David A. Drachman

Statins and the risk of dementia

BACKGROUNDnDementia affects an estimated 10% of the population older than 65 years. Because vascular and lipid-related mechanisms are thought to have a role in the pathogenesis of Alzheimers disease and vascular dementia, we did an epidemiological study of the potential effect of HMGCoA (3 hydroxy-3methylglutaryl-coenzyme A) reductase inhibitors (statins) and other lipid-lowering agents on dementia.nnnMETHODSnWe used a nested case-control design with information derived from 368 practices which contribute to the UK-based General Practice Research Database. The base study population included three groups of patients age 50 years and older: all individuals who had received lipid-lowering agents (LLAs); all individuals with a clinical diagnosis of untreated hyperlipidaemia; and a randomly selected group of other individuals. From this base population, all cases with a computer-recorded clinical diagnosis of dementia were identified. Each case was matched with up to four controls derived from the base population on age, sex, practice, and index date of case.nnnFINDINGSnThe study encompassed 284 cases with dementia and 1080 controls. Among controls 13% had untreated hyperlipidaemia, 11% were prescribed statins, 7% other LLAs, and 69% had no hyperlipidaemia or LLA exposure. The relative risk estimates of dementia adjusted for age, sex, history of coronary-artery disease, hypertension, coronary-bypass surgery and cerebral ischaemia, smoking and body mass index for individuals with untreated hyperlipidaemia (odds ratio 0.72 [95% CI 0.45-1.14]), or treated with nonstatin LLAs (0.96 [0.47-1.97], was close to 1.0 and not significant compared with people who had no diagnosis of hyperlipidaemia or exposure to other lipid-lowering drugs. The adjusted relative risk for those prescribed statins was 0.29 (0.13-0.63; p=0.002).nnnINTERPRETATIONnIndividuals of 50 years and older who were prescribed statins had a substantially lowered risk of developing dementia, independent of the presence or absence of untreated hyperlipidaemia, or exposure to nonstatin LLAs. The available data do not distinguish between Alzheimers disease and other forms of dementia.

A Double-Blind, Placebo-Controlled Multicenter Study of Tacrine for Alzheimer's Disease

BACKGROUNDnIn Alzheimers disease, there is a marked decline in the function of cholinergic neurons in the brain. However, studies of treatment with cholinesterase inhibitors have produced conflicting results. We conducted a multicenter trial to evaluate whether the cholinesterase inhibitor tacrine (1,2,3,4-tetrahydro-9-acridinamine monohydrochloride monohydrate) could improve cognition in patients with Alzheimers disease.nnnMETHODSnOf 632 eligible patients with probable Alzheimers disease, 215 improved while receiving tacrine during a preliminary crossover phase to determine responsiveness and the best dose. The 215 patients were randomly assigned to receive either placebo or their best dose of tacrine (10 or 20 mg four times a day) in a six-week, double-blind trial. The primary measures of efficacy were the cognitive subscale of the Alzheimers Disease Assessment Scale and the Clinical Global Impression of Change scale; the secondary measures included the Mini-Mental State Examination and the assessment of the activities of daily living.nnnRESULTSnAt the end of the six-week trial, the patients receiving tacrine had a mean adjusted cognitive-subscale score of 30.3 (Alzheimers Disease Assessment Scale) as compared with 32.7 in patients receiving placebo. This represents a smaller decline (by 2.4 points) in cognitive performance in the tacrine group (P < 0.001). There were no differences between the groups in their global-rating scores. The tacrine group had a significantly smaller decline in the activities of daily living. The results of the Mini-Mental State Examination favored tacrine, but the differences were small and not statistically significant (a score of 16.0 with tacrine vs. 15.3 with placebo; P = 0.08). Gastrointestinal symptoms, elevation of aminotransferase levels, and headache were the most frequent side effects; all could be reversed by reducing the dose or discontinuing treatment.nnnCONCLUSIONSnIn this short-term study in patients with Alzheimers disease who were selected for apparent responsiveness to tacrine, treatment with tacrine resulted in a statistically significant reduction in the decline of cognitive function, although this reduction was not large enough to be detected by the study physicians global assessments of the patients.

Novel ubiquitin neuropathology in frontotemporal dementia with valosin-containing protein gene mutations

Frontotemporal dementia (FTD) with inclusion body myopathy and Paget disease of bone (IBMPFD) is a rare, autosomal-dominant disorder caused by mutations in the valosin-containing protein (VCP) gene, a member of the AAA-ATPase gene superfamily. The neuropathology associated with sporadic FTD is heterogeneous and includes tauopathies and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). However, there is limited information on the neuropathology in IBMPFD. We performed a detailed, systematic analysis of the neuropathologic changes in 8 patients with VCP mutations. A novel pattern of ubiquitin pathology was identified in IBMPFD that was distinct from sporadic and familial FTLD-U without VCP gene mutations. This was characterized by ubiquitin-positive neuronal intranuclear inclusions and dystrophic neurites. In contrast to FTLD-U, only rare intracytoplasmic inclusions were identified. The ubiquitin pathology was abundant in the neocortex, less robust in limbic and subcortical nuclei, and absent in the dentate gyrus. Only rare inclusions were detected with antibodies to VCP and there was no biochemical alteration in the VCP protein. VCP is associated with a variety of cellular activities, including regulation of the ubiquitin-proteasome system. Our findings are consistent with the hypothesis that the pathology associated with VCP gene mutations is the result of impairment of ubiquitin-based degradation pathways.

Diagnosis and evaluation of dementia

This document will outline what we believe to be the most useful components of the diagnostic evaluation of elderly patients with cognitive complaints. It will focus on identifying and diagnosing the two major dementing disorders, Alzheimer’s disease (AD) and vascular dementia (VD). AD, the most common cause of cognitive decline in the elderly, has an estimated prevalence of 3 to 11% in communitydwelling persons over age ~ixty-five.l-~ This age group is increasing, and therefore the number of patients with dementia and AD will increase. It is estimated that there will be at least 7 million AD patients in the United States by the early 21st cent ~ r y . ~ , ~ The financial consequences will be staggering, as costs may approach 50 to 100 billion dollars per year.6 In view of increasing life expectancy, AD and its complications may rank as the fourth or fifth most common cause of death in the United state^.^ Accurate diagnosis of dementia syndromes is important to detect reversible or arrestable dementias. In addition, the impact of dementia on a patient’s family is substantial, and accurate diagnosis enables the clinician to provide the patient and family with a more reliable prediction of the disease course. This will facilitate planning to provide the necessary social resources. Finally, standardization of the diagnostic approach to dementia and AD is important in clinical research, including epidemiologic surveys and therapeutic trials. The impact on health care costs of diagnostic evaluations for dementia, like all medical practices, has recently come under much scrutiny. Some question the expense of the assessment, citing the economic burden of “routine work-ups” in this era of fiscal responsibility. Although the estimated cost of the average dementia evaluation (

The amyloid hypothesis, time to move on: Amyloid is the downstream result, not cause, of Alzheimer's disease

1,000 to

Familial and sporadic Alzheimer's disease Neuropathology cannot exclude a final common pathway

1,200) may seem high, we believe it is highly cost-effective when compared with the average expenditure for institutionalization (

Novel VCP mutations in inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia.

25,000 to

Analysis of the prion protein gene in thalamic dementia

35,000 per year for several years) when a case of reversible dementia is missed. Background. The DSM-III-R (1987P defines the term “dementia” as a syndrome (produced by many disorders) characterized by impairment from a previously higher level of intellectual functioning. The impairment involves memory and other cognitive domains, including language, orientation, constructional abilities, abstract thinking, problem solving, and praxis, and must be of sufficient severity to interfere with occupational or social performance or both, ie, functional impairment. Changes in personality and affect are often noted, but a normal level of consciousness is preserved until the very late stages of the disorder. Patients with cognitive impairment without evidence of a functional decline do not strictly meet DSM-III-R criteria for dementia. These patients are often classified in a variety of ways, such as having “benign senescent forgetfulness” or “age-associated memory impairment,” or being “at risk” for dementia. Upon follow-up, however, many of them are found to have a progressive dementia.g Several sets of criteria have been developed for the diagnosis of AD. The two most widely used are those of the DSM-III-R and those formulated by the NINCDS-ADRDA joint task force in 1984.’O The DSM-III-R requires an insidious onset with a generally progressive deteriorating course and exclusion of all other specific causes of dementia. The more detailed NINCDS criteria reserve the designation of “definite” AD for cases with biopsy or autopsy confirmation. Criteria for the diagnosis of “probable” AD, the maximum level of certainty possible without pathologic confirmation, include the insidious onset of decline in memory and at least one other area of cognition, a progressive course, a preserved level of consciousness, and the exclusion of other conditions that could cause these symptoms. Patients with an atypical course, focal neurologic findings, or coexistent disorders that by themselves alone may produce dementia are designated

Familial Alzheimer's disease: Site of mutation influences clinical phenotype

The “amyloid hypothesis” has dominated Alzheimer research for more than 20 years, and proposes that amyloid is the toxic cause of neural/synaptic damage and dementia. If correct, decreasing the formation or removing amyloid should be therapeutic. Despite discrepancies in the proposed mechanism, and failed clinical trials, amyloid continues to be considered the cause of a degenerative cascade. Alternative hypotheses must explain three features: (i) why amyloid toxicity is not the etiology of Alzheimers disease (AD), (ii) what alternative mechanisms cause the degeneration and dementia of AD, and (iii) why increased amyloid accumulates in the brain in AD. We propose that AD, which occurs in elderly, already vulnerable brains, with multiple age‐related changes, is precipitated by impaired microvascular function, resulting primarily from decreased Notch‐related angiogenesis. With impaired microvasculature, a lack of vascular endothelial‐derived trophic factors and decreased cerebral blood flow cause the atrophy of neural structures. Therapeutic strategies should focus on supporting normal angiogenesis.

2014 Report on the Milestones for the US National Plan to Address Alzheimer's Disease

Whether all etiologic forms of Alzheimers disease (AD) share a final common pathway is a major issue.We determined the severity and regional distribution of neuronal loss, amyloid plaques, neuritic plaques (NPs), and neurofibrillary tangles (NFTs), and calculated the ratio of neuronal loss to NPs and NFTs in brains of 19 familial AD (FAD) patients with linkage to chromosome 14, six AD patients with mutations of chromosome 21 (codon 717 of the beta-amyloid precursor protein gene), and 11 sporadic AD (SAD) patients. There was no difference in the pattern of distribution of the various pathologic features or in the ratio of neuronal loss to NPs or NFTs in any AD group. However, FAD groups could be distinguished from SAD by the greater severity and the lack of influence of apolipoprotein E genotype on pathology. These differences may reflect differences in age at onset rather than different etiopathologic mechanisms. The similarity of pathologic findings in the different AD groups provides evidence for a final common pathophysiologic pathway in AD. NEUROLOGY 1996;46: 406-212