White matter tract integrity in aging and Alzheimer's disease

The pattern of degenerative changes in the brain white matter (WM) in aging, mild cognitive impairment (MCI), and Alzheimer's disease (AD) has been under debate. Methods of image analysis are an important factor affecting the outcomes of various studies. Here we used diffusion tensor imaging (DTI) to obtain fractional anisotropy (FA) measures of the WM in healthy young (n = 8), healthy elderly (n = 22), MCI (n = 8), and AD patients (n = 16). We then applied "tract-based spatial statistics" (TBSS) to study the effects of aging, MCI, and AD on WM integrity. Our results show that changes in WM integrity (that is, decreases in FA) are different between healthy aging and AD: in healthy older subjects compared with healthy young subjects decreased FA was primarily observed in frontal, parietal, and subcortical areas whereas in AD, compared with healthy older subjects, decreased FA was only observed in the left anterior temporal lobe. This different pattern of decreased anatomical connectivity in normal aging and AD suggests that AD is not merely accelerated aging.     

Decreasing myelin density reflected increasing white matter pathology in Alzheimer's disease--a neuropathological study

BACKGROUND: White matter disease (WMD) is frequently seen in Alzheimer's disease (AD) at neuropathological examination. It is defined as a subtotal tissue loss with a reduction of myelin, axons and oligodendrocytes as well as astrocytosis. Studies quantitatively defining the myelin loss in AD are scarce. The aim was to develop a method that could provide numerical values of myelin density in AD. The purpose was to compare the myelin contents in increasing grades of pathology of WMD, with age and cortical AD pathology as well as in different regions of the brain in AD. MATERIAL AND METHODS: Sixteen cases with AD and concomitant WMD were investigated with an in-house developed image analysis technique to determine the myelin attenuation with optical density (OD) in frontoparietal, parietal, temporal and occipital white matter on whole brain coronal sections stained for myelin with Luxol Fast Blue (LFB). The OD values in LFB were compared grouped according to Haematoxylin/Eosin (HE) evaluated mild, moderate and severe WMD or normal tissue. The OD values were also correlated with age and cortical AD pathology and compared between the different studied white matter regions. RESULTS: Increasing severity of WMD was associated with a statistically significant OD reduction. No correlation was seen between age and OD or overall cortical AD pathology. The OD values were significantly lower in frontoparietal-compared to occipital white matter. CONCLUSIONS: Myelin loss in AD with WMD is a marked morphologic component of the disease and it is possible to determine the reduction objectively in neuropathological specimens with quantitative measures. This may be of use for clinical diagnostics including brain imaging.     

Distinct white matter injury associated with medial temporal lobe atrophy in Alzheimer's versus semantic dementia

This study aims at further understanding the distinct vulnerability of brain networks in Alzheimer's disease (AD) versus semantic dementia (SD) investigating the white matter injury associated with medial temporal lobe (MTL) atrophy in both conditions. Twenty‐six AD patients, twenty‐one SD patients, and thirty‐nine controls underwent a high‐resolution T1‐MRI scan allowing to obtain maps of grey matter volume and white matter density. A statistical conjunction approach was used to identify MTL regions showing grey matter atrophy in both patient groups. The relationship between this common grey matter atrophy and white matter density maps was then assessed within each patient group. Patterns of grey matter atrophy were distinct in AD and SD but included a common region in the MTL, encompassing the hippocampus and amygdala. This common atrophy was associated with alterations in different white matter areas in AD versus SD, mainly including the cingulum and corpus callosum in AD, while restricted to the temporal lobe — essentially the uncinate and inferior longitudinal fasciculi — in SD. Complementary analyses revealed that these relationships remained significant when controlling for global atrophy or disease severity. Overall, this study provides the first evidence that atrophy of the same MTL region is related to damage in distinct white matter fibers in AD and SD. These different patterns emphasize the vulnerability of distinct brain networks related to the MTL in these two disorders, which might underlie the discrepancy in their symptoms. These results further suggest differences between AD and SD in the neuropathological processes occurring in the MTL. Hum Brain Mapp 38:1791–1800, 2017. © 2017 Wiley Periodicals, Inc.     

The behavioral pathology in Alzheimer's disease scale (BEHAVE-AD): factor structure among community-dwelling Alzheimer's disease patients

Objective. The aims of this study were to (a) determine the factor structure of the Behavioral Pathology in Alzheimer's Disease Scale (BEHAVE-AD), and (b) examine the associations of the observed factors to the level of cognitive impairment. Design. Cross-sectional study of geriatric patients evaluated at an outpatient memory disorders clinic. Sample. One hundred and fifty-one consecutive patients diagnosed with Alzheimer's disease (AD) according to NINCDS–ADRDA diagnostic criteria. Results. Principal factors analysis with Varimax rotation resulted in a five-factor solution that accounted for 40·0% of the common variance. The factors included agitation/anxiety (agitation, anxiety of upcoming events; other anxiety), psychosis (delusions of theft, suspiciousness/paranoia; visual hallucinations), aggression (verbal aggressiveness; physical threats/violence; fear of being left alone; other delusions), depression (tearfulness; depressed mood) and activity disturbance (wandering; delusion one's house is not one's home). Several factors were associated with level of cognitive impairment as assessed by the Mini-Mental State Examination (MMSE). Conclusion. The results of this study suggest that the BEHAVE-AD measures a wide range of behavioral pathology that can be empirically represented by five independent symptom clusters among outpatient AD patients. Copyright © 1998 John Wiley & Sons, Ltd.     

Entorhinal cortex pathology in Alzheimer's disease.

The anatomical distribution of pathological changes in Alzheimer's disease, although highly selective for only certain brain areas, can be widespread at the endstage of the illness and can affect many neural systems. Propriety for onset among these is a question of importance for clues to the etiology of the disease, but one that is formidable without an experimental animal model. The entorhinal cortex (Brodmann's area 28) of the ventromedial temporal lobe is an invariant focus of pathology in all cases of Alzheimer's disease with selective changes that alter some layers more than others. The authors' findings reveal that it is the most heavily damaged cortex in Alzheimer's disease. Neuroanatomical studies in higher mammals reveal that the entorhinal cortex gives rise to axons that interconnect the hippocampal formation bidirectionally with the rest of the cortex. Their destruction in Alzheimer's disease could play a prominent role in the memory deficits that herald the onset of Alzheimer's disease and that characterize it throughout its course.     

Aging and Alzheimer's disease pathology

The number of people with dementia worldwide is predicted to increase to 131.5 million by 2050. When studying dementia, understanding the basis of the neuropathological background is very important. Taking Alzheimer's disease (AD) neuropathology as an example, we know that the accumulation of abnormal structures such as senile plaques and neurofibrillary tangles is a hallmark. Macroscopic atrophy affects the entorhinal area and hippocampus, amygdala, and associative regions of the neocortex. Braak advocates the spread of tau deposits from the entorhinal to associative regions of the neocortex as the disease progresses. If the AD has only tau pathology, the degree and distribution of tau deposition may be associated with clinical symptoms. However, AD is also accompanied by amyloid-β deposition and even atrophy. Although it is possible to make a neuropathological diagnosis of AD from the spread of amyloid and tau depositions, neuropathological abnormal protein accumulation cannot explain all clinical symptoms of AD. There is an ambiguity between clinical symptoms and neuropathological findings. It is important to understand neuropathological findings while understanding that this ambiguity exists. So, for the reader's help, first we briefly explain the changes in the brain with age, and then describe AD as a typical disease of dementia; finally we will describe the diseases that mimic AD for neurologists who are not experts in neuropathology.     

Comparison of minaprine and placebo in the treatment of Alzheimer's disease and multi-infarct dementia

Minaprine, an aminopyridazine derivative, represents a new class of antidepressants; in addition minaprine has been shown to possess cholinomimetic properties in rodents. Thus it seemed of interest to study the efficacy and tolerance of minaprine in the treatment of depressed mood, behavioural impairment and cognitive deterioration of senile dementia. A total of 122 patients were included in this three-month, randomized, double-blind, placebo-controlled, multicentric trial; 63 patients suffered from senile dementia of Alzheimer's type (SDAT) and 59 from multi-infarct dementia (MID). In both SDAT and MID, minaprine (100 mg bid) was more effective than placebo in relieving depressed mood. In some MID patients, minaprine also improved behavioural impairment. In SDAT patients, minaprine seemed to improve some aspects of cognitive function, as judged by a limited battery of psychometric tests. Overall, minaprine appeared to be more effective in MID, although longer treatment and/or higher dosage may be necessary in SDAT. The incidence of side-effects was low in both treatment groups.     

Recent advances in drug treatment for Alzheimer's dementia

The increasing ageing population and subsequent increase in dementia means that the need for finding appropriate treatments has become more important. Current treatments are limited and only provide some symptomatic improvements in patients. This article reviews the recent drug advances in treatment for Alzheimer's disease which have been of varying success. It appears that a combination of these will be required.     

Hypertension, white matter change and response to cholinesterase inhibitors in Alzheimer's disease

BACKGROUND: Cholinesterase inhibitors are used to treat mild to moderate Alzheimer's disease. Their role in patients with concurrent cerebrovascular disease has been less well studied, and the influence of vascular risk factors on response to treatment is uncertain. We investigated the effect of hypertension and white matter lesions (WML) on response. METHODS: A retrospective sample of 160 consecutive out-patients who had blood pressure measured and the presence or absence of WML recorded at baseline and who completed six months treatment with a cholinesterase inhibitor was studied. Subjects scored either zero or one on the Modified Hachinski Ischaemic Scale. Subjects were assessed using the Mini-Mental State Examination (MMSE), the Digit Symbol Substitution test (DSST) and both the Instrumental Activities of Daily Living (IADL) and Social Behaviour (SB) sub-scales of the Nurses Observation Scale for Geriatric Patients (NOSGER). RESULTS: 43.9% of the total study population were classified as good responders using our criteria. Neither the presence of hypertension nor the presence of WML alone influenced outcome. However, there was a statistically significant interaction between blood pressure and WML on outcome variables on multiple analysis of variance (MANOVA) (F(4, 139) = 5.60, p < 0.0005). Subjects with both hypertension and WML deteriorate to a significantly greater extent in IADL and SB scores than any other group (p < 0.05 in each case). This effect could not be explained by age or by smoking status. CONCLUSION: Our results support the hypothesis that there is an interaction between hypertension and WML that adversely influences functional change during cholinesterase inhibitor treatment. Our results are a contrast to suggestions that subjects with vascular disease show a better response to cholinesterase inhibitors. We recommend careful exploration of factors that may influence outcome.     

Comparing cerebral perfusion in Alzheimer's disease and Parkinson's disease dementia: an ASL-MRI study

Emerging evidence suggests that Alzheimer''s disease (AD) and Parkinson''s disease dementia (PDD) share neurodegenerative mechanisms. We sought to directly compare cerebral perfusion in these two conditions using arterial spin labeling magnetic resonance imaging (ASL-MRI). In total, 17 AD, 20 PDD, and 37 matched healthy controls completed ASL and structural MRI, and comprehensive neuropsychological testing. Alzheimer''s disease and PDD perfusion was analyzed by whole-brain voxel-based analysis (to assess absolute blood flow), a priori specified region of interest analysis, and principal component analysis (to generate a network differentiating the two groups). Corrections were made for cerebral atrophy, age, sex, education, and MRI scanner software version. Analysis of absolute blood flow showed no significant differences between AD and PDD. Comparing each group with controls revealed an overlapping, posterior pattern of hypoperfusion, including posterior cingulate gyrus, precuneus, and occipital regions. The perfusion network that differentiated AD and PDD groups identified relative differences in medial temporal lobes (AD<PDD) and right frontal cortex (PDD<AD). In conclusion, the pattern of cerebral hypoperfusion is very similar in AD and PDD. This suggests closely linked mechanisms of neurodegeneration mediating the evolution of dementia in both conditions.     

Alzheimer's disease in real life--the dementia carer's survey

BACKGROUND: Informal care from relatives provides the foundation of care for people with Alzheimer's disease (AD). It is important to understand the conditions under which carers perform their, often neglected, task. The dementia carer's survey aimed to identify carers' needs, differences between countries with regard to dementia care and the level of satisfaction of carers with utilised services. METHODS: The survey was conducted through Alzheimer Europe's member organisations in France, Germany, Poland, Spain and UK (Scotland). The survey was in the form of a questionnaire, and topics addressed included: demographics of carers and people with AD; time spent caring; disclosure of diagnosis; symptoms prompting diagnosis; diagnostic process; current and most distressing symptoms; carers' information requirements; evaluation of services. RESULTS: Each country had approximately 200 responders. Time spent caring increases with disease severity, and 50% of carers of people with late-stage dementia spent more than 10 h/day caring. Activities of daily living and behaviour were cited as the most problematic symptoms, reported by 68% and 50% of carers, respectively. Provision of information on all aspects of AD was felt to be inadequate, with key services such as home support not available to the majority of carers. Only 17% of carers considered the level of care for the elderly in their country as good. CONCLUSIONS: Further development of services and information provision are required to help carers in their everyday caring, including coping with problematic symptoms influencing areas such as activities of daily living and behaviour.