not detect any genome-wide significant signals (P ≤ 5 × 10 − 8 ) but identified seven X-chromosome-wide significant loci (P ≤ 1.6 × 10 − 6 ). The index variants were common for the Xp22.32, FRMPD4, DMD and Xq25 loci, and rare for the WNK3 , PJA1 , and DACH2 loci. Overall, this well-powered XWAS found no genetic risk factors for AD on the non-pseudoautosomal region of the X-chromosome, but it identified suggestive signals warranting further investigations.
Neuropsychiatric symptoms and reduced health-related quality of life (HRQoL) are frequent in multiple sclerosis, where are associated with structural brain changes, but have been less studied in clinically isolated syndrome (CIS).To characterize HRQoL, neuropsychiatric symptoms (depressive symptoms, anxiety, apathy and fatigue), their interrelations and associations with structural brain changes in CIS.Patients with CIS (n = 67) and demographically matched healthy controls (n = 46) underwent neurological and psychological examinations including assessment of HRQoL, neuropsychiatric symptoms and cognitive functioning, and MRI brain scan with global, regional and lesion load volume measurement.The CIS group had more, mostly mild, depressive symptoms and anxiety, and lower HRQoL physical and social subscores (p≤0.037). Neuropsychiatric symptoms were associated with most HRQoL subscores (β≤-0.34, p≤0.005). Cognitive functioning unlike clinical disability was associated with depressive symptoms and lower HRQoL emotional subscores (β≤-0.29, p≤0.019). Depressive symptoms and apathy were associated with right temporal, left insular and right occipital lesion load (ß≥0.29, p≤0.032). Anxiety was associated with lower white matter volume (ß = -0.25, p = 0.045).Mild depressive symptoms and anxiety with decreased HRQoL are present in patients with CIS. Neuropsychiatric symptoms contributing to decreased HRQoL are the result of structural brain changes and require complex therapeutic approach in patients with CIS.
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