Functional, global and cognitive decline correlates to accumulation of Alzheimer's pathology in MCI and AD.

BACKGROUND: Cognitive, global and functional instruments have been extensively investigated for correlations with neuropathological changes such as neurofibrillary tangles (NFTs), plaques, and synapse loss in the brain. OBJECTIVE: Our objective is to correlate the functional, global and cognitive decline assessed clinically with the neuropathological changes observed in a large prospectively characterized cohort of mild cognitive impairment (MCI) and Alzheimer's disease (AD). METHODS: We examined 150 subjects (16 MCI and 134 AD) that were prospectively assessed and longitudinally followed to autopsy. MCI subjects clinically met Petersen criteria for single or multi-domain amnestic MCI. AD subjects clinically met NINCDS-ADRDA criteria for probable or possible AD. All subjects received the Functional Assessment Staging (FAST), the Global Deterioration Scale (GDS), and the Mini Mental State Examination (MMSE) ante-mortem. Plaque and tangle counts were gathered for hippocampus, entorhinal cortex, frontal, temporal and parietal cortices. Braak staging was performed as well. RESULTS: The GDS, FAST and MMSE correlated with plaque counts in all regions. The GDS, FAST and MMSE correlated with tangle counts in in all regions. The three instruments also correlated with the Braak score. The MMSE and GDS correlate better than the FAST in most regions. CONCLUSIONS: Accumulation of neuropathology appears to correlate with functional, global, and cognitive decline as people progress from MCI through AD.

Neuroprotection by novel antagonists at the NMDA receptor channel and glycineB sites.

Glutamate may act via an N-methyl-D-Aspartate (NMDA)-sensitive receptor site to destroy cholinergic neurons within the nucleus basalis magnocellularis in age-associated neurodegenerative diseases. Multiple interesting properties of the NMDA receptor are relevant to its excitotoxic actions, e.g., glutamate is ineffective unless a glycine (gly) modulatory site is also occupied. Thus, the antagonism of glutamate receptor-related toxicity by blockade of either the NMDA-sensitive recognition site or the gly binding site may therefore have therapeutic applications. The current study investigated the ability of four novel noncompetitive antagonists at these two sites: one NMDA open channel antagonist (MRZ 2/579: 1-amino-1,3,3,5,5-pentamethyl-cyclohexane hydrochloride), and three glyB receptor antagonists (MRZ 2/570: 8-bromo-4-hydroxy-1-oxo-1,2-dihydropyridaziono [4,5-beta] quinoline-5-oxide choline salt; MRZ 2/57: 8-fluoro-4-hydroxy-1-oxo-1,2-dihydropyridaziono [4,5-beta] quinoline-5-oxide choline; MRZ 2/576: 8-chloro-4-hydroxy-1-oxo-1,2-dihydropyridaziono [4,5-beta] quinoline-5-oxide choline) administered acutely, to provide neuroprotection from a NMDA receptor agonist within the nucleus basalis magnocellularis of young rats. Injection of NMDA into the nucleus basalis magnocellularis significantly decreased cortical choline acetyltransferase activity. Acute administration (i.p.) of MRZ 2/579, 2/570, 2/571 and 2/576 provided significant neuroprotection from NMDA.

Chronic neuroinflammation in rats reproduces components of the neurobiology of Alzheimer's disease.

Inflammatory processes may play a critical role in the pathogenesis of the degenerative changes and cognitive impairments associated with Alzheimer's disease (AD). In the present study, lipopolysaccharide (LPS) from the cell wall of gram-negative bacteria was used to produce chronic, global inflammation within the brain of young rats. Chronic infusion of LPS (0.25 microgram/h) into the 4th ventricle for four weeks produced (1) an increase in the number of glial fibrillary acidic protein-positive activated astrocytes and OX-6-positive reactive microglia distributed throughout the brain, with the greatest increase occurring within the temporal lobe, particularly the hippocampus, (2) an induction in interleukin-1 beta, tumor necrosis factor-alpha and beta-amyloid precursor protein mRNA levels within the basal forebrain region and hippocampus, (3) the degeneration of hippocampal CA3 pyramidal neurons, and (4) a significant impairment in spatial memory as determined by decreased spontaneous alternation behavior on a T-maze.

Novel glycineB antagonists show neuroprotective activity in vivo.

The degeneration or dysfunction of cholinergic neurons within the basal forebrain of patients with Alzheimer's disease (AD) may be related to the vulnerability of these cells to endogenous glutamate (Beal, 1995; Greenamyre and Young, 1989). The administration of drugs that attenuate the toxic actions of glutamate in the early stages of the disease might significantly delay its rate of progression. Two approaches to neuroprotection from endogenous glutamatergic function were investigated and found to be effective: blockade of voltage-dependent, NMDA-type glutamate receptor channels and antagonism of an NMDA-receptor related glycineB modulatory site.

The effects of selective cholinergic basal forebrain lesions and aging upon expectancy in the rat.

The effects of selective cholinergic cell loss within the basal forebrain (BF) were determined using a task that requires shifting of attention between two visual stimuli. Discriminability between two stimuli and response bias were determined in young and old F-344 rats given BF injections of IgG-192 saporin (100 ng). The lesion reduced ChAT activity in the frontal and parietal cortices, hippocampus, and olfactory bulbs. The lesion did not significantly alter Na+/K(+)-ATPase activity in cortex, hippocampus, or olfactory bulbs, or endogenous levels of neuropeptide Y and neurokinin B within the BF. The BF lesions impaired both stimulus discriminability and response bias in young and old rats. The BF lesions had a significantly greater effect upon stimulus discriminability and response bias in aged rats, compared to young rats, only when the stimulus duration was very brief, i.e., when the task was most difficult to solve. At longer stimulus durations, aging and lesions showed no interaction. The results suggest that the selective loss of cholinergic cells in the BF, but not normal aging, impairs the ability to discriminate between independent sensory stimuli. The loss of these cells confers a response bias in simple operant tasks involving motor responses to reward-related visual stimuli.

Age-related decrease in vulnerability to excitatory amino acids in the nucleus basalis.

The present study investigated the effects of nucleus basalis magnocellularis (NBM) lesions in young (3 months), adult (9 months), and aged (24 months) rats by injections of either NMDA or AMPA upon performance of a delayed alternation task on a T maze. During phase 1 of testing, the interchoice interval (ICI) was 5 s and each rat was given 10 trials per day during phase 2, the ICI was 30 s across 10 trials per day; during phase 3, the ICI was 5 s across 20 trials per day. Analyses of variance revealed (a) a significant effect of age during phase 1 (i.e., 24-month-old rats performed worse than 3-month-old rats); (b) a significant effect of age and lesion in phase 2 (i.e., the lesions impaired choice accuracy equally in all age groups when the ICIs were 30 s); (c) a significant effect of age and lesions, and a significant interaction in phase 3 (i.e., young rats were more impaired by the lesions than were aged rats.

Behavioral, biochemical, histological, and electrophysiological effects of 192 IgG-saporin injections into the basal forebrain of rats.

The behavioral, biochemical, histological, and electrophysiological effects of a basal forebrain injection of saporin, a ribosome-inactivating protein, coupled to a monoclonal antibody against the low-affinity NGF receptor (192 IgG) were investigated in adult rats. Within the basal forebrain region, the low-affinity NGF receptor is exclusively expressed by cholinergic neurons in the medial septal area, diagonal band, and nucleus basalis magnocellularis (NBM). The presence of this receptor upon these cells confers a degree of specificity to the 192 IgG-saporin that could not previously be achieved by previous lesioning techniques, such as excitatory amino acids. Rats with unilateral injections of different amounts of 192 IgG-saporin were prepared to determine the optimal conditions in order to produce a lesion restricted to the NBM that would not destroy cholinergic afferents to hippocampus or nearby regions. Electroencephalographic (EEG) recordings were taken from these lesioned rats before and during treatment with scopolamine (1 mg/kg, i.p.). Another group of rats received bilateral NBM injections of 192 IgG-saporin and were behaviorally tested using a rewarded, delayed-alternation task on a T-maze and a passive avoidance task. Finally, histological and biochemical investigations confirmed the effectiveness and specificity of the 192 IgG-saporin. The results showed that the 192 IgG-saporin did not destroy neurotensin, galanin, somatostatin, NADPH-diaphorase, or neuropeptide Y neurons within the NBM. Also, biomarkers of cholinergic function were significantly decreased throughout the neocortex and within the NBM, but not in the olfactory bulbs, hippocampus, or dorsal caudate nucleus. Intraperitoneal injections of scopolamine, but not NBM injections of 192 IgG-saporin, increased total power across all frequency bands; however, slow-wave frequencies showed a greater increase in power as compared to fast-wave frequencies. Acquisition, and performance of the delayed-alternation or passive avoidance tasks were not impaired by the lesions. These data confirm the effectiveness and specificity of this novel lesioning tool and suggest that selective loss of NBM cholinergic cells is not sufficient to impair performance in these behavioral tasks.

Homozygous Brattleboro rats display attenuated conditioned freezing responses.

In the present study we examined the influence of arginine vasopressin (AVP) on conditioned freezing behavior to aversive shock treatment by comparing the responses of Brattleboro homozygous (DI) rats, Brattleboro heterozygous (HZ) rats, and Long-Evans (LE) rats. Each animal was placed in a sound-attenuated shock chamber on the training day and given a series of 3 footshocks. On the following 4 consecutive days the rats were placed in the chambers where they had received their shock and levels of spontaneous freezing were evaluated. Levels of circulating vasopressin-associated neurophysin (NP) were subsequently determined in each rat strain. For each of the 4 test days, DI rats displayed significantly less freezing behavior when compared with LE rats and HZ rats. HZ rats displayed trends towards attenuated freezing responses when compared with LE rats. The data indicate that a relationship exists between the levels of central nervous system (CNS) and circulating AVP, and the amount of freezing displayed by each strain. These preliminary results suggest that vasopressin may be involved in appropriate autonomic and emotional responses to fearful stimuli in fear conditioning paradigms.

Oxytocin and vasopressin hexapeptide fragments have opposing influences on conditioned freezing behavior.

We investigated the influence of C-terminal fragments of oxytocin (OT) and arginine vasopressin (AVP) on conditioned freezing behavior. Subcutaneous injections of 0.3 microgram AVP(4-9) or OT(4-9) given to rats after shock training or before behavioral observation significantly altered fear-induced freezing behavior. Animals treated with OT hexapeptide froze less than controls, while animals treated with AVP hexapeptide froze more. These results support the concept that the hexapeptide metabolites of oxytocin and vasopressin can selectively modulate certain behavioral processes, and that these peptides have opposite effects on performance in behavioral tests designed to evaluate memory consolidation and retrieval.