Effect of oral donepezil on intraocular pressure in normotensive Alzheimer patients

Donepezil, a selective acetylcholinesterase (AChE) inhibitor, has been shown to reduce intraocular pressure (IOP) in ocular normotensive rabbit eyes. The aim of this investigation was to evaluate the effect of oral donepezil on IOP and pupil diameter after mid-term oral treatment in normotensive persons. Thirty-two newly diagnosed Alzheimer patients with normal IOP and no further antiglaucomatous treatment were included in the study. IOP and pupil diameter were evaluated before and 4 weeks after daily intake of 5 mg donepezil. IOP and pupil diameter were significantly lower/smaller after 4 weeks of treatment. The mean IOP of all 63 eyes was 14.1 mmHg before and 12.8 mmHg after treatment (8.8% reduction). Mean pupil diameter constricted from 3.9 to 3.6 mm (-7.4%). These findings show that donepezil, and, possibly, other selective AChE inhibitors, can potentially be used to treat glaucoma. They are also known to have neuroprotective effects in Alzheimer's, and, therefore, might have an additional therapeutic benefit.

Is the clustering of β-amyloid (Aβ) deposits in the frontal cortex of Alzheimer patients determined by blood vessels?

The clustering pattern of diffuse, primitive and classic β-amyloid (Aβ) deposits was studied in the upper laminae of the frontal cortex of 9 patients with sporadic Alzheimer's disease (AD). Aβ stained tissue was counterstained with collagen type IV antiserum to determine whether the clusters of Aβ deposits were related to blood vessels. In all patients, Aβ deposits and blood vessels were clustered, with in many patients, a regular periodicity of clusters along the cortex parallel to the pia. The classic Aβ deposit clusters coincided with those of the larger blood vessels in all patients and with clusters of smaller blood vessels in 4 patients. Diffuse deposit clusters were related to blood vessels in 3 patients. Primitive deposit clusters were either unrelated to or negatively correlated with the blood vessels in six patients. Hence, Aβ deposit subtypes differ in their relationship to blood vessels. The data suggest a direct and specific role for the larger blood vessels in the formation of amyloid cores in AD. © 1995.

Social capabilities in Alzheimer's patients

Patients with stage-I (very mild and mild) Alzheimer's disease were asked to participate in a Dictator Game, a type of game in which a subject has to decide how to allocate a certain amount of money between himself and another person. The game enables the experimenter to examine the influence of social norms and social preferences on the decision-making process. When the results of treatments involving Alzheimer's disease patients were compared with those of identical treatments involving patients with mild cognitive impairment or healthy control subjects, with similar ages and social backgrounds, no statistically significant difference was found. This finding suggests that stage-I Alzheimer's disease patients may be as capable of making decisions involving social norms and preferences as other individuals of their age. Whatever brain structures are affected by the disease, they do not appear to influence, at this early stage, the neural basis for cooperation-enhancing social interactions.

SET translocation is associated with increase in caspase cleaved amyloid precursor protein in CA1 of Alzheimer and Down syndrome patients.

Caspase cleaved amyloid precursor protein (APPcc) and SET are increased and mislocalized in the neuronal cytoplasm in Alzheimer Disease (AD) brains. Translocated SET to the cytoplasm can induce tau hyperphosphorylation. To elucidate the putative relationships between mislocalized APPcc and SET, we studied their level and distribution in the hippocampus of 5 controls, 3 Down syndrome and 10 Alzheimer patients. In Down syndrome and Alzheimer patients, APPcc and SET levels were increased in CA1 and the frequency of both localizations in the neuronal cytoplasm was high in CA1, and low in CA4. As the increase of APPcc is already present at early stages of AD, we overexpressed APPcc in CA1 and the dentate gyrus neurons of adult mice with a lentiviral construct. APPcc overexpression in CA1 and not in the dentate gyrus induced endogenous SET translocation and tau hyperphosphorylation. These data suggest that increase in APPcc in CA1 neurons could be an early event leading to the translocation of SET and the progression of AD through tau hyperphosphorylation.

Language disorders in dementia of the Alzheimer type

The language profile of a group of 18 Alzheimer patients is documented and their performance on a standard aphasia test battery compared to a group of institutionalized, nonneurologically impaired control subjects matched for age, sex, and educational level. The Alzheimer patients scored significantly lower than the controls in the areas of verbal expression, auditory comprehension, repetition, reading, and writing. Articulation abilities were the same in each group. A language deficit was evident in all Alzheimer patients. The language disorder exhibited resembled a transcortical sensory aphasia. Syntax and phonology remained relatively intact but semantic abilities were impaired. The results support the inclusion of a language deficit as a diagnostic criterion of Alzheimer's disease.

Social capabilities in Alzheimer’s patients

Patients with stage-I (very mild and mild) Alzheimer s disease were asked to participatein a Dictator Game, a type of game in which a subject has to decide how to allocate acertain amount of money between himself and another person. The game enables theexperimenter to examine the influence of social norms and social preferences on thedecision-making process. When the results of treatments involving Alzheimer s diseasepatients were compared with those of identical treatments involving patients with mildcognitive impairment or healthy control subjects, with similar ages and socialbackgrounds, no statistically significant difference was found. This finding suggests thatstage-I Alzheimer s disease patients may be as capable of making decisions involvingsocial norms and preferences as other individuals of their age. Whatever brain structuresare affected by the disease, they do not appear to influence, at this early stage, the neuralbasis for cooperation-enhancing social interactions.

Postsynaptic density protein PSD-95 expression in Alzheimer's disease and okadaic acid induced neuritic retraction.

In order to understand how plasticity is related to neurodegeneration, we studied synaptic proteins with quantitative immunohistochemistry in the entorhinal cortex from Alzheimer patients and age-matched controls. We observed a significant decrease in presynaptic synaptophysin and an increase in postsynaptic density protein PSD-95, positively correlated with beta amyloid and phosphorylated Tau proteins in Alzheimer cases. Furthermore, Alzheimer-like neuritic retraction was generated in okadaic acid (OA) treated SH-SY5Y neuroblastoma cells with no decrease in PSD-95 expression. However, in a SH-SY5Y clone with decreased expression of transcription regulator LMO4 (as observed in Alzheimer's disease) and increased neuritic length, PSD-95 expression was enhanced but did not change with OA treatment. Therefore, increased PSD-95 immunoreactivity in the entorhinal cortex might result from compensatory mechanisms, as in the SH-SY5Y clone, whereas increased Alzheimer-like Tau phosphorylation is not related to PSD-95 expression, as suggested by the OA-treated cell models.

Improving the Quality of EEG Data in Patients With Alzheimers Disease Using ICA

Does Independent Component Analysis (ICA) denature EEG signals? We applied ICA to two groups of subjects (mild Alzheimer patients and control subjects). The aim of this study was to examine whether or not the ICA method can reduce both group di®erences and within-subject variability. We found that ICA diminished Leave-One- Out root mean square error (RMSE) of validation (from 0.32 to 0.28), indicative of the reduction of group di®erence. More interestingly, ICA reduced the inter-subject variability within each group (¾ = 2:54 in the ± range before ICA, ¾ = 1:56 after, Bartlett p = 0.046 after Bonfer- roni correction). Additionally, we present a method to limit the impact of human error (' 13:8%, with 75.6% inter-cleaner agreement) during ICA cleaning, and reduce human bias. These ¯ndings suggests the novel usefulness of ICA in clinical EEG in Alzheimer's disease for reduction of subject variability.

MemoryCon : Una aplicació d'Android per a potenciar la memòria dels malalts d'Alzheimer

This Degree Project is the development of an application for mobile devices with Android operating system. It is based on a generic manual with exercises for Alzheimer patients. The aim of the manual -and therefore, of the video game- is simply to be helpful in stimulating cognitive abilities of patients, ie players.

Der Einfluss von Apolipoprotein E auf die zellulären Mechanismen der Alzheimer Erkrankung

Die massive Bildung und Ablagerung von aggregiertem Amyloid Beta-Peptid im Gehirn wird allgemein als zentrales Ereignis im Rahmen des Neurodegenerationsprozesses der Alzheimer Demenz betrachtet. Als einer der ursächlichen Risikofaktoren gilt das Vorliegen des ε4-Allels des Apolipoprotein E. Die Alzheimer´sche Krankheit ist dabei in sehr vielfältige Weise mit Apolipoprotein E verknüpft. ApoE begünstigt isoformenabhängig Aβ-Ablagerungen, ApoE-Fragmente kommen im Gehirn und der Cerebrospinalflüssigkeit von Alzheimer Patienten vor und ApoE ist darüber hinaus als Cholesterintransportprotein über den zellulären Cholesterinstoffwechsel mit der Amyloidbildung verknüpft. Mit Hilfe einer Doppeltransfektion von ApoE und ADAM10 in HEK-Zellen und durch Studien mit Inhibitoren der ADAM-Familie an HepG-2-Zellen wurde in vitro gezeigt, dass ApoE nicht durch α-Sekretasen der ADAM-Familie gespalten wird. Weiterhin konnte bewiesen werden, dass ApoE in Astrogliomazellen keinen Einfluss auf die APP-Prozessierung ausübt. Durch in vitro Modulation des Cholesteringehaltes an Astrogliomazellen mit MβCD und seine Cholesterin-Komplexverbindungen ist gezeigt worden, dass die ApoE-Sekretion durch abnehmenden Cholesteringehalt gesenkt wird. Indem Statine alleine oder in Kombination mit Isoprenylierungssubstraten eingesetzt wurden ist der Beweis erbracht worden, dass Statine in vitro die ApoE-Sekretionsinhibition alleine durch Hemmung der Cholesterinbiosynthese bewirken. Bestätigt wurde dies weiterhin durch Experimente mit Isoprenylierungsinhibitoren. Aus dem Wirkmechanismus von Statinen auf die ApoE-Sekretionssenkung leitet sich womöglich der für bestimmte Statine berichtete neuroprotektive Effekt bei Morbus Alzheimer in retrospektiven Humanstudien ab, der sich durch reine Cholesterinsenkung nicht erklären lässt. Im Zusammenhang mit der Cholesterinhomöostase und dem gesteigerten 24(S)-Hydroxycholesterinspiegel bei Morbus Alzheimer, haben die Ergebnisse gezeigt, dass 24(S)-Hydroxycholesterin [24(S)-OH-chol] zur ApoE-Sekretions- und Expressionssteigerung führt. In dieser Arbeit konnte erstmals der Nachweis erbracht werden, dass der stimulatorische Effekt von 24(S)-OH-Chol durch gleichzeitige Lovastatingabe reduziert werden kann. Dies stellt einen möglichen Ansatz im Kampf gegen die Alzheimer Demenz dar. Weiterführend müssen diese Ergebnisse noch in vivo beispielsweise durch Versuche an ApoE-transgenen Mäusen bestätigt werden. Darüber hinaus könnte nach einer Statintherapie der ApoE-Gehalt in humaner, cerebrospinaler Flüssigkeit ermittelt werden.

Neuroprotective strategy for Alzheimer disease: intranasal administration of a fatty neuropeptide.

Neurodegenerative diseases, in which neuronal cell disintegrate, bring about deteriorations in cognitive functions as is evidenced in millions of Alzheimer patients. A major neuropeptide, vasoactive intestinal peptide (VIP), has been shown to be neuroprotective and to play an important role in the acquisition of learning and memory. A potent lipophilic analogue to VIP now has been synthesized, [stearyl-norleucine17]VIP ([St-Nle17]VIP), that exhibited neuroprotection in model systems related to Alzheimer disease. The beta-amyloid peptide is a major component of the cerebral amyloid plaque in Alzheimer disease and has been shown to be neurotoxic. We have found a 70% loss in the number of neurons in rat cerebral cortical cultures treated with the beta-amyloid peptide (amino acids 25-35) in comparison to controls. This cell death was completely prevented by cotreatment with 0.1 pM [St-Nle17]VIP. Furthermore, characteristic deficiencies in Alzheimer disease result from death of cholinergic neurons. Rats treated with a cholinergic blocker (ethylcholine aziridium) have been used as a model for cholinergic deficits. St-Nle-VIP injected intracerebroventricularly or delivered intranasally prevented impairments in spatial learning and memory associated with cholinergic blockade. These studies suggest both an unusual therapeutic strategy for treatment of Alzheimer deficiencies and a means for noninvasive peptide administration to the brain.

Acurácia do teste de labirinto no rastreamento de déficits cognitivos em idosos

This study intended to evaluate the maze test accuracy in cognitive deficit screening in elderly with or without neuropsychological pathology. The sample included 40 healthy young (18-25 years old; mean- 21 ± 1.6), 40 healthy old (60-77 years old; mean- 67 ± 5.1) and 18 patients with probable diagnosis of Alzheimer s disease initial stage (52-90 years old; mean- 78 ± 9.2). Data analysis was made using Anova with Tukey s post hoc, multiple linear regression analysis and ROC curve analysis. According to Tukey s test Alzheimer patients spent more time (46843 ± 37926 ms) to execute the test than healthy young (5482 ± 2873 ms; p= 0.0001) and elderly (17978 ± 13700; p= 0.0001); healthy young executed test n lower time (p= 0.035). According to the regression analysis of age, education level and cognitive performance of the three groups, the cognitive performance was the predictor of the execution time. When analyzing young and elderly only age was the predictor and the cognitive performance was the only factor to influence the test of old aged healthy and patients. The ROC curve analysis indicated 72% accuracy for young and elderly and 36% for healthy and elderly patients. The maze execution time represented a better balance between sensibility (75%) and the specificity (61%) was near 13575 ms, indicating that those subjects that execute the maze in a time higher to this value may show cognitive deficit related to the executive function. According to the results it is suggested that the maze test used in this study shows a good accuracy in the cognitive deficit tracking and may discriminate age changes

Nutritional status of selenium in Alzheimer`s disease patients

Studies have shown that various antioxidants are decreased in different age-related degenerative diseases and thus, oxidative stress would have a central role in the pathogenesis of many disorders that involve neuronal degeneration, including Alzheimer`s disease (AD). The present study aimed to assess the nutritional status of Se in AD patients and to compare with control subjects with normal cognitive function. The case control study was carried out on a group of elderly with AD (n 28) and compared with a control group (n 29), both aged between 60 and 89 years. Se intake was evaluated by using a 3-d dietary food record. Se was evaluated in plasma, erythrocytes and nails by using the method of hydride generation atomic absorption spectroscopy. Deficient Se intake was largely observed in the AD group. AD patients showed significantly lower Se levels in plasma, erythrocytes and nails (32.59 mu g/l, 43.74 mu g/l and 0.302 mu g/g) when compared with the control group (50.99 mu g/l, 79.16 mu g/l and 0.400 mu g/g). The results allowed us to suggest that AD has an important relation with Se deficiency.