Developing a Brief Neuropsychological Battery for Early Diagnosis of Cognitive Impairment

ObjectivesEarly diagnosis of cognitive impairment is increasingly emphasized in the literature to facilitate timely preventive interventions. Although bedside cognitive tests such as the Montreal Cognitive Assessment (MoCA) are widely used for such early diagnostic purposes, they may not have comparable performance to a full neuropsychological battery (FNB) in diagnosing early cognitive impairment. This study investigated whether a small subset of neuropsychological tests can be added on to MoCA to match its performance to that of the FNB in discriminating mild cognitive impairment and dementia (MCI/dementia) from normal cognition.DesignCross-sectional diagnostic study.SettingAlzheimer's Disease Centers across the United States.ParticipantsOlder participants (≥50 years) who completed MoCA and the FNB (N = 9187).MeasuresThe study sample was split into two: the derivation sample (n = 1837) was used to develop a brief neuropsychological battery that best discriminated MCI/dementia (using the best-subset approach with 10-fold cross-validation); while the validation sample (n = 7350) verified its actual performance in discriminating MCI/dementia.ResultsA 3-item neuropsychological battery was identified, comprising MoCA, Benson Complex Figure Recall, and Craft Story 21 Delayed Recall. It had excellent performance in discriminating MCI/dementia from normal cognition (area under the receiver operating characteristic curve [AUROC] 90.0%, 95% confidence interval [CI] 89.2%-90.7%), which was comparable to that of the FNB (AUROC 88.4%, 95% CI 87.6%-89.2%). By contrast, MoCA alone had significantly worse AUROC (86.9%, 95% CI 86.0%-87.7%) than that of the FNB.Conclusions/ImplicationsUsing rigorous methods, this study developed a brief neuropsychological battery that maintained the brevity of a bedside cognitive test, while rivaling the diagnostic performance of an FNB in early cognitive impairment. This brief battery offers a viable alternative when the FNB is needed but cannot be feasibly administered in nonspecialty clinics. It can have a wider health systems effect of improving patients’ access to accurate diagnosis in early cognitive impairment and facilitating timely interventions to delay the progression of cognitive impairment.     

Ultrastructural characterization of the tau-immunoreactive tubules in the oligodendroglial perikarya and their inner loop processes in progressive supranuclear palsy

Coiled bodies and interfascicular threads are conspicuous white matter abnormalities of brains of patients with progressive supranuclear palsy (PSP). Both structures are argyrophilic and immunoreactive for the microtubule-binding protein tau. This report concerns the ultrastructural localization of interfascicular threads and their relationship to coiled bodies in five PSP patients. We showed for the first time that abnormal tubules with a 13- to 15-nm diameter and fuzzy outer contours were the common structures of coiled bodies in the oligodendroglial perikarya and of interfascicular threads. Moreover, the tubules were immunolabeled by anti-tau antibodies. The abnormal tau-positive tubules of interfascicular threads were located in the inner loop of the myelin sheath. Our study further indicated that the thread-like structures in the white matter comprised, at least in part, oligodendroglial processes, and that they were also present in gray matter. We consider that the formation of coiled bodies in the perikarya and of interfascicular threads represents a common cytoskeletal abnormality of the oligodendroglia of PSP patients. Moreover, even though the white matter alterations of PSP resemble those of corticobasal degeneration, there are certain ultrastructural differences in the abnormal oligodendroglial tubules of the two diseases. Received: 4 October 1996 / Accepted: 6 December 1996     

Extracellular or ghost Pick bodies and their lack of tau immunoreactivity: a histological,immunohistochemical and electron microscopic study

Histological, immunohistochemical, and electron microscopic evidence of an extracellular, or ghost Pick body has been found in the granular cell layer and, rarely, in the pyramidal cell layer of the hippocampus of an autopsy case of Pick's disease. The ghost Pick body appeared as a blurred, weak argyrophilic mass in the neuropil, and it was composed of accumulated fibrillary structures, 13 nm in diameter, intermingled with glial filament bundles. These ghost Pick bodies did not react with anti-tau and antiubiquitin antibodies, but did react weakly with antiglial fibrillary acidic protein antibody, whereas intracytoplasmic Pick bodies were strongly immunolabeled with anti-tau but only weakly with anti-ubiquitin anti-bodies. These results suggest that the Pick body is discharged into the neuropil after destruction of the mother neuron, loses its immunoreactivity to certain tau and ubiquitin antibodies during this process (thereby inducing a glial reaction) and remains in the neuropil as a ghost Pick body.     

Tau immunoreactivity and SDS solubility of two populations of paired helical filaments that differ in morphology

To further understand the processes that lead to the formation of neurofibrillary tangles from paired helical filaments (PHF) in Alzheimer brains, we studied two morphologically distinct fractions of PHF separated on sucrose density gradient. In a fraction with mostly short and non-aggregated PHF, the majority of filaments could be solubilized in SDS. In a fraction containing primarily PHF aggregated into clusters or bundles, sometimes resembling neurofibrillary tangles, filaments were less soluble in SDS. Immunogold labelling with a panel of tau-immunoreactive antibodies demonstrated that N-terminal epitopes of tau were preserved in the short filaments, but were reduced or absent in aggregated filaments. In contrast, C-terminal epitopes were present in both fractions. Furthermore, the accessibility of the microtubule-binding domain to immunolabelling was markedly impaired in short and non-aggregated filaments compared to aggregated filaments. These results are consistent with proteolytic degradation of the N-terminal epitopes and preservation of the C-terminal epitopes and the microtubule-binding domain of tau in the aggregated filaments. Partial proteolysis may be involved in the generation of aggregated PHF in neurofibrillary tangles.     

全凭静脉麻醉老龄大鼠海马tau蛋白磷酸化水平与认知功能的关系

目的 探讨咪唑安定、芬太尼、丙泊酚联用对老龄大鼠认知功能的影响以及这种影响是否与海马tau蛋白磷酸化水平有关.方法 雄性18月龄SD大鼠40只,随机分成全麻组和对照组,每组20只.每组分别于处理后第1和第7天各断头处死10只,HE染色光镜下观察海马神经元结构,免疫组化染色法检测海马tall蛋白Thr231和Ser404位点磷酸化蛋白的表达水平.其中后处死大鼠于处理后第1周行水迷宫实验.结果 处理后第1天,全麻组大鼠寻找平台的时间明显长于对照组(P＜0.01),但第2～7天与对照组比较差异无统计学意义.处理后第1天,全麻组海马tau蛋白Thr231位点的磷酸化水平高于对照组(P＜0.05).第7天,两组Thr231、Ser404位点的磷酸化水平差异无统计学意义.光镜下各组大鼠海马神经元结构未见明显异常.结论 咪唑安定、芬太尼、丙泊酚联用可引起老龄大鼠麻醉后第1天出现短暂的认知功能减退,海马tau蛋白Thr231位点的过度磷酸化可能与其有关.     

GSK-3 dependent phosphoepitopes recognized by PHF-1 and AT-8 antibodies are present in different tau isoforms

It is widely known that the tau protein that forms the aggregates found in tauopathies like Alzheimer’s disease (AD) is hyperphosphorylated. Many of the sites that are hyperphosphorylated in AD can also be found phosphorylated in non-pathological control brains, although to a lesser extend. Among the different kinases that are able to phosphorylate tau in these sites, GSK-3 has emerged as a key effector of AD pathogenesis in view of its interaction with many of the proteins involved in the ethiology of AD. In this work, we have tested if control samples show only a decrease in the amount of phosphorylated tau molecules, or if the phosphorylation at different sites occurs in different tau isoforms, whereas in the pathological situation a single tau isoform is modified simultaneously at the different sites. Our results indicate that the second possibility takes place and that the differences in the phosphorylation of different tau isoforms could be due to a different subcellular distribution of these different tau isoforms in a neuron.     

凝聚态Aβ 25～35可通过JNK/p38 MAPK途径诱导胎鼠皮层神经元Tau蛋白过度磷酸化

目的 探讨JNK/p38 MAPK在β淀粉样蛋白多肽片段25～35(Aβ25～35)诱导的阿尔茨海默病(AD)样胎鼠皮层神经元Tau蛋白过度磷酸化中的作用.方法 应用蛋白免疫印迹和免疫细胞化学染色的方法,观察Tau蛋白磷酸化和JNK/p38丝裂原活化的蛋白激酶(JNK/p38 MAPK)的表达情况.结果 凝聚态Aβ25～35(20μmol/L)作用于皮层神经元12h,Tau蛋白Ser396、Ser199/202、Thr205位点的磷酸化水平明显增高,同时JNK/p38 MAPK的总量及其活性形式-磷酸化JNK/p38 MAPK的蛋白表达水平也增加.结论 Aβ25～35可通过激活JNK/p38 MAPK使Tau蛋白的磷酸化水平增高.     

Age-related progression of tau pathology in brains of baboons

Recently, cytoskeletal changes associated with abnormally phosphorylated tau protein were demonstrated in neurons and glial cells of two aged baboons (Papio). The present study examines the effects of age on the development of tau pathology in baboons. Brains of 50 baboons ranging in age from 1 to 30 years were categorized into four age groups: Group I: 1–10 years [n = 9], group II: 11–20 years [n = 13], group III: 21–25 years [n = 17], group IV: 26–30 years [n = 11]). Whole hemisphere sections (100 μm) were examined using phosphorylation-dependent anti-tau antibodies. Cytoskeletal changes were completely absent in animals of group I. In group II four animals (31%) exhibited cytoskeletal changes which were rated as mild or moderate. In group III abnormal tau was found in 12 brains (71%) ranging in severity from mild to severe. Finally, in group IV 10 out of 11 animals (91%) exhibited some degree of tau pathology which was rated as severe in 4 animals (36%). A statistically significant relationship was found between advancing age and progression of tau pathology in baboons. In conclusion, the present findings underline the value of the baboon as a potential nonhuman primate model for age-related tau pathology afflicting the human brain.     

Cholinesterases colocalize with sites of neurofibrillary degeneration in aged and Alzheimer's brains

Acetylcholinesterase and butyrylcholinesterase have been associated with structures undergoing neurofibrillary degeneration, as well as with all types of senile plaques, in non-demented aged and Alzheimer's brains. At the electron microscope level, the reaction product of both enzymes, appeared to decorate paired helical filaments, straight filaments and A4 amyloid fibrils. Recent studies showed that cholinesterases were associated with amyloid at early stages, e.g., in diffuse plaques. In the present study, the interrelationship of cholinesterases to structures undergoing neurofibrillary degeneration was analyzed further. Tau immunoreactivity was compared to the staining pattern observed with the two esterases. Double protocols consecutively performed on the same sections, and counterstaining with thioflavin-S, confirmed the presence of cholinesterases in all structures with neurofibrillary degeneration. The conclusion that cholinesterases consistently colocalize with both neurofibrillary bundles and A4 amyloid fibrils at all stages of their accumulation, allows us to speculate on the possible role that these enzymes may play in either the formation or the consolidation of fibrillary aggregates.Supported by Fondo de Investigaciones Sanitarias de la Seguridad Social No. 93/0198, Spain     

Monitoring pathological assembly of tau and β-amyloid proteins in Alzheimer's disease

This double-labelling confocal microscopy study of the neuropathology of Alzheimer's disease (AD) reports the use of a fluorescent dye, thiazin red, which has staining properties similar to thioflavin-S. Thiazin red fluorescence can be visualised selectively in the red channel, and we have used this property to compare it with the labelling seen using monoclonal antibody (mAb) 423, which detects tau protein C-terminally truncated at Glu-391, and mAb 4G8, which detects -amyloid protein. Thiazin red is shown to recognized the typical histopathological deposits associated with both proteins. However, not all deposits containing these proteins are stained. Specifically, diffuse -amyloid plaques and severely degraded extracellular tangles are unlabelled. Likewise a characteristic mAb 423-reactive granular plaque-like structure, typically present in cases with abundant extracellular tangels, is unlabelled by thiazin red. Such plaques can be shown to be continuous with the basal dendrites of degraded tanglebearing pyramidal cells. These findings suggest that paired helical filaments (PHFs) continue to undergo degradation in the extracellular space, which is associated with loss of thiazin red binding sites, but preservation of mAb 423 immunoreactivity. This epitope appears to be characteristic of a stable core element of the PHF which is highly resistant to proteolysis. Compounds such as thiazin red with high affinity for -pleated protein structures can be used to monitor the state of pathological assembly of amyloidogenic protein species found in AD.Supported in part by CONACyT grant #1624-N9208 (to R.M.), the Medical Research Council (U.K.), Zeneca Pharmaceuticals and the Alzheimer Disease Research Fund and the Leopold Muller Estate