Peter J. Whitehouse

Alteration of proteins regulating apoptosis, Bcl-2, Bcl-x, Bax, Bak, Bad, ICH-1 and CPP32, in Alzheimer's disease.

Recently, apoptosis has been implicated in the selective neuronal loss of Alzheimers disease (AD). Apoptosis is regulated by the B cell leukemia-2 gene product (Bcl-2) family (Bcl-2, Bcl-x, Bax, Bak and Bad) and the caspase family (ICH-1 and CPP32), with apoptosis being prevented by Bcl-2 and Bcl-x, and promoted by Bax, Bak, Bad, ICH-1 and CPP32. In the present study, we examined the levels of these proteins in the membranous and cytosolic fractions of temporal cortex in AD and control brain. In the membranous fraction, the levels of Bcl-2 alpha, Bcl-xL, Bcl-x beta, Bak and Bad were increased in AD. In the cytosolic fractions, the level of Bcl-x beta was increased, while Bcl-xL, Bax, Bak, and Bad and ICH-1L were unchanged. CPP32 was not detected in AD or control brain. These findings demonstrate a differential involvement of cell death-regulatory proteins in AD and suggest that Bak, Bad, Bcl-2 and Bcl-x are upregulated in AD brains.

Assessment of behavioral and affective symptoms in Alzheimer's disease

Noncognitive behavioral symptoms occurring during the prior week were studied in 34 Alzheimers disease (AD) patients and 21 spousal control subjects via caregiver and patient interviews using the Behavioral Pathology in Alzheimers Disease Rating Scale and the Cornell Scale for Depression in Dementia. Delusional or paranoid features were reported in 13 subjects (38%) and hallucinations in six (18%); patients with these psychoticlike symptoms had lower scores on the Folsteins Mini-Mental State Examination. Other behavioral symptoms reported in AD patients included anxiety (50%) and activity disturbances (44%). Six AD subjects (18%) and two controls (10%) showed mild to moderate symptoms of depression ; AD subjects were more likely than controls to show behavioral signs and symptoms of depression, but the two groups did not differ in terms of mood-related, cyclical, or physical signs and symptoms. (J Geriatr Psychiatry Neurol 1990;3:21-30).

Alzheimer's Disease and Down's Syndrome*

DONALD L . PRICE, t

Vinpocetine for cognitive impairment and dementia.

j PETER J . WHITEHOUSE,I ROBERT G. STRUBLE,t j JOSEPH T. COYLE,I[ ARTHUR W. CLARK,t

Cellular pathology in Alzheimer's and Parkinson's diseases

MAHLON R. DELONG,

Cholinergic receptors in aging and Alzheimer's disease.

LINDA C. CORK,t ( ( and J O H N C . HEDREENtj t Department of Pathology 1 Department of Neurology

Emerging antidementia drugs: A preliminary ethical view

Neuropathology Laboratory 7 Departments of Neuroscience, Psychiatry and Pharmacology and Experimental Therapy I( Division of Comparative Medicine The Johns Hopkins University School of Medicine Baltimore, Maryland 21205

Multiple benzodiazepine receptors: autoradiographic localization in normal human amygdala

BACKGROUNDnVinpocetine is a synthetic ethyl ester of apovincamine, a vinca alkaloid obtained from the leaves of the Lesser Periwinkle (Vinca minor) and discovered in the late 1960s. Although used in human treatment for over twenty years, it has not been approved by any regulatory body for the treatment of cognitive impairment. Basic sciences studies have been used to claim a variety of potentially important effects in the brain. However, despite these many proposed mechanisms and targets, the relevance of this basic science to clinical studies is unclear.nnnOBJECTIVESnTo assess the efficacy and safety of vinpocetine in the treatment of patients with cognitive impairment due to vascular disease, Alzheimers disease, mixed (vascular and Alzheimers disease) and other dementias.nnnSEARCH STRATEGYnThe Cochrane Dementia & Cognitive Improvement Groups Specialized Register was searched using the terms vinpocetin*, cavinton, kavinton, Rgh-4405, Tcv-3B, ethyl apovincaminate, vinRx, periwinkle, myrtle vincapervinc and cezayirmeneksesi. The manufacturers of vinpocetine were asked for information on trials of vinpocetine for dementia. In addition we tried to collect articles not listed in MEDLINE or other sources on the Internet (e.g. articles in Hungarian and Romanian).nnnSELECTION CRITERIAnAll human, unconfounded, double-blind, randomized trials in which treatment with vinpocetine was administered for more than a day and compared to control in patients with vascular dementia, Alzheimers dementia or mixed Alzheimers and vascular dementia and other dementias. Non-randomized trials were excluded.nnnDATA COLLECTION AND ANALYSISnData were independently extracted by the two reviewers (SzSz and PW) and cross-checked. Data from washout periods were not used for the analysis. For continuous or ordinal variables, such as cognitive test results, the main outcomes of interest were the change in score from baseline. The categorical outcome of global impression was transformed to binary data (improved or not improved) as was the occurrence of adverse effects; here the endpoint itself was of interest the Peto method of the typical odds ratio was used. A test for heterogeneity of treatment effects between the trials was made if appropriate. Data synthesis and analysis were performed using the Cochrane Review Manager software (RevMan version 4.1).nnnMAIN RESULTSnAll identified studies were performed before the 1990s and used various terms and criteria for cognitive decline and dementia. The three studies included in the review involved a total of 583 people with dementia treated with vinpocetine or placebo. The reports of these studies did not make possible any differentiation of effects for degenerative or vascular dementia. The results show benefit associated with treatment with vinpocetine 30mg/day and 60 mg/day compared with placebo, but the number of patients treated for 6 months or more was small. Only one study extended treatment to one year. Adverse effects were inconsistently reported and without regard for relationship to dose. The available data do not demonstrate many problems of adverse effects but intention-to-treat data were not available for any of the trials.nnnREVIEWERS CONCLUSIONSnAlthough the basic science is interesting, the evidence for beneficial effect of vinpocetine on patients with dementia is inconclusive and does not support clinical use. The drug seems to have few adverse effects at the doses used in the studies. Large studies evaluating the use of vinpocetine for people suffering from well defined types of cognitive impairment are needed to explore possible efficacy of this treatment.

Corticotropin-releasing hormone (CRH) is decreased in the basal ganglia in Huntington's disease

Abstract Alzheimers disease (AD) and Parkinsons disease (PD), the two most common types of adult-onset chronic degenerative disorders of the CNS 1,2 are characterized by degeneration of certain populations of neurons with relative sparing of other groups of nerve cells 3,4 . Dysfunction of at-risk neurons is associated with several types of cytoskeletal pathology. As these nerve cells degenerate alterations occur in neurotransmitter markers. Dysfunction/death of neurons in these systems result in the clinical syndromes of AD and PD. The bradykinesia and rigidity of PD are associated with lesions in the nigrostriatal dopaminergic system, whereas the dementia of AD is attributed to abnormalities of nerve cells in monoaminergic brainstem nuclei, in the basal forebrain cholinergic system, and in neuronal populations within the amygdala, hippocampus, and neocortex. On the basis of clinical and histopathological criteria, AD and PD are distinguished from other adult-onset degenerative neurological disorders, including Picks disease, progressive supranuclear palsy, the Guamanian parkinsonism—dementia complex, etc. The present review describes the current status of our understanding of cellular abnormalities occurring in at-risk neuronal populations in AD and PD.

Alteration of Phospholipase C-δ Protein Level and Specific Activity in Alzheimer's Disease

Although Alzheimers disease (AD) is a disorder involving multiple neurotransmitter systems, the basal forebrain cholinergic system (Ch system) is severely and consistently affected in this condition. In both animals and man, the nature of age-associated alterations in the Ch system is unclear. In addition, available studies of cholinergic receptors in AD and aging are not consistent. In normal aging, the density of muscarinic cholinergic receptors (MCR) is reported to be either unchanged or decreased. In AD, increased, unchanged, or decreased densities have been reported. Recently, a subtype of MCR (M2), thought to be located presynaptically, has been reported to be reduced in neocortex and amygdala. In both AD and aging, nicotinic cholinergic receptors (NCR) have not been adequately studied. Our recent studies using [3H] acetylcholine and [3H] nicotine have demonstrated a reduction in NCR in AD. Possible explanations for some of the inconsistent findings are discussed, and directions for future studies are suggested.