Jody Corey-Bloom

The importance of neuritic plaques and tangles to the development and evolution of AD

Objective: To determine the relation of neuritic plaques (NPs) and neurofibrillary tangles (NFTs) to the development and evolution of Alzheimer disease (AD). Methods: An autopsy series of 102 patients with dementia and pathologically confirmed AD and 29 normal control subjects (NCs) was studied. AD cases were stratified according to their last Mini-Mental State Examination (MMSE) before death as mild, moderate, severe, or very severe. NPs and NFTs were enumerated in the midfrontal (MF), inferior parietal (IP), superior temporal (ST), hippocampal (Hip), or entorhinal cortices using thioflavin-S preparations. Results: Most (87%) of the NCs had allocortical NFTs, whereas only a minority (37%) displayed neocortical NPs, and even fewer (19%) showed Hip NPs. In contrast, none of the NCs exhibited neocortical NFTs, except one case with a single ST tangle. However, neocortical NFTs were not detected in even 10% of the patients with AD and, in particular, were absent in nearly 50% of those with mild disease at death. Thus, their sensitivity as a marker of AD was lower than that of NPs, which, conversely, were found in all patients with AD. Comparing NCs and patients with mild AD, significant differences were found for numbers of NPs only. Across the AD groups, in contrast, although NP and NFT density increased with dementia severity, significant differences consistently emerged for NFTs alone. Conclusions: Deterioration in Alzheimer disease appears to be driven by neuritic plaques and neurofibrillary tangles at different stages of the disease. The significant increase in neuritic plaques, but not neurofibrillary tangles, in patients with even mild Alzheimer disease at death compared with normal control subjects suggests that only neuritic plaques are associated with the earliest symptoms of Alzheimer disease.

Cholinergic dysfunction in diseases with Lewy bodies

Objective: To evaluate cholinergic activity in diseases with Lewy bodies (LB; LB variant of AD [LBV], diffuse LB disease [DLBD], and Parkinson’s disease [PD]) to determine if 1) AD changes are requisite to cholinergic dysfunction, 2) cholinergic activity declines to the same extent in neocortical and archicortical areas, and 3) cholinergic loss is influenced by APOE genotype. Background: Like AD, diseases with LB are associated with decreased choline acetyltransferase (ChAT) activity. Increased APOE ε4 allele frequency has been reported in LBV. Whether APOE genotype affects cholinergic function in LBV remains unclear. Methods: An autopsy series of 182 AD (National Institute on Aging and Consortium to Establish a Registry for Alzheimer’s Disease criteria), 49 LBV, 11 PD, 6 DLBD, and 16 normal control (NC) subjects. APOE genotype and ChAT activity (nmol/h/100 mg) in the midfrontal and hippocampal cortices were determined. Results: Mean midfrontal ChAT activity was markedly reduced in diseases with LB (LBV: 53.3 ± 39.0; PD: 54.8 ± 35.7; DLBD: 41.3 ± 24.8) compared to NC (255.4 ± 134.6; p < 0.001) and AD (122.6 ± 78.9; p < 0.05). Among diseases with LB, midfrontal ChAT activity was decreased to a similar extent in patients with (LBV) and without (DLBD and PD) AD pathology. Although mean ChAT activity for LBV was less than half that for AD in the midfrontal cortex, it was similar to that for AD in the hippocampus (LBV: 243.5 ± 189.7; AD: 322.8 ± 265.6; p > 0.05). However, hippocampal ChAT activity for both AD and LBV was lower than that for NC (666.5 ± 360.3; p < 0.001). The ε4 allele dosage did not influence midfrontal ChAT activity in LBV. Conclusions: Marked losses in midfrontal ChAT activity occur in diseases with LB, independent of coexistent AD changes. A greater midfrontal, as opposed to hippocampal, cholinergic deficit may differentiate LBV from AD. The lack of a relationship between ε4 allele dosage and midfrontal ChAT activity suggests that other factors may play a role in its decline in LBV.

Weight Loss Precedes Dementia in Community‐Dwelling Older Adults

OBJECTIVE: To determine whether the weight loss associated with Alzheimers disease precedes or follows the dementia.

Influence of Alzheimer pathology on clinical diagnostic accuracy in dementia with Lewy bodies

Objective: To determine whether AD neurofibrillary pathology influences clinical diagnostic accuracy in dementia with Lewy bodies (DLB). Background: Pathologic diagnosis of DLB mandates Lewy bodies but also allows for AD pathology in the form of plaques and tangles. Because clinical diagnostic accuracy of DLB remains low, the authors questioned whether the severity of AD pathology in the form of tangles might affect the clinician’s ability to correctly diagnose DLB in life. Design/Methods: Ninety-eight subjects with autopsy-proven DLB who had been evaluated annually at the University of California San Diego AD Research Center were identified. The clinical diagnosis used was the last diagnosis before death. Pathologic diagnosis of DLB was made according to Consensus guidelines, and Braak staging was used to assess the degree of neurofibrillary AD pathology. The clinical characteristics of subjects with DLB with low vs high Braak stages were compared and the clinical diagnostic accuracy for subjects stratified according to Braak stage was determined. Results: Only 27% of the subjects with DLB demonstrated both visual hallucinations and spontaneous extrapyramidal signs (EPS). The low Braak stage (0 to 2, n = 24) subjects had a higher frequency of visual hallucinations (65%) than did subjects with DLB with higher (3 to 6, n = 66) Braak stages (33%, p = 0.008), and showed a slightly greater but not significant degree of EPS. Although clinical diagnostic accuracy for DLB was relatively low (49%), it was higher for subjects with low (75%) compared to high (39%) Braak stages (p = 0.0039). Conclusions: The degree of concomitant AD tangle pathology has an important influence on the clinical characteristics and, therefore, the clinical diagnostic accuracy of DLB.

Increased Light Exposure Consolidates Sleep and Strengthens Circadian Rhythms in Severe Alzheimer's Disease Patients

Sleep in the nursing home environment is extremely fragmented, possibly in part as a result of decreased light exposure. This study examined the effect of light on sleep and circadian activity rhythms in patients with probable or possible Alzheimers disease. Results showed that both morning and evening bright light resulted in more consolidated sleep at night, as measured with wrist actigraphy. Evening light also increased the quality of the circadian activity rhythm, as measured by a 5-parameter extended cosine model (amplitude, acrophase, nadir, slope of the curve, and relative width of the peak and trough). Increasing light exposure throughout the day and evening is likely to have the most beneficial effect on sleep and on circadian rhythms in patients with dementia. It would behoove nursing homes to consider increasing ambient light in multipurpose rooms where patients often spend much of their days.

Cognitive Effects of Treating Obstructive Sleep Apnea in Alzheimer's Disease: A Randomized Controlled Study

OBJECTIVES: To examine whether treatment of obstructive sleep apnea (OSA) with continuous positive airway pressure (CPAP) in patients with Alzheimers disease (AD) results in better cognitive function.

Quantification of Five Neuropsychological Approaches to Defining Mild Cognitive Impairment

OBJECTIVES Operational definitions of cognitive impairment have varied widely in diagnosing mild cognitive impairment (MCI). Identifying clinical subtypes of MCI has further challenged diagnostic approaches because varying the components of the objective cognitive assessment can significantly impact diagnosis. Therefore, the authors investigated the applicability of diagnostic criteria for clinical subtypes of MCI in a naturalistic research sample of community elders and quantified the variability in diagnostic outcomes that results from modifying the neuropsychological definition of objective cognitive impairment. DESIGN Cross-sectional and longitudinal study. SETTING San Diego, CA, Veterans Administration Hospital. PARTICIPANTS Ninety nondemented, neurologically normal, community-dwelling older adults were initially assessed and 73 were seen for follow-up approximately 17 months later. MEASUREMENTS Participants were classified via consensus diagnosis as either normally aging or having MCI via each of the five diagnostic strategies, which varied the cutoff for objective impairment and the number of neuropsychological tests considered in the diagnostic process. RESULTS A range of differences in the percentages identified as MCI versus cognitively normal were demonstrated, ranging from 10-74%, depending on the classification criteria used. A substantial minority of individuals demonstrated diagnostic instability over time and across diagnostic approaches. The single domain nonamnestic subtype diagnosis was particularly unstable (e.g., prone to reclassification as normal at follow up). CONCLUSION Our findings provide empirical support for a neuropsychologically derived operational definition of clinical subtypes of MCI and point to the importance of using comprehensive neuropsychological assessments. Diagnoses, particularly involving nonamnestic MCI, were variable over time. The applicability and utility of this particular MCI subtype warrants further investigation.

Low body weight in Alzheimer's disease is associated with mesial temporal cortex atrophy

There are reports of weight loss and low body mass index (BMI) in patients with AD.The mesial temporal cortex (MTC) is involved in feeding behavior and memory and is preferentially involved in AD. We studied 74 subjects, including 58 AD patients and 16 control subjects, to determine whether BMI is associated with atrophy of the MTC or other brain regions. We used MRI morphometric analysis to provide measures of regional brain atrophy. AD patients had significant brain atrophy in all measured brain regions, except the white matter, compared with normal control subjects. The MTC was the only brain region significantly associated with BMI in AD patients (r = 0.39, p = 0.003). Multiple-regression analysis indicated that addition of brain regions other than the MTC to the model did not significantly add to the prediction of BMI. We conclude that low BMI correlates best and specifically with MTC atrophy. This finding supports a connection between limbic system damage and low body weight in AD. NEUROLOGY 1996;46: 1585-1591

Impact of APOE genotype on neuropathologic and neurochemical markers of Alzheimer disease.

Background: The APOE ε4 allele has emerged as a major genetic factor for Alzheimer disease (AD), and its presence has been associated with an increase in β-amyloid senile plaques (SPs) and neuritic plaques (NPs). Whether it affects neurofibrillary tangle (NFT) accumulation or cholinergic losses in AD remains controversial. In contrast, the ε2 allele has been reported to decrease the risk for AD. However, its effect on neuropathologic and neurochemical markers of disease is unclear. Objective: To investigate the relationship between APOE genotype and both pathologic severity and cholinergic dysfunction in AD. Methods: In an autopsy series of 296 patients with AD, APOE genotype was determined in blood or postmortem brain tissue. NPs and NFTs were counted in the midfrontal (MF), inferior parietal (IP), and superior temporal (ST) cortices and the hippocampus. Choline acetyltransferase (ChAT) activity was assessed in the MF, IP, and ST cortices. Results: Compared with patients with no ε4 alleles, ε4 carriers (patients with either one or two ε4 alleles) did not differ significantly with regard to any pathologic or neurochemical measures, except for increased ST NPs. However, when cases were stratified into three groups according to the number of ε4 alleles, patients with two ε4 alleles had significantly more NPs and NFTs in all neocortical regions than those with either one or no ε4 alleles. The association of the ε4/4 genotype with neocortical pathologic severity remained significant even after adjusting for age at onset or age at death. In contrast, there were no significant group differences with regard to neocortical ChAT activity. When pathologic and neurochemical measures were compared between patients with the ε2 allele and those without, a strong relationship emerged between the ε2 allele and decreased NPs in all neocortical regions. Conclusions: The ε4 allele does not predict cholinergic decline in AD. Although the presence of a single ε4 allele appears to have no effect, the presence of two ε4 alleles is an important determinant of both NP and NFT accumulation. A putative protective role for the ε2 allele in AD may be mediated by reduced plaque burden.

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 (