A volumetric study of hippocampus and amygdala in depressed patients with subjective memory problems

MRI was used to measure amygdalar and hippocampal volumes in 14 nondemented depressed patients who persistently complained of "memory" difficulties and in 14 control subjects. Mild neuropsychological impairment had been detected in 5 patients before the study but had later improved. The volume of the left amygdala was smaller in depressed subjects, and there was a trend for smaller left hippocampus in the 5 patients who had exhibited mild cognitive impairment. The authors conclude that subjective memory complaints in depressed patients do not translate into a clinical picture of dementia, but that abnormalities in the amygdala and hippocampus may be relevant in explaining affective and cognitive symptoms.     

Cerebral blood flow and metabolic changes in hippocampal regions of a modified rat model with chronic cerebral hypoperfusion

Chronic cerebral hypoperfusion (CCH) causes neurodegeneration which contributes to the cognitive impairment. This study utilized a modified rat model with CCH to investigate cerebral blood flow (CBF) and hippocampal metabolic changes. CBF was measured by laser Doppler flowmetry. Various metabolic ratios were evaluated from selective volumes of interest (VOI) in left hippocampal regions using in vivo proton magnetic resonance spectroscopy (¹H-MRS). The ultrastructural changes with special respect to ribosomes in rat hippocampal CA1 neurons were studied by electron microscopy. CBF decreased immediately after CCH and remained reduced significantly at 1 day and 3 months postoperatively. ¹H-MRS revealed that CCH led to a significant decrease of N-acetyl aspartate/creatine (NAA/Cr) ratio in the hippocampal VOI in the model rats compared with the sham-operated control rats. However, no changes of myo-inositol/Cr, choline/Cr and glutamate and glutamine/Cr ratios between the model and control groups were observed. Under electron microscopy, most rosette-shaped polyribosomes were relatively evenly distributed in the hippocampal CA1 neuronal cytoplasms of the control rats. After CCH, most ribosomes were clumped into large abnormal aggregates in the model rats. Our data suggests that both permanent decrease of CBF and reduction of NAA/Cr ratio in the hippocampal regions may be related to the cognitive deficits in rats with CCH.     

Correlations between antemortem hippocampal volume and postmortem neuropathology in AD subjects

Antemortem measures of hippocampal volume have been used to distinguish subjects with and without probable Alzheimer disease (AD). However, relatively little information is available about how well such antemortem measures correlate with postmortem measures of disease in AD subjects. In this study, antemortem magnetic resonance scans were collected from 10 subjects with probable AD and 3 nondemented controls who later came to autopsy. Significant correlations were observed between antemortem hippocampal volumes and both dementia severity and the density of hippocampal neurofibrillary tangles at autopsy. Total cerebral volumes, in contrast, were significantly correlated with the density of hippocampal senile plaques. The data suggest that hippocampal volume assessed in living subjects with probable AD is both a good marker of dementia severity and of an underlying element of the AD disease process.     

Longitudinal trajectory of Amyloid‐related hippocampal subfield atrophy in nondemented elderly

Hippocampal atrophy and abnormal β‐Amyloid (Aβ) deposition are established markers of Alzheimer's disease (AD). Nonetheless, longitudinal trajectory of Aβ‐associated hippocampal subfield atrophy prior to dementia remains unclear. We hypothesized that elevated Aβ correlated with longitudinal subfield atrophy selectively in no cognitive impairment (NCI), spreading to other subfields in mild cognitive impairment (MCI). We analyzed data from two independent longitudinal cohorts of nondemented elderly, including global PET‐Aβ in AD‐vulnerable cortical regions and longitudinal subfield volumes quantified with a novel auto‐segmentation method (FreeSurfer v.6.0). Moreover, we investigated associations of Aβ‐related progressive subfield atrophy with memory decline. Across both datasets, we found a converging pattern that higher Aβ correlated with faster CA1 volume decline in NCI. This pattern spread to other hippocampal subfields in MCI group, correlating with memory decline. Our results for the first time suggest a longitudinal focal‐to‐widespread trajectory of Aβ‐associated hippocampal subfield atrophy over disease progression in nondemented elderly.     

Hippocampal,amygdalar, and global brain atrophy in different apolipoprotein E genotypes

The epsilon4 allele of the APOE gene increases the risk for AD, whereas the epsilon2 allele may be protective. The authors assessed the impact of APOE genotype on hippocampal, amygdalar, and global brain atrophy as putative markers of preclinical AD in a nondemented population. Carriers of epsilon4 had significantly more hippocampal and amygdalar atrophy than epsilon3epsilon3 subjects, but not more global brain atrophy. Carriers of epsilon2 did not have less brain atrophy than epsilon3epsilon3 subjects.     

Cerebral blood flow in nondemented elderly subjects with extensive deep white matter lesions on magnetic resonance imaging

Our previous study showed that deep white matter lesions (DWML) were associated with subtle cognitive decline in community-dwelling elderly people. However, even extensive (EXT)-DWML, found in 7 (4%) of 178 subjects aged 60 years or older, did not cause dementia. The purpose of the present study was to investigate brain circulation in nondemented elderly subjects with EXT-DWML. We compared cerebral blood flow in the deep white matter and frontal cortex between 5 subjects with EXT-DWML and 5 without such lesions, using a xenon-enhanced computed tomography (CT) method. Although the difference of deep white matter findings on magnetic resonance imaging (MRI) was the greatest possible (i.e., extensive v no or minimum lesions), cerebral blood flow values in anterior deep white matter and frontal cortex were 21.4 ± 5.3 standard deviation (SD) mL/100 g/minute and 42.7 ± 4.1, respectively, in subjects with extensive lesions, which were not significantly different from 24.3 ± 4.3 and 44.0 ± 7.1 in subjects without DWML. The present study suggests that EXT-DWML in nondemented elderly individuals do not necessarily indicate apparent hypoperfusion or marked cognitive decline.     

Depressive symptoms and cognitive decline in late life: a prospective epidemiological study

CONTEXT: Depression is associated with cognitive impairment and dementia. It is less clear whether depression contributes to further cognitive decline over time, independently of incipient dementia. OBJECTIVE: To examine the relationship between depressive symptoms and subsequent cognitive decline in a cohort of nondemented older adults, some of whom remained dementia free during follow-up and others in whom incident dementia eventually developed. DESIGN: Twelve-year prospective epidemiological study, including biennial measurement of cognition and depressive symptoms, biennial assessment of dementia, and comparison of cognitive function at baseline and over time in persons with and without baseline depressive symptoms in the dementia-free and eventual-dementia groups, using random-effects models. SETTING: A largely blue-collar rural community. PARTICIPANTS: Population-based sample of 1265 adults 67 years and older without dementia at baseline. MAIN OUTCOME MEASURES: Scores over time on each of several cognitive test composites. RESULTS: Among 1094 participants who remained dementia free, those with baseline depressive symptoms had significantly lower baseline scores on all cognitive composites than the nondepressed participants. Among the 171 individuals in whom dementia later developed, depression was associated with worse performance in some but not all baseline cognitive composites. Cognitive decline over time was minimal in the dementia-free group, whereas marked decline was seen in the eventual-dementia group. Depressive symptoms were not associated with rate of cognitive decline over time in either group. CONCLUSIONS: Depressive symptoms are cross-sectionally associated with cognitive impairment but not subsequent cognitive decline. Substantial cognitive decline over time cannot be explained by depression and most likely reflects incipient dementia.     

Rates of decrease of cerebral blood flow in progressive dementias

To determine whether cerebral blood flow (CBF) progressively decreases as dementia progresses, we studied 133Xe washout at two or three different times in 23 demented patients. All 15 patients with Alzheimer's and 5 of 8 patients with vascular dementias had more rapid declines of CBF than did nondemented age-matched controls. Mean rate of change in Alzheimer's disease was -0.60 per month, compared with +0.29 per month in four controls tested twice. Regression analysis of CBF with age in 30 controls tested once showed a decline of CBF with aging at a rate of -0.013 per month. The rates of CBF decline in dementia were significantly correlated with rates of change of behavioral score measuring functional impairment.     

Alzheimer disease pathology in subjects without dementia in 2 studies of aging: the Nun Study and the Adult Changes in Thought Study

Individuals with antemortem preservation of cognition who show autopsy evidence of at least moderate Alzheimer disease (AD) pathology suggest the possibility of brain reserve, that is, functional resistance to structural brain damage. This reserve would, however, only be relevant if the pathologic markers correlate well with dementia. Using data from the Nun Study (n = 498) and the Adult Changes in Thought (ACT) Study (n = 323), we show that Braak staging correlates strongly with dementia status. Moreover, participants with severe(Braak stage V-VI) AD pathology who remained not demented represent only 12% (Nun Study) and 8% (ACT study) of nondemented subjects. Comparison of these subjects to those who were demented revealed that the former group was often significantly memory-impaired despite not being classified as demented. Most of these nondemented participants showed only stage V neurofibrillary pathology and frontal tangle counts that were slightly lower than a comparable (Braak stage V) dementia group. In summary, these data indicate that, in individuals with AD-type pathology who do not meet criteria for dementia, neocortical neurofibrillary tangles are somewhat reduced and incipient cognitive decline is present. Our data provide a foundation for helping to define additional factors that may impair, or be protective of, cognition in older adults.     

Correlation between cortical theta activity and hippocampal volumes in health, mild cognitive impairment, and mild dementia.

Cognitive decline is known to be associated with both increased theta power over frontal regions and hippocampal atrophy. The aim of this study was to reveal the relation between these parameters in groups with mild dementia, mild cognitive impairment, and healthy control subjects. The authors examined a preliminary randomly selected sample of 39 right-handed subjects joining the Leipzig Longitudinal Study of the Aged, consisting of 17 normal elderly subjects, 12 patients with mild cognitive impairment, and 10 patients with mild dementia assessed by Clinical Dementia Rating. All subjects were between 75 and 85 years old (mean age, 78 years; standard deviation, 2.78 years) and underwent EEG and brain MRI. Mean spectral power densities were calculated, and hippocampal body volume was measured. Significant negative linear correlations between theta power over frontal regions and hippocampal volumes were found. The results support the assumption about a relationship between hippocampal atrophy and theta power, and may be helpful for a better understanding of the course of Alzheimer's disease.     

Loss of entorhinal cortex and hippocampal volumes compared to whole brain volume in normal aging: The SMART-Medea study

In non-demented elderly age-related decline in hippocampal volume has often been observed, but it is not clear if this loss is disproportionate relative to other brain tissue. Few studies examined age-related volume loss of the entorhinal cortex. We investigated the association of age with hippocampal and entorhinal cortex (ERC) volumes in a large sample of middle-aged and older persons without dementia. Within the SMART-Medea study, cross-sectional analyses were performed in 453 non-demented subjects (mean age 62±9years, 81% male) with a history of arterial disease. Hippocampal and ERC volumes were assessed by manual segmentation on three-dimensional fast field-echo sequence T1-weighted magnetic resonance images. Automated segmentation was used to quantify volumes of BV and ICV. Hippocampal and ERC volumes were divided by intracranial volume (ICV) as well as total brain volume (BV) to determine whether age-related differences were disproportionate relative to other brain tissue. Total crude hippocampal volume was 5.96±0.7ml and total crude ERC volume was 0.34±0.06ml. Linear regression analyses adjusted for sex showed that with increasing age, hippocampal volume divided by ICV decreased (B per year older=-0.01ml; 95% CI -0.02 to -0.004). However, no age-related decline in hippocampal volume relative to BV was observed (B per year older=0.005ml; 95% CI -0.002 to 0.01). No age-related decline in ERC volume relative to ICV or BV was observed. In this population of nondemented patients with a history of vascular disease no age-related decline in entorhinal cortex volume was observed and although hippocampal volume decreased with age, it was not disproportionate relative to total brain volume.     

Apathy may herald cognitive decline and dementia in Parkinson's disease

Apathy is usually defined as a lack of motivation. It may occur as part of another disorder (notably depression and dementia) or as an isolated syndrome. In Parkinson's disease (PD), apathy is common and several studies have reported an association between this condition and more severe cognitive symptoms, such as executive dysfunction. However, this association has not been thoroughly investigated. The aim of this study (in nondepressed, nondemented PD patients) was to examine whether or not cognitive decline and/or dementia occurred more frequently in apathetic subjects than in nonapathetic subjects. Forty consecutive PD patients participated in the study (20 with apathy and 20 without). None of the subjects were either demented or depressed at the time of study entry. The patients' cognitive functions were extensively assessed twice: at study entry and after an 18‐month follow‐up period. At study entry, the apathetic PD patients had significantly lower global cognitive status and executive function scores than the nonapathetic subjects. After a median period of 18 months, the rate of conversion to dementia was found to be significantly higher in the apathetic group than in the nonapathetic group (8 of 20 and 1 of 20, respectively). Even in nondemented patients, the decrease over time in cognitive performance (mainly executive function but also memory impairment) was significantly greater in apathetic subjects than in nonapathetic subjects. These findings suggest that in nondemented, nondepressed PD patients, apathy may be a predictive factor for dementia and cognitive decline over time. © 2009 Movement Disorder Society     

Pathological markers associated with normal aging and dementia in the elderly

We investigated the associations of pathological markers of Alzheimer's disease (AD) and diffuse Lewy body disease as well as possible markers of vascular dementia with cognitive function in a sample of 20 nondemented and 35 demented subjects (median age of both groups, 88 years) who had been studied prospectively for 4.0 ± 2.1 years. Very old demented subjects almost always had nonneuritic senile plaques, but over half had no neuritic senile plaques and little other AD pathology. Five subjects had cortical Lewy bodies; all were demented. We propose that hippocampal sclerosis, leukoencephalopathy, and multiple lacunae are possible markers of vascular dementia. When grouped together, these markers were significantly associated with dementia and occurred in 40% of demented subjects. As the relative frequency of neuritic markers of AD (and possibly AD itself) declines in the tenth decade, vascular dementia may become an increasingly important type of dementia.     

Minocycline reduces microgliosis and improves subcortical white matter function in a model of cerebral vascular disease

Chronic cerebral hypoperfusion is a key mechanism associated with white matter disruption in cerebral vascular disease and dementia. In a mouse model relevant to studying cerebral vascular disease, we have previously shown that cerebral hypoperfusion disrupts axon‐glial integrity and the distribution of key paranodal and internodal proteins in subcortical myelinated axons. This disruption of myelinated axons is accompanied by increased microglia and cognitive decline. The aim of the present study was to investigate whether hypoperfusion impairs the functional integrity of white matter, its relation with axon‐glial integrity and microglial number, and whether by targeting microglia these effects can be improved. We show that in response to increasing durations of hypoperfusion, the conduction velocity of myelinated fibres in the corpus callosum is progressively reduced and that paranodal and internodal axon‐glial integrity is disrupted. The number of microglial cells increases in response to hypoperfusion and correlates with disrupted paranodal and internodal integrity and reduced conduction velocities. Further minocycline, a proposed anti‐inflammatory and microglia inhibitor, restores white matter function related to a reduction in the number of microglia. The study suggests that microglial activation contributes to the structural and functional alterations of myelinated axons induced by cerebral hypoperfusion and that dampening microglia numbers/proliferation should be further investigated as potential therapeutic benefit in cerebral vascular disease.     

Accelerated hippocampal atrophy rates in stable and progressive amnestic mild cognitive impairment

Studies suggest that smaller hippocampal volume predicts Alzheimer's disease (AD) in mild cognitive impairment (MCI). However, few studies have demonstrated decline rates in cognition and hippocampal volume in MCI subjects with stable clinical presentation. Furthermore, the effects of apolipoprotein E (ApoE) on the change rates of medial temporal structures and cognition in MCI are rarely investigated. Fifty-eight subjects with amnestic MCI and 20 normal aging elderly controls received annual neuropsychological and magnetic resonance imaging (MRI) assessments. Annual decline rates in neuropsychological test scores, hippocampal and amygdalar volumes were calculated. ApoE genotypes were examined. Nineteen (32.7%) MCI subjects converted to AD during an average 22.5-month follow-up period. The annual hippocampal atrophy rate was correlated with a decline in memory test scores. The presence of the ApoE ?4 allele did not affect the change rates in neuropsychological test scores and medial temporal structures volume. Compared to subjects with stable MCI (MCI-S) and normal aging, progressive MCI (MCI-P) had the highest annual decline rates in cognition and hippocampal volume. Logistic regression analysis showed that higher annual decline rates in hippocampal volume and global cognitive test scores were associated with conversion to AD. Furthermore, although MCI-S subjects had little cognitive decline, their hippocampal atrophy rates were higher than those of normal aging controls. Therefore, accelerated hippocampal atrophy rates may be an early and important presentation in MCI subjects.     

Cerebral hypoperfusion and glucose hypometabolism: Key pathophysiological modulators promote neurodegeneration,cognitive impairment,and Alzheimer's disease

Aging, hypertension, diabetes, hypoxia/obstructive sleep apnea (OSA), obesity, vitamin B12/folate deficiency, depression, and traumatic brain injury synergistically promote diverse pathological mechanisms including cerebral hypoperfusion and glucose hypometabolism. These risk factors trigger neuroinflammation and oxidative‐nitrosative stress that in turn decrease nitric oxide and enhance endothelin, Amyloid‐β deposition, cerebral amyloid angiopathy, and blood–brain barrier disruption. Proinflammatory cytokines, endothelin‐1, and oxidative‐nitrosative stress trigger several pathological feedforward and feedback loops. These upstream factors persist in the brain for decades, upregulating amyloid and tau, before the cognitive decline. These cascades lead to neuronal Ca²⁺ increase, neurodegeneration, cognitive/memory decline, and Alzheimer's disease (AD). However, strategies are available to attenuate cerebral hypoperfusion and glucose hypometabolism and ameliorate cognitive decline. AD is the leading cause of dementia among the elderly. There is significant evidence that pathways involving inflammation and oxidative‐nitrosative stress (ONS) play a key pathophysiological role in promoting cognitive dysfunction. Aging and several comorbid conditions mentioned above promote diverse pathologies. These include inflammation, ONS, hypoperfusion, and hypometabolism in the brain. In AD, chronic cerebral hypoperfusion and glucose hypometabolism precede decades before the cognitive decline. These comorbid disease conditions may share and synergistically activate these pathophysiological pathways. Inflammation upregulates cerebrovascular pathology through proinflammatory cytokines, endothelin‐1, and nitric oxide (NO). Inflammation‐triggered ONS promotes long‐term damage involving fatty acids, proteins, DNA, and mitochondria; these amplify and perpetuate several feedforward and feedback pathological loops. The latter includes dysfunctional energy metabolism (compromised mitochondrial ATP production), amyloid‐β generation, endothelial dysfunction, and blood–brain‐barrier disruption. These lead to decreased cerebral blood flow and chronic cerebral hypoperfusion‐ that would modulate metabolic dysfunction and neurodegeneration. In essence, hypoperfusion deprives the brain from its two paramount trophic substances, viz., oxygen and nutrients. Consequently, the brain suffers from synaptic dysfunction and neuronal degeneration/loss, leading to both gray and white matter atrophy, cognitive dysfunction, and AD. This Review underscores the importance of treating the above‐mentioned comorbid disease conditions to attenuate inflammation and ONS and ameliorate decreased cerebral blood flow and hypometabolism. Additionally, several strategies are described here to control chronic hypoperfusion of the brain and enhance cognition. © 2016 Wiley Periodicals, Inc.     

Serial quantitative CT analysis of brain morphometrics in adult Down's syndrome at different ages

Quantitative CT demonstrated increased CSF and 3rd ventricular volumes, and decreased gray matter and white matter volume, in older (greater than 45 years) Down's syndrome (DS) adults with dementia as compared with younger DS adults. Serial CT studies repeated after periods of up to 2 years demonstrated significant progressive cerebral atrophy. Older DS adults without dementia, but with cognitive decline, did not show cerebral atrophy as compared with young DS subjects. These results suggest brain atrophy must be present to accompany dementia in older DS subjects, despite the presence of Alzheimer's disease neuropathology in all older subjects. The Alzheimer's disease process in DS may occur in 2 stages, the 1st with neuropathology and cognitive decline, the 2nd with additional cerebral atrophy and dementia.     

Cerebral perfusion alterations in type 2 diabetes and its relation to insulin resistance and cognitive dysfunction

To explore the effect of T2DM on cerebral perfusion, and the relationship between cerebral perfusion changes and cognitive impairment as well as diabetic variables, by using a whole-brain arterial spin-labeling (ASL) MRI technique. This prospective study was approved by the local institutional review board and was performed between November 2012 and October 2013. All subjects provided informed consent. Forty T2DM patients and 41 age-, sex- and education-matched healthy controls were included. Cerebral blood flow (CBF) map was obtained by pulsed ASL perfusion imaging at 3 T MRI. Voxel-wise comparisons on CBF maps with and without partial volume effects (PVEs) correction were performed between groups. Associations between CBF and cognitive functioning, and between CBF and diabetic variables were investigated by using voxel-wise, whole-brain correlation analyses. In T2DM patients, PVEs uncorrected CBF was decreased in the posterior cingulate cortex (PCC), precuneus and bilateral occipital lobe, and increased in the anterior cingulate cortex (corrected P < .05). These changes were largely unchanged after PVEs correction. Correlation analyses revealed that in patients, hypoperfusion in PCC and precuneus regions were related to higher insulin resistance level and deficits in clock-drawing performance, while the occipital hypoperfusion was associated with worse visual-memory performance, regardless of PVEs correction. The cerebral hypoperfusion pattern in T2DM resembles the pattern observed in the early stage of dementia, and increased insulin resistance might be an important risk factor as well as treatment target for such CBF dysregulation.     

Pathophysiology of neuronal energy crisis in Alzheimer's disease

A large body of evidence indicates that sporadic Alzheimer's disease (AD) is a vascular disorder with neurodegenerative consequences and needs to be treated and managed as such. Epidemiologic studies of vascular risk factors, together with preclinical detection tools for AD are proof of concept that cerebral hypoperfusion is one of the earliest pathological signs in the development of cognitive failure. Vascular risk factors involving heart disease and stroke in the elderly individual who already possesses a dwindling cerebrovascular reserve due to advancing age contribute to further decline in cerebral blood flow (CBF) resulting in unrelenting brain hypoperfusion. Brain hypoperfusion, in turn, can reach a critically attained threshold of cerebral hypoperfusion (CATCH) giving rise to a neuronal energy crisis via reduced ATP synthesis. The ensuing metabolic energy crisis initially carves up ischemic-sensitive neurons in the hippocampus and posterior parietal cortex setting up cognitive meltdown and progressive neurodegenerative and atrophic changes in the brain. Neuronal energy compromise accelerates oxidative stress, excess production of reactive oxygen species, aberrant protein synthesis, ionic membrane pump dysfunction, signal transduction impairment, neurotransmitter failure, abnormal processing of amyloid precursor protein resulting in beta-amyloid deposition and axonal microtubule disruption from tau hyperphosphorylation. The high energy metabolic changes leading to oxidative stress and cellular hypometabolism precede clinical expression of AD. Regional CBF measurements using neuroimaging techniques can predict AD preclinically at the mild cognitive impairment stage or even before any clinical manifestation of dementia is expressed. Clinical diagnostic assessment of elderly persons who could develop or already present with memory complaints can prevent, reverse or slow down AD development. Although pathologic aging is the subject of thousands of studies, the question of why the elderly (and not younger people) succumb to AD has not been adequately addressed. The explanation(s) as to why vascular risk factors, for example, can trigger AD or vascular dementia usually in the elderly and not the young should provide vital clues in the search for a strategically effective dementia treatment. This review offers inductive hypothetical darts relative to that critical question.     

Hippocampal and amygdalar volumes in relation to handedness in adults aged 60-64

We evaluated the association between handedness and manual tracings of hippocampal and amygdalar volumes. Brain MRI and handedness data were obtained for 441 community dwelling participants aged 60-64 years of whom 31 were left-handed. Both absolute and normalized hippocampal volumes were larger in left-handed women than right-handed women. Hippocampal volume was not associated with handedness in men, and amygdalar volume was not associated with handedness in men or women. There was no right-left asymmetry in hippocampal or amygdalar volumes in either gender. We conclude that volumetric differences by handedness must be taken into account where hippocampal volumes are of clinical importance. Our results may also explain reports of lower rates of dementia in left-handed individuals.