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Howard H Feldman

Publications and source records attributed to Howard H Feldman.

10 recordsLinked to original sources
PubMed2006

Dropouts and refusals in observational studies: lessons for prevention trials.

The success of prevention trials of Alzheimer disease and other dementias (AD/dementia) hinges on their ability to recruit and retain at-risk study populations. Losing subjects is a threat to the power to detect a treatment effect and, potentially, to the validity of these studies. Observational cohort studies accumulate data around participant outcomes that can help to inform the design of future prevention trials. Our objectives were to investigate the rates of refusal and dropout within observational cohort studies and to evaluate their characteristics and impact. This study examined data from the Canadian Cohort Study of Cognitive Impairment and Related Dementias (ACCORD), a 2-year observational cohort study of patients newly referred to dementia clinics. The sample included 124 Not Cognitively Impaired (NCI) and 342 Cognitively Impaired Not Demented (CIND) subjects. Subjects who refused initial neuropsychological (NP) testing were compared to those who completed NP testing and subjects who dropped out to those who attended follow-up. Refusal was common, with 40% of subjects not completing neuropsychological testing at baseline. Dropout was also substantial, with 55% lost to the 2-year follow-up. Subjects who refused NP testing were significantly older and less educated. CIND refusers had lower cognitive and functional scores at entry and a 2-year progression rate to dementia twice as high as that of non-refusers. CIND dropouts also had lower baseline cognitive and functional scores. These observations suggest that dropouts and refusals in prevention trials include those subjects who are at high risk for progression to AD/dementia. Targeted strategies to retain these individuals within prevention studies will be needed to achieve sufficient study power and validity.

Aged↗
PubMed2006

Outcomes of cognitively impaired not demented at 2 years in the Canadian Cohort Study of Cognitive Impairment and Related Dementias.

BACKGROUND: People who are cognitively impaired not demented (CIND) can be at an increased risk for developing dementia, but little is known about the natural history of CIND in clinical settings. METHOD: We examined the 2-year outcome of CIND subjects in the Canadian Cohort Study of Cognitive Impairment and Related Dementias.CIND was diagnosed when at least one positive item was endorsed on the DSM-III-R dementia criteria, but not all criteria were met. CIND was further subclassified as: pre-Alzheimer's disease (pre-AD), vascular cognitive impairment (VCI-ND), non-AD degenerative, psychiatric, other neurologic, other medical conditions, mixed disorders and no etiology identified (not otherwise specified [NOS]). RESULT: Of 146 CIND patients with 2-year follow-up data available, 49 (34%) progressed to dementia, while 20 (14%) recovered to not cognitively impaired (NCI). Progressors were significantly older than stable CIND and reverters (p < 0.0001; mean age = 71.1, 64.3, and 59.1, respectively), and there were significantly (p = 0.001) more ApoE epsilon4 carriers among progressors (67%) than stable CIND (29%) and reverters (12%). Pre-AD CIND and VCI-ND had the highest rate of conversion to dementia (41.0 and 40.0%, respectively), while psychiatric CIND and CIND NOS had highest rate of recovery to NCI (20.0 and 30.0%, respectively). All conversions in pre-AD CIND were to 'probable AD'. CONCLUSION: CIND consists of a heterogeneous group of disorders that can be classified syndromically. Many subclassess - not just those with pre-AD CIND - are at high risk of progression to dementia, usually to Alzheimer's disease.

Aged↗
PubMed2006

Progress in clinical neurosciences: Canadian guidelines for the development of antidementia therapies: a conceptual summary.

The magnitude of the problems faced by an aging Canadian society has been clearly identified. Perhaps the single most important problem is the increasing incidence of dementia. Alzheimer's disease (AD) accounts for 50-60% of the dementias in later life within a spectrum of other contributing dementias. Regulatory approval has been given to Acetylcholinesterase inhibitors for the symptomatic treatment of mild to moderate AD, and conditional approval to memantine for the symptoms of moderate to severe AD. There has been no regulatory approval for the treatment of the degenerative dementias beyond AD. The very rapid progress in the past decade in biotechnology and in the molecular biology of the dementias is supporting a new generation of innovative treatment strategies that will more directly target the underlying disease pathogenic mechanisms. Such treatments will foreseeably include immunotherapies, anti-aggregants that may prevent misfolding and deposition of proteins, and neuroregenerative interventions. These Guidelines follow the 2nd Canadian Conference on the Development of Antidementia Therapies, held in 2004, which covered a range of design, methodological and ethical issues facing clinical researchers and regulatory authorities. They are intended to provide a common point of reference and guidance in Canada for therapeutic development of the dementias.

Canada↗
PubMed2006

The neuropathology of frontotemporal lobar degeneration caused by mutations in the progranulin gene.

The most common pathology in frontotemporal dementia (FTD) is tau-negative, ubiquitin-immunoreactive (ub-ir) neuronal inclusions (FTLD-U). Recently, we identified mutations in the progranulin (PGRN) gene as the cause of autosomal dominant FTLD-U linked to chromosome 17. Here, we describe the neuropathology in 13 patients from 6 different families, each with FTD caused by a different PGRN mutation. The most consistent feature was the presence of ub-ir lentiform neuronal intranuclear inclusions (NII) in the neocortex and striatum. In addition, the neocortex showed moderate-to-severe superficial laminar spongiosis, chronic degenerative changes, ub-ir neurites and well-defined ub-ir neuronal cytoplasmic inclusions (NCI). In the striatum, there were numerous ub-ir neurites. NCI in the hippocampus usually had a granular appearance. In contrast, familial FTLD-U cases without PGRN mutations had no NII, less severe neocortical and striatal pathology and hippocampal NCI that were more often solid. Eight cases in which genetic analysis was not available also had NII and an overall pathology similar to those with proven mutations. None of our cases of FTLD-U without NII showed the same pattern of pathology as those with mutations. These findings suggest that FTD caused by PGRN mutations has a recognizable pathology with the most characteristic feature being ub-ir NII.

Aged↗
PubMed2005

Cholesterol in Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of neurodegenerative dementia and affects up to 15 million people worldwide. Although no single cause of AD has been identified, recent research has suggested that several pathogenetic factors influence risk and expression. A growing amount of evidence underscores a mechanistic link between cholesterol metabolism in the brain and the formation of amyloid plaques. Excess brain cholesterol has been associated with increased formation and deposition of amyloid-beta peptide from amyloid precursor protein. Cholesterol-lowering statins have become a focus of research in AD. Genetic polymorphisms associated with pivotal points in cholesterol metabolism in brain tissues may contribute to the risk and pathogenesis of AD. In this review, we summarise current knowledge of the role of cholesterol metabolism in the pathogenesis of AD and examine the potential of statins in the prevention and treatment of AD.

Alzheimer Disease↗
PubMed2005

Ubiquitin immunohistochemistry suggests classic motor neuron disease, motor neuron disease with dementia, and frontotemporal dementia of the motor neuron disease type represent a clinicopathologic spectrum.

One of the characteristic pathologic changes in classic motor neuron disease (MND) is the presence of ubiquitin-immunoreactive (ub-ir) inclusions in the cytoplasm of lower motor neurons. In addition, cases of MND with dementia (MND-d) also have ub-ir neuronal cytoplasmic inclusions and dystrophic neurites in extramotor neocortex and hippocampus. Although this extramotor pathology is a highly sensitive marker for dementia in MND, similar changes are found in a subset of patients with frontotemporal dementia (FTD) with no motor symptoms (FTD-MND type). The purpose of this study is to more fully describe and compare the pattern of ub-ir pathology in these 3 conditions. We performed ubiquitin immunohistochemistry on postmortem tissue, representing a wide range of neuroanatomic structures, in cases of classic MND (n = 20), MND-d (n = 15), and FTD-MND type (n = 15). We found the variety of morphologies and the anatomic distribution of ub-ir pathology to be greater than previously documented. Moreover, the degree of overlap suggests that MND, MND-d, and FTD-MND type represent a spectrum of clinical disease with a common pathologic substrate. The only finding restricted to a specific subgroup of patients was the presence of ub-ir neuronal intranuclear inclusions in some cases of familial FTD.

Adult↗
PubMed2005

Mild cognitive impairment.

Mild cognitive impairment (MCI) describes a state of cognitive functioning that is below defined norms, yet falls short of dementia in severity. It exists across a cognitive continuum with borders that are difficult to define precisely. Within our "graying" western societies, its prevalence increases with age. A number of subtypes of MCI, including age-associated memory impairment (AAMI), age-associated cognitive decline (AACD), amnestic MCI (MCIa), and cognitive impairment not dementia (CIND) have contributed to our understanding of MCI. Recent efforts have been directed at developing a uniform diagnostic classification for MCI that reflects the maturation of knowledge about this state. There is considerable etiological and clinical heterogeneity within MCI; however, there is a unifying increased risk of progression to dementia. The diagnostic process for MCI involves assessment of multiple cognitive domains, with particular attention to episodic and semantic memory, while neuroimaging with structural MRI and PET both add to the diagnostic and prognostic evaluation of MCI. Although there are no pharmacological treatments at present that are capable of delaying the long-term progression of MCI to dementia, there is some evidence of short-term symptomatic benefits with acetylcholinesterase inhibitors. MCI is an important clinical problem, which clinicians can expect to face with increasing frequency. The essentials of management include a thorough assessment directed at etiological determination and counseling and judicious use of available therapeutics.

Aged↗
PubMedDate not supplied

Cognition, function, and caregiving time patterns in patients with mild-to-moderate Alzheimer disease: a 12-month analysis.

Placebo data were pooled from two 1-year, randomized, double-blind, placebo-controlled trials of sabeluzole in patients with mild-to-moderate Alzheimer disease (AD). Cognition was assessed using the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and activities of daily living (ADL) with the Disability Assessment in Dementia (DAD). Time spent assisting with ADL was estimated according to the caregiver for each DAD domain in the 2 weeks before assessment. Progressive annual decline was seen on ADAS-cog (5.6 +/- 7.3 [mean +/- SD]) and DAD (-12.4 +/- 17.8), with greater decline in moderate patients (Mini-Mental State Examination [MMSE] < or =18) than mild patients (MMSE >18). An MMSE score of 16 appeared to be a key transition point at which most instrumental ADL were lost and major losses of basic ADL began to occur over the next 12 months. Caregivers spent, on average, 14 hours more assisting with ADL over 2 weeks at the end of 1 year. The proportion of care provided by paid caregivers increased relative to the time spent by informal caregivers. Patients with mild-to-moderate AD experience predictable annual decline in cognition and daily functioning, with measurably increased caregiver time. Small changes in ADAS-cog are nevertheless associated with a substantial measurable effect on the daily lives of both patients and caregivers.

Activities of Daily Living↗
PubMedDate not supplied

Activities of daily living in moderate-to-severe Alzheimer disease: an analysis of the treatment effects of memantine in patients receiving stable donepezil treatment.

In moderate-to-severe Alzheimer disease (AD), there are significant losses of activities of daily living (ADL). In a recent prospective, randomized, placebo-controlled trial, memantine treatment lessened the overall functional decline in AD patients already on stable donepezil therapy. In this trial, patients (n=404) with Mini-Mental State Examination scores of 5 to 14 receiving stable donepezil treatment were randomized to double-blind treatment with memantine (10 mg b.i.d.; n=203) or placebo (n=201). A primary outcome measure was the 19-item Alzheimer's Disease Cooperative Study--Activities of Daily Living Inventory (ADCS-ADL(19)). To further evaluate the treatment effects of memantine on function, we performed post hoc analyses of ADCS-ADL(19) data from this trial, including ADL items and new subscales derived from factor analysis. Using mixed model analyses, patients receiving memantine had statistically significant less decline in total ADCS-ADL(19) scores compared with placebo. An item analysis revealed statistically significant benefits of memantine on grooming, toileting, conversing, watching television, and being left alone. Statistically significant improvements were noted in subscales evaluating higher-level functions and connectedness/autonomy with memantine compared with placebo. These post hoc analyses in moderate-to-severe AD patients receiving stable donepezil treatment suggest that memantine may impact overall functional levels, and some of the cognitive processing underlying ADL performance.

Activities of Daily Living↗