Lack of accuracy for the proposed 'Dubois criteria' in Alzheimer's disease: a validation study from the Swedish brain power initiative.

BACKGROUND/AIMS: Our purpose was to investigate whether the new research criteria for Alzheimer's disease proposed in 2007 by Dubois et al. are valid in a naturalistic memory clinic sample. METHOD: Retrospective diagnostic analyses were carried out to compare the traditional diagnostic criteria for dementia with the new criteria suggested by Dubois et al. No patient had gone through all procedures postulated as additional features in the proposed new Dubois criteria. MATERIAL: Two independent experienced geriatricians re-examined 150 complete patients' records. The study physicians were blinded to any of the results of the core and additional features suggested by Dubois et al. to avoid circular diagnostic bias. RESULTS: Among our 96 patients with a clinical diagnosis of subjective cognitive impairment and/or mild cognitive impairment, 2 of the patients with subjective cognitive impairment and 5 patients with mild cognitive impairment would classify as pre-dementia Alzheimer's disease according to the Dubois criteria. In our 23 Alzheimer patients diagnosed clinically, only 12 of the cases fulfilled the criteria for Alzheimer's disease suggested by Dubois et al. INTERPRETATION: The proposed new criteria for Alzheimer's disease are valid in 55% of our patients clinically diagnosed as having full-blown Alzheimer dementia. Additionally, 7.3% 'true' Alzheimer cases will be identified in a group of 96 clinically non-demented patients. Our results show that there is a large heterogeneity in a clinical naturalistic sample of patients with an Alzheimer phenotype. CONCLUSION: There is a need to further validate the currently existing biomarkers in large unselected samples and avoid the pitfall of workup bias and circular diagnostic processes. Additionally, valid age-specific cut-off values for the diagnostic markers in question have to be defined.

Alterations in alpha-adrenoceptors in aging intraocular hippocampal grafts.

Age-related changes of hippocampal alpha 1- and alpha 2-adrenoceptors were investigated using intraocular hippocampal transplants combined with 3H-prazocin and 3H-para-aminoclonidine (3H-PAC) autoradiography. Young hippocampal grafts in young hosts and old grafts in old hosts innervated by noradrenergic sympathetic fibers were studied. In addition, young and old hippocampal grafts were examined following noradrenergic denervation by superior cervical ganglion removal. The 3H-PAC binding was significantly reduced in aged grafts as compared to young grafts whereas the 3H-prazocin binding did not change with age. After sympathetic denervation, both 3H-PAC and 3H-prazocin binding increased significantly in young grafts. In aged adrenergically denervated grafts, alpha 2-receptor binding was again significantly reduced whereas alpha 1-receptor binding was not significantly different from that in young denervated grafts. Taken together, these results indicate a selective age-related reduction in hippocampal postsynaptic alpha 2-receptors which is intrinsically determined.

Role of growth factors in degeneration and regeneration in the central nervous system; clinical experiences with NGF in Parkinson's and Alzheimer's diseases.

Neurotrophin-mediated mechanisms are integral to development and maintenance of the adult central nervous system. Neurotrophin expression has been shown to change rapidly in response to many different types of neuronal stress such as excitotoxic injury, mechanical lesions, epileptogenesis and ischemia. It therefore appears as if they are not only to be regarded as target-derived trophic factors in the classical sense, but also as providers of local trophic support and neuronal protection. These discoveries suggest that neurotrophins or compounds with neurotrophin-like actions might become useful in developing new treatment strategies, not only for neurodegenerative diseases, but also for other diseases and injuries to the nervous system including stroke.

Intracerebroventricular infusion of nerve growth factor induces pain-like response in rats.

New strategies have recently been developed where infusion of neurotrophic factors into the brain can rescue different neuronal populations. However, negative side effects have been observed in clinical trials infusing nerve growth factor (NGF) into the lateral ventricle in man, namely pain. Little is known about pain behavior in animals after intracerebroventricular (i.c.v.) neurotrophic injections. Thus, we have examined the effects of i.c.v. infusion of NGF for 2 weeks on the behavioral response of rats to mechanical, cold and heat stimulation. Seven micrograms/day of NGF elicited a significant decrease in vocalization threshold to mechanical stimulation and a significantly increased response to cold and heat stimuli as compared with control. The concentration of NGF in cerebrospinal fluid (CSF) was significantly increased as compared with non-allodynic rats. The enhanced responses to mechanical and heat, but not to cold, stimulation were significantly reduced by CP-99994, a selective antagonist to tachykinin NK-1 receptors. When NGF was infused into the brain parenchyma (striatum, cortex and septum) no allodynic nor hyperalgesic responses could be detected. These results indicate that in rats i.c.v. but not intraparenchymal infusion of NGF induce mechanical and cold allodynia as well as heat hyperalgesia, which is mediated, at least in part, by activation of NK-1 receptors.

Progression of Alzheimer disease in Europe: data from the European ICTUS study.

The clinical progression of Alzheimer disease (AD) was studied in European subjects under treatment with AChE inhibitors (AChE-I) in relation to geographical location over a 2-years period. One thousand three hundred and six subjects from 11 European countries were clustered into 3 regions (North, South, West) and investigated with biannual follow-up over 2 years. Primary outcomes were cognitive, functional and behavioral measures. Caregiver burden, hospital admission and admission to nursing home were also recorded. Participant cognitive function declined non-linearly over time (MMSE: -1.5 pts/first year, -2.5 pts/second year; ADAScog: + 3.5 pts/first year, + 4.8 pts/second year), while the progression of behavioral disturbances (NPI scale) was linear. Neither scale showed regional differences, and progression of the disease was similar across Europe despite different health care systems. Functional decline (ADL, IADL) tended to progress more rapidly in Southern Europe (p=0.09), while progression of caregiver burden (Zarit Burden Interview) was most rapid in Northern Europe (5.6 pts/y, p=0.04). Incidences of hospital admission (10.44, 95%CI: 8.13-12.75, p < 0.001) and admission to nursing home (2.97, 95%CI: 1.83-4.11, p < 0.001) were lowest in Southern Europe. In general cognitive and functional decline was slower than in former cohorts. European geographical location reflecting differences in culture and in health care system does not impact on the progression of AD but does influence the management of AD subjects and caregiver burden.

Age and diagnostic performance of Alzheimer disease CSF biomarkers.

OBJECTIVES: Core CSF changes in Alzheimer disease (AD) are decreased amyloid ß(1-42), increased total tau, and increased phospho-tau, probably indicating amyloid plaque accumulation, axonal degeneration, and tangle pathology, respectively. These biomarkers identify AD already at the predementia stage, but their diagnostic performance might be affected by age-dependent increase of AD-type brain pathology in cognitively unaffected elderly. METHODS: We investigated effects of age on the diagnostic performance of CSF biomarkers in a uniquely large multicenter study population, including a cross-sectional cohort of 529 patients with AD dementia (median age 71, range 43-89 years) and 304 controls (67, 44-91 years), and a longitudinal cohort of 750 subjects without dementia with mild cognitive impairment (69, 43-89 years) followed for at least 2 years, or until dementia diagnosis. RESULTS: The specificities for subjects without AD and the areas under the receiver operating characteristics curves decreased with age. However, the positive predictive value for a combination of biomarkers remained stable, while the negative predictive value decreased only slightly in old subjects, as an effect of the high AD prevalence in older ages. CONCLUSION: Although the diagnostic accuracies for AD decreased with age, the predictive values for a combination of biomarkers remained essentially stable. The findings highlight biomarker variability across ages, but support the use of CSF biomarkers for AD even in older populations.

Postoperative delirium in elderly patients after major abdominal surgery.

BACKGROUND: The aim of this study was to investigate the occurrence of postoperative delirium (POD) in elderly patients undergoing major abdominal surgery and to identify factors associated with delirium in this population. METHODS: Data were collected prospectively from 51 patients aged 65 years or more. Delirium was diagnosed by the Confusion Assessment Method and from the medical records. The Mini Mental State Examination (MMSE) was used to identify cognitive impairment. RESULTS: POD occurred in 26 of 51 patients. Delirium lasted for 1-2 days in 14 patients (short POD group) and 3 days or more in 12 patients (long POD group). The latter patients had significantly greater intraoperative blood loss and intravenous fluid infusion, a higher rate of postoperative complications, a lower MMSE score on postoperative day 4 and a longer hospital stay than patients without POD. Patients in the short POD group were significantly older than those in the long POD group and those who did not develop delirium. CONCLUSION: Approximately half of the elderly patients in this study developed POD. Bleeding was found to be an important risk factor for delirium.

Intracerebroventricular infusion of nerve growth factor in three patients with Alzheimer's disease.

Nerve growth factor (NGF) is important for the survival and maintenance of central cholinergic neurons, a signalling system impaired in Alzheimer's disease. We have treated 3 patients with Alzheimer's disease with a total of 6.6 mg NGF administered continuously into the lateral cerebral ventricle for 3 months in the first 2 patients and a total of 0.55 mg for 3 shorter periods in the third patient. The patients were extensively evaluated with clinical, neuropsychological, neurophysiological and neuroradiological techniques. Three months after the NGF treatment ended, a significant increase in nicotine binding was found in several brain areas in the first 2 patients and in the hippocampus in the third patient as studied by positron emission tomography. A clear cognitive amelioration could not be demonstrated, although a few neuropsychology tests showed slight improvements. The amount of slow-wave cortical activity as studied by electroencephalography was reduced in the first 2 patients. Two negative side effects occurred with NGF treatment: first, a dull, constant back pain was observed in all 3 patients, which in 1 patient was aggravated by axial loading resulting in sharp, shooting pain of short duration. When stopping the NGF infusion, the pain disappeared within a couple of days. Reducing the dose of NGF lessened the pain. Secondly, a marked weight reduction during the infusion with a clear weight gain after ending the infusion was seen in the first 2 patients. We conclude from this limited trial that, while long-term intracerebroventricular NGF administration may cause certain potentially beneficial effects, the intraventricular route of administration is also associated with negative side effects that appear to outweigh the positive effects of the present protocol. Alternative routes of administration, and/or lower doses of NGF, perhaps combined with low doses of other neurotrophic factors, may shift this balance in favor of positive effects.