Cognitive frailty: rational and definition from an (I.A.N.A./I.A.G.G.) international consensus group.

The frailty syndrome has recently attracted attention of the scientific community and public health organizations as precursor and contributor of age-related conditions (particularly disability) in older persons. In parallel, dementia and cognitive disorders also represent major healthcare and social priorities. Although physical frailty and cognitive impairment have shown to be related in epidemiological studies, their pathophysiological mechanisms have been usually studied separately. An International Consensus Group on "Cognitive Frailty" was organized by the International Academy on Nutrition and Aging (I.A.N.A) and the International Association of Gerontology and Geriatrics (I.A.G.G) on April 16th, 2013 in Toulouse (France). The present report describes the results of the Consensus Group and provides the first definition of a "Cognitive Frailty" condition in older adults. Specific aim of this approach was to facilitate the design of future personalized preventive interventions in older persons. Finally, the Group discussed the use of multidomain interventions focused on the physical, nutritional, cognitive and psychological domains for improving the well-being and quality of life in the elderly. The consensus panel proposed the identification of the so-called "cognitive frailty" as an heterogeneous clinical manifestation characterized by the simultaneous presence of both physical frailty and cognitive impairment. In particular, the key factors defining such a condition include: 1) presence of physical frailty and cognitive impairment (CDR=0.5); and 2) exclusion of concurrent AD dementia or other dementias. Under different circumstances, cognitive frailty may represent a precursor of neurodegenerative processes. A potential for reversibility may also characterize this entity. A psychological component of the condition is evident and concurs at increasing the vulnerability of the individual to stressors.

The primary care physician and Alzheimer's disease: an international position paper.

This paper aims to define the role of the primary care physician (PCP) in the management of Alzheimer's disease (AD) and to propose a model for a work plan. The proposals in this position paper stem from a collaborative work of experts involved in the care of AD patients. It combines evidence from a literature review and expert's opinions who met in Paris, France, on July 2009 during the International Association of Geriatrics and Gerontology (IAGG) World Congress. The PCP's intervention appears essential at many levels: detection of the onset of dementia, diagnostic management, treatment and follow-up. The key role of the PCP in the management of AD, as care providers and care planners, is consolidated by the family caregiver's confidence in their skills. In primary care practice the first step is to identify dementia. The group proposes a "case finding" strategy, in target situations in which dementia should be detected to allow, secondarily, a diagnosis of AD, in certain cases. We propose that the PCP identifies 'typical' cases. In typical cases, among older subjects, the diagnosis of "probable AD" can be done by the PCP and then confirm by the specialist. While under-diagnosis of AD exists, so does under-disclosure. Disclosure to patient and family should be done by both specialist and PCP. Then, the PCP has a central role in management of the disease with the general objectives to detect, prevent and treat, when possible, the complications of the disease (falls, malnutrition, behavioural and psychological symptoms of dementia). The PCP needs to give basic information to the caregiver on respite care and home support services in order to prevent crisis situations such as unplanned institutionalisation and "emergency" hospital admission. Finally, therapeutic research must be integrated in the daily practice of PCP. It is a matter of patients' right to benefit from access to innovation and clinical research whatever his age or diseases, while of course fully respecting the rules and protective measures that are in force.

Follow-up for Alzheimer patients: European Alzheimer Disease Consortium position paper.

BACKGROUND AND PURPOSE: Alzheimer disease (AD) is one of the leading causes of dependence in the elderly. Providing care for patients with AD is complex and the type of care required depends on the stage of the disease and varies over time. The aim of this article is to discuss available care strategies once the AD diagnosis has been made and to propose a follow-up plan as standard of care at a European level. METHODS: The proposals developed in this article stem from the collaborative work of a panel of multidisciplinary experts involved in the care of AD patients (European Alzheimer Disease Consortium) based on the results of published scientific studies and on their experience from clinical practice. CONCLUSION: Suggestions for follow-up frequency and easily administered and scored assessment tools are provided, thereby increasing efficiency and quality of care for patients with Alzheimer disease.

Cortical function in elderly non-insulin dependent diabetic patients. Behavioral and electrophysiologic studies.

Neurobehavioral and electrophysiologic studies were carried out to determine the effect of diabetes mellitus on cognitive function in subjects over the age of 60 years. Forty-three non-insulin-dependent diabetic men were compared with 41 male nondiabetic age-matched controls. The diabetic patients were significantly inferior to the control group in the serial learning task and Benton's Visual Retention Test. The digit span test showed no difference between the groups. Electroencephalogram (EEG)-frequency-band analysis revealed slowing over the central cortex and reduction of alpha activity over the parietal area in diabetic patients. Acute hyperglycemia induced in healthy volunteers with the administration of 50 g of intravenous glucose did not have any effect on the dominant EEG rhythms. The checkerboard elicited P100 wave did not reveal a significant increase in latency nor were the P300 wave latencies significantly different in diabetic patients. However, a trend toward longer latencies in diabetics was evident at Fz and Cz recording sites. Acute hyperglycemia in healthy volunteers did not alter the P300 wave component. The results indicate that elderly type 2 diabetic patients have an impairment in retrieval of recently learned material with preservation of auditory attention and immediate recall. The EEG data suggest that there may be some central neural pathologic condition associated with diabetes.

Influence of D-1 receptor system on the D-2 receptor-mediated hypothermic response in mice.

The hypothermia induced by apomorphine, a mixed dopamine (DA) agonist in male Swiss-Webster mice, was not blocked by the selective D-1 antagonist SCH 23390 but was completely blocked by the selective D-2 antagonists haloperidol, sulpiride and YM-09151-2. The selective D-1 agonist SKF 38393 did not elicit hypothermic response but the selective D-2 agonist quinpirole caused a marked lowering of rectal temperature. D-2 antagonists blocked this response to quinpirole. SCH 23390 enhanced and SKF 38393 attenuated the hypothermia induced by quinpirole. Ineffective doses of haloperidol and SKF 38393, when given together, completely blocked the effect of quinpirole. It was concluded that hypothermia is a D-2 receptor mediated response but modulated by the D-1 receptor system. In another series of experiments the influence of neuroleptics and antidepressants on the hypothermic effect of apomorphine and quinpirole was investigated. The hypothermic effect of a low dose (1 mg/kg) of apomorphine was blocked by the D-2 receptor antagonists, but not by classical antidepressants. However, the response to a high dose (10 mg/kg) of apomorphine was blocked by both classical antidepressants and D-2 antagonists (except haloperidol). These drugs did not show similar effect on quinpirole-induced hypothermia. It is clear that the hypothermic response, especially that of quinpirole, is not a suitable model for testing either neuroleptics or antidepressants.

Interaction between clozapine and a lipophilic alpha 1-adrenergic agonist.

Acute intraperitoneal injection of clozapine produced marked hypothermia and ataxia in Swiss-Webster mice. These two effects were almost completely blocked by the lipophilic alpha 1-adrenergic agonist, St 587, but not by the peripherally-acting alpha 1 agonist methoxamine. It was inferred that these effects of clozapine are central in origin and probably resulted from alpha 1 adrenergic blockade. However, since prazosin, a selective alpha 1-adrenergic antagonist did not elicit either hypothermia or ataxia in mice it became clear that the alpha 1 adrenergic blocking effect of clozapine is not entirely responsible for these effects, but has a major contributory role in their production. Both clozapine and prazosin inhibited the d-amphetamine-induced locomotor stimulation in mice. St 587 did not significantly reduce this amphetamine-blocking effect of clozapine. It was inferred that this response to d-amphetamine involving the release of mesolimbic dopamine is distinct from the other two St 587-sensitive responses. The hypothermic and ataxic effects of clozapine developed complete tolerance after just four days of treatment, but ten days of such treatment was required for the development of tolerance to the amphetamine-blocking effect of clozapine. The possible relationships between St 587-sensitive and insensitive effects of clozapine and its antipsychotic property are discussed.

Isolation and the fluorometric, high-performance liquid chromatographic determination of tacrine.

Tacrine (THA; 1,2,3,4-tetrahydro-9-aminoacridine) is an anticholinesterase agent which has been used clinically, most recently in the treatment of Alzheimer-type dementias. This paper describes the methodology for the isolation and quantitation of THA at therapeutic levels in serum from human subjects. Using C18 Bond Elut columns and an HPLC/fluorometry system, this assay exhibits a considerable improvement in sensitivity over previous uv methods, and allows routine testing of THA levels in serum samples of reasonable volume from human subjects.

Diagnosis of Alzheimer's disease and multiple infarct dementia by tomographic imaging of iodine-123 IMP.

Tomographic imaging of the brain was performed using a rotating slant hole collimator and [123I]N-isopropyl p-iodoamphetamine (IMP) in normal subjects (n = 6) and patients with either Alzheimer's disease (n = 5) or multiple infarct dementia (n = 3). Four blinded observers were asked to make a diagnosis from the images. Normal subjects and patients with multiple infarct dementia were correctly identified. Alzheimer's disease was diagnosed in three of the five patients with this disease. One patient with early Alzheimer's disease was classified as normal by two of the four observers. Another patient with Alzheimer's disease had an asymmetric distribution of IMP and was incorrectly diagnosed as multiple infarct dementia by all four observers. Limited angle tomography of the cerebral distribution of 123I appears to be a useful technique for the evaluation of demented patients.

An in vivo pharmacological method for the quantitative evaluation of the central effects of alpha 1 adrenoceptor agonists and antagonists.

A new in vivo pharmacological method for the quantitative evaluation of alpha 1-adrenoceptor agonists and antagonists has been developed. It consists of recording the myoclonic twitch activity (MTA) of the suprahyoideal muscle of rats anesthetized with urethane. In these animals, the isomers of amphetamine elicited myoclonic twitch activity; their effects were dose-related and the d-isomer was approximately 3.5 times more effective than the l-isomer. While pimozide did not block this response, the postsynaptic alpha 1-antagonist prazosin fully blocked the myoclonic twitch activity induced by d-amphetamine. Other postsynaptic alpha 1-antagonists, such as haloperidol, phenoxybenzamine and clozapine, were also effective in blocking this response to d-amphetamine. Since d-amphetamine elicited myoclonic twitch activity in rats pretreated with reserpine and alpha-methyl-p-tyrosine, it was concluded that d-amphetamine exerted a direct alpha 1-adrenoceptor stimulation. In rats pretreated with nialamide and pimozide, l-DOPA elicited myoclonic twitch activity which was dose-related. This effect of l-DOPA was promptly and fully blocked by prazosin. It was concluded that this response to l-DOPA resulted from stimulation of alpha 1-adrenoceptors. The relative potencies of four alpha 1-adrenoceptor stimulants, namely, cirazoline, St-587, (-)SKF 89748A and Sgd 101/75 were determined using this method. The results correlated very well with their relative potencies to increase the diastolic blood pressure of pithed rats. Evidence that myoclonic twitch activity is a centrally-mediated response has also been presented. It appears that the method is a simple, sensitive, versatile and easily quantifiable procedure for the evaluation of the central effects of alpha 1-adrenoceptor agonists and antagonists.