Tau PET imaging predicts cognition in atypical variants of Alzheimer's disease

Accumulation of paired helical filament tau contributes to neurodegeneration in Alzheimer's disease (AD). ¹⁸F‐flortaucipir is a positron emission tomography (PET) radioligand sensitive to tau in AD, but its clinical utility will depend in part on its ability to predict cognitive symptoms in diverse dementia phenotypes associated with selective, regional uptake. We examined associations between ¹⁸F‐flortaucipir and cognition in 14 mildly‐impaired patients (12 with cerebrospinal fluid analytes consistent with AD pathology) who had amnestic (n = 5) and non‐amnestic AD syndromes, including posterior cortical atrophy (PCA, n = 5) and logopenic‐variant primary progressive aphasia (lvPPA, n = 4). Amnestic AD patients had deficits in memory; lvPPA in language; and both amnestic AD and PCA patients in visuospatial function. Associations with cognition were tested using sparse regression and compared to associations in anatomical regions‐of‐interest (ROIs). ¹⁸F‐flortaucipir uptake was expected to show regionally‐specific correlations with each domain. In multivariate analyses, uptake was elevated in neocortical areas specifically associated with amnestic and non‐amnestic syndromes. Uptake in left anterior superior temporal gyrus accounted for 67% of the variance in language performance. Uptake in right lingual gyrus predicted 85% of the variance in visuospatial performance. Memory was predicted by uptake in right fusiform gyrus and cuneus as well as a cluster comprising right anterior hippocampus and amygdala; this eigenvector explained 57% of the variance in patients' scores. These results provide converging evidence for associations between ¹⁸F‐flortaucipir uptake, tau pathology, and patients' cognitive symptoms.     

Mildronate improves cognition and reduces amyloid‐β pathology in transgenic Alzheimer's disease mice

Mildronate, a carnitine congener drug, previously has been shown to provide neuroprotection in an azidothymidine‐induced mouse model of neurotoxicity and in a Parkinson's disease rat model. The aim of this study was to investigate the effects of mildronate treatment on cognition and pathology in Alzheimer's disease (AD) model mice (APP_SweDI). Mildronate was administered i.p. daily at 50 or 100 mg/kg for 28 days. At the end of treatment, the animals were behaviorally and cognitively tested, and brains were assessed for AD‐related pathology, inflammation, synaptic markers, and acetylcholinesterase (AChE). The data show that mildronate treatment significantly improved animal performance in water maze and social recognition tests, lowered amyloid‐β deposition in the hippocampus, increased expression of the microglia marker Iba‐1, and decreased AChE staining, although it did not alter expression of proteins involved in synaptic plasticity (GAP‐43, synaptophysin, and GAD67). Taken together, these findings indicate mildronate's ability to improve cognition and reduce amyloid‐β pathology in a mouse model of AD and its possible therapeutic utility as a disease‐modifying drug in AD patients. © 2013 Wiley Periodicals, Inc.     

Quetiapine improves psychotic symptoms and cognition in Parkinson's disease.

Twenty-nine elderly patients who failed treatment with clozapine, risperidone, or olanzapine entered this 24-week, single-center, open-label trial to assess the efficacy of quetiapine (12.5-400 mg/day) for psychosis in patients with Parkinson's disease (PD). Psychiatric, motor, and cognitive assessments were administered at baseline and at periodic intervals for 24 weeks. These included the Brief Psychiatric Rating Scale (BPRS), Neuropsychiatric Inventory (NPI), Unified Parkinson's Disease Rating Scale (UPDRS) and tests of intellectual functioning, attention, and memory. Repeated measures statistical analysis was used to assess change from baseline. The results revealed significant improvements in the 24-week BPRS total score and NPI psychosis subscale scores, with no decline in UPDRS total or motor subscale scores. There was also significant improvement in recall scores on cognitive measures. These results indicate that quetiapine may treat psychotic symptoms and improve cognition without worsening motor function in patients with PD, suggesting that quetiapine is an effective and well-tolerated antipsychotic in this population.     

Functional imaging of cognition in Alzheimer's disease using positron emission tomography

Positron emission tomography in Alzheimer's disease (AD) demonstrates a metabolic decrease, predominantly in associative posterior cortices (comprising the posterior cingulate cortex), and also involving medial temporal structures and frontal regions at a lesser degree. The level of activity in this wide network is roughly correlated with dementia severity, but several confounds (such as age, education or subcortical ischemic lesions) may influence the brain-behaviour relationship. Univariate analyses allow one to segregate brain regions that are particularly closely related to specific neuropsychological performances. For example, a relationship was established between the activity in lateral associative cortices and semantic performance in AD. The role of semantic capacities (subserved by temporal or parietal regions) in episodic memory tasks was also emphasized. The residual activity in medial temporal structures was related to episodic memory abilities, as measured by free recall performance, cued recall ability and recognition accuracy. More generally, AD patients' performance on episodic memory tasks was correlated with the metabolism in several structures of Papez's circuit (including the medial temporal and posterior cingulate regions). Multivariate analyses should provide complementary information on impaired metabolic covariance in functional networks of brain regions and the consequences for AD patients' cognitive performance. More longitudinal studies are being conducted that should tell us more about the prognostic value of initial metabolic impairment and the neural correlates of progressive deterioration of cognitive performance in AD.     

Testosterone and cognition in normal aging and Alzheimer's disease: an update

There is evidence to suggest that testosterone loss constitutes a risk for cognitive decline and possibly dementia, and that elderly men might benefit from exogenous supplementation of testosterone. Studies in non-human animals repeatedly report neuroexcitatory and neuroprotective properties of testosterone and enhanced memory performance after acute or chronic treatment. Positive effects of testosterone supplementation in older men have been reported in several, but not all, studies and require replication in larger randomized clinical trials before recommendations for clinical practice can be made. The current review summarizes recent studies on the neurobiological connection between testosterone and cognitive function in humans and non-human animals. When appropriate, we use the hippocampus as a model structure given it's involvement in sexually dymorphic spatial ability and sensitivity to both androgens and aging. In addition, a number of potential explanations of the discrepancy between data obtained in humans and non-human animals are discussed.     

Social cognition in Alzheimer's disease: A separate construct contributing to dependence

The extent to which social cognitive changes reflect a discrete constellation of symptoms dissociable from general cognitive changes in Alzheimer's disease (AD) is unclear. Moreover, whether social cognitive symptoms contribute to disease severity and progression is unknown. The current multicenter study investigated cross-sectional and longitudinal associations between social cognition measured with six items from the Blessed Dementia Rating Scale, general cognition, and dependence in 517 participants with probable AD. Participants were monitored every 6 months for 5.5 years. Results from multivariate latent growth curve models adjusted for sex, age, education, depression, and recruitment site revealed that social cognition and general cognition were unrelated cross-sectionally and throughout time. However, baseline levels of each were related independently to dependence, and change values of each were related independently to change in dependence. These findings highlight the separability of social and general cognition in AD. Results underscore the relevance of considering social cognition when modeling disease and estimating clinical outcomes related to patient disability.     

褪黑素对Alzheimer病模型大鼠认知功能和海马tau蛋白过度磷酸化的影响

目的 研究褪黑素(MT)对Alzheimer病(AD)模型大鼠认知功能和海马tau蛋白过度磷酸化的影响.方法 给大鼠海马内注射凝聚态β-淀粉样蛋白(Aβ)25-35制作AD模型;MT组大鼠从制模前7 d至制模后19 d每日腹腔注射MT,AD组大鼠制模后腹腔注射生理盐水;用Morris水迷宫试验检测大鼠的认知功能,银染法观察海马神经元形态,免疫组化法观察过度磷酸化tau蛋白的表达,并与正常对照组比较.结果 MT组大鼠Morris水迷宫试验结果明显好于AD组(均P＜0.001);海马CA1区磷酸化tau蛋白阳性细胞数(60.0±2.3)明显少于AD组(98.4±3.0)(P＜0.001),与正常对照组比较差异无统计学意义;海马CA1区神经元纤维形态较AD组规则.结论 MT可明显改善AD大鼠的认知功能,并且抑制海马tau蛋白的过度磷酸化.     

Vision and cognition in Alzheimer's disease

Alzheimer's disease (AD) is known to affect visual pathways, but potential concomitant effects on vision and cognitive performance are not well understood. We studied 43 individuals with AD of mild severity and 22 individuals without dementia on a battery of tests designed to measure multiple aspects of basic and higher-order visual perception and cognition. All subjects performed on the same visual and cognitive test batteries. The results showed no differences between groups on tests of static visual acuity, stereoacuity, dynamic visual acuity or motion direction discrimination. However, individuals with AD performed significantly worse on tests of static spatial contrast sensitivity, visual attention, shape-from-motion, color, visuospatial construction and visual memory. Correlation analyses showed strong relationships between visual and cognitive scores. The findings show that AD affects several aspects of vision and are compatible with the hypothesis that visual dysfunction in AD may contribute to performance decrements in other cognitive domains. The pattern of involvement indicates that AD affects multiple visual neural pathways and regions. It is possible that better understanding of vision-related dysfunction could aid diagnosis and interventions to improve functional capacity in patients with dementia.     

Laminar distribution of neuritic plaques in normal aging,Alzheimer's disease and Down's syndrome

Summary Quantitative studies of neuritic (senile) plaques in six cortical layers were carried out in brains from people with confirmed clinical and neuropathological diagnosis of senile dementia of the Alzheimer type (SDAT) and Down's syndrome (DS). The same studies were performed on brains of normal old-aged people. In Alzheimer disease (AD) and DS cases the highest numbers of neuritic plaques (NP) were observed in temporal lobe layers III and II and occipital lobe layers III, IV and II. In normal old-aged people the highest numbers of NP were found in temporal lobe III and V and in occipital lobe IV, III, and V layer. The plaque numbers in both temporal and occipital cortices of AD and DS were significantly higher than that of normal old-aged people but there was no difference between AD and DS.Supported in part by Grant Nos. AGO-4220 and HD22634 from the National Institutes of Health     

The characterisation and impact of 'fluctuating' cognition in dementia with Lewy bodies and Alzheimer's disease

BACKGROUND: Case reports and clinical observations suggest that fluctuating cognition (FC) is common in all the major dementias, particularly dementia with Lewy bodies (DLB) where it is one of three core clinical diagnostic features. The purpose of this study was to characterise FC and determine its impact upon activities of daily living. METHODS: Forty matched subjects (15 DLB, 15 AD, 10 elderly controls) were assessed using the activities of daily living scale (ADLD), the cognitive drug research (CDR) computerised neuropsychological test battery and a semi-standardised assessment of FC. The CDR battery was completed three times across a 1-week period, to evaluate variability in attention, visuospatial ability, working memory and delayed recall. RESULTS: There was a strong positive correlation between clinical FC scores and total mean ADLD. Measures of cognitive variability also demonstrated strong significant correlations with independent clinical severity ratings of FC across several cognitive domains. These associations were most powerful between attentional measures and clinical FC ratings. CONCLUSIONS: Although attention is the cognitive domain which fluctuates most markedly, other cognitive domains are also affected. FC also has a significant independent impact on activities of daily living.     

Physical exercise alleviates debilities of normal aging and Alzheimer's disease

Both healthy aging and the pathologic incidence of disorders associated with aging involve an array of debilities. Physical exercise harnesses implicit and inherent biologic characteristics amenable to the putative interventional influences under clinical, institutional or laboratory conditions. The neurodegenerative and pathophysiologic progressions that constitute Alzheimer's disease (AD), amnestic mild cognitive impairment (aMCI), normal aging, and different animal models of AD have shown the existence of several putative mechanisms. A large variety of moderating factors have demonstrated that the ever-proliferating plethora of neurotrophic factors, neurogenesis as observed through generality of expression and neuronal arborization. The insistent efficacy of brain vascular angiogenesis may delay also the comorbid incidence of depressive disorders with dementia pathology. The pathogenesis of aging may be contained by selective treatments: these diverse conditions, linked to the basis of the aging concept, have been shown, to greater or lesser extents, to respond to a variety of scheduled applications of physical exercise. The range of reports that provide accounts of the mechanisms mediating the positive progressive response to exercise intervention is far-ranging; these studies indicate that subtle changes at molecular, neuronal, vascular and epigenetic levels may exert notable consequence at functional expression and, perhaps most essentially, offer convincing expectancy of significant benefits.     

Associations between physical function,dual-task performance and cognition in patients with mild Alzheimer's disease

Objective: Alzheimer's disease (AD) causes a gradual decline in cognition, limitations of dual-tasking and physical function leading to total dependence. Hence, information about the interaction between physical function, dual-task performance and cognition may lead to new treatment strategies with the purpose of preserving function and quality of life.

The objective of this study was to investigate the associations between physical function, dual-task performance and cognition in community-dwelling patients with mild AD.

Methods: Baseline results from 185 participants (50–90 years old) in the single blinded multicenter RCT ‘ADEX’ (Alzheimer's disease: the effect of physical exercise) were used.

Assessments included tests of physical function: 400-m walk test, 10-m walk test, Timed Up and Go test and 30-s chair stand test; dual-task performance, i.e., 10-m walk while counting backwards from 50 or naming the months backwards; and cognition, i.e., Mini Mental State Examination, Symbol Digit Modalities Test, the Stroop Color and Word Test, and Lexical verbal fluency test.

Results: Results in the 30-s chair stand test correlated significantly with all tests of cognition (r = .208–.242) while the other physical function tests only randomly correlated with tests of cognition. Results in the dual-task counting backwards correlated significantly with results in all tests of cognition (r = .259–.388), which accounted for 7%–15% of the variation indicating that a faster time to complete dual-task performance was associated with better cognitive performance.

Conclusion: The evidence of the associations between physical function, dual-task performance and cognition is important when creating new rehabilitation interventions to patients with mild AD.     

Postprandial hypotension in Alzheimer's disease

The degree of postprandial hypotension in patients with Alzheimer's disease (AD) is not known. We therefore studied ten AD patients and 23 controls before and after a meal. Seven AD patients but only six controls showed a fall in blood pressure (BP) of 20 mmHg or more. Maximum BP fall in AD patients was observed between 20 and 120 min after food ingestion. This differed from the time course in other groups with primary chronic autonomic failure. Postural hypotension occurred in two controls, but not in AD patients. Abnormalities in cardiac vasomotor regulation, gut peptide liberation or both could be responsible for postprandial hypotension in AD.     

Independent deficits of visual word and motion processing in aging and early Alzheimer's disease

We tested whether visual processing impairments in aging and Alzheimer's disease (AD) reflect uniform posterior cortical decline, or independent disorders of visual processing for reading and navigation. Young and older normal controls were compared to early AD patients using psychophysical measures of visual word and motion processing. We find elevated perceptual thresholds for letters and word discrimination from young normal controls, to older normal controls, to early AD patients. Across subject groups, visual motion processing showed a similar pattern of increasing thresholds, with the greatest impact on radial pattern motion perception. Combined analyses show that letter, word, and motion processing impairments are independent of each other. Aging and AD may be accompanied by independent impairments of visual processing for reading and navigation. This suggests separate underlying disorders and highlights the need for comprehensive evaluations to detect early deficits.     

Association between neuropsychiatric and autonomic dysfunction in Alzheimer's disease

We sought to determine whether there was an association between specific neuropsychiatric deficits and autonomic dysfunction in patients with Alzheimer's disease (AD). We studied 20 patients and 20 age-matched control subjects with neuropsychiatric tests (Blessed, Cornell depression and NPI scores) and autonomic tests (Deep breath (HRdb), 30:15 ratio and orthostatic hypotension (Bpoh)). The 30:15 ratio was consistently reduced in AD patients as compared to control subjects (1.05 ± 0.07 for patients and 1.18 ± 0.1 for controls, p 0.001). Whereas there were no significant differences in the HRdb and presence of Bpoh. In AD patients with an abnormal 30:15 ratio, there were significant abnormalities in the Blessed score and in the apathy, delusions and aberrant motor behavior items of the NPI. The other autonomic tests did not correlate with any neuropsychiatric score. The relationship between abnormal cortical function and impaired 30:15 ratio suggested that a lack of cortical modulation of autonomic circuits may underlie cardiovascular instability in these patients. Received: 24 January 2001, Accepted: 10 December 2001