Intervention for Cognitive Reserve Enhancement in Delaying the Onset of Alzheimer's Symptomatic Expression (INCREASE) Study: Results from a Randomized Controlled Study of Medication Therapy Management Targeting a Delay in Prodromal Dementia Symptom Progression.

BACKGROUND: Cognitive reserve has been hypothesized as a mechanism to explain differences in individual risk for symptomatic expression of Alzheimer's Disease (AD). Inappropriate medications may diminish cognitive reserve, precipitating the transition from preclinical AD (pAD) to a symptomatic state. To date, there is limited data on the potential impact of medication optimization as a potential tool for slowing the symptomatic expression of AD. OBJECTIVES: (1) To test the efficacy of a medication therapy management intervention designed to bolster cognitive reserve in community-dwelling older adults without dementia. (2) To evaluate the efficacy of intervention by baseline pAD status. DESIGN: A 1-year randomized controlled trial was conducted in community-dwelling older adults without dementia. Randomization was stratified by amyloid ß positron emission tomography levels. SETTING: Community-based, Lexington, Kentucky. PARTICIPANTS: Adults 65 years or older with no evidence of dementia and reporting at least one potentially inappropriate medication as listed in the Beers 2015 criteria were recruited. The study aimed to enroll 90 participants based on the a priori sample size calculation. INTERVENTION: Medication therapy management versus standard of care. MEASUREMENTS: Primary outcomes were: (1) one-year changes in the Medication Appropriateness Index; (2) one-year changes in Trail Making Test B under scopolamine challenge. RESULTS: The medication therapy management intervention resulted in significant improvement in Medication Appropriateness Index scores. Overall, there was no beneficial effect of the medication therapy management on Trail Making Test B scores, however stratified analysis demonstrated improvement in Trail Making Test B challenged scores associated with the medication therapy management for those with elevated amyloid ß positron emission tomography levels consistent with pAD. CONCLUSIONS: Medication therapy management can reduce inappropriate medication use in older adults at risk for AD. Our study indicated beneficial cognitive effects in those with preclinical Alzheimer's Disease. No statistically significant effects were evident in the study group as a whole, or in those without preclinical cerebral amyloidosis. Further work designed to improve the effectiveness of the medication therapy management approach and defining other preclinical pathologic states that may benefit from medication optimization are readily achievable goals for promoting improved cognitive health and potentially delaying the onset of symptomatic AD.

Identifying dementia in Down syndrome with the Severe Impairment Battery, Brief Praxis Test and Dementia Scale for People with Learning Disabilities.

BACKGROUND: Individuals with Down syndrome (DS) are at high risk for dementia, specifically Alzheimer's disease. However, many measures regularly used for the detection of dementia in the general population are not suitable for individuals with DS due in part to floor effects. Some measures, including the Severe Impairment Battery (SIB), Brief Praxis Test (BPT) and Dementia Scale for People with Learning Disabilities (DLD), have been used in clinical trials and other research with this population. Validity research is limited, particularly regarding the use of such tools for detection of prodromal dementia in the DS population. The current project presents baseline cross-sectional SIB, BPT and DLD performance in order to characterise their predictive utility in discriminating normal cognition, possible dementia and probable dementia in adult DS. METHOD: Baseline SIB, BPT and DLD performances from 100 individuals (no dementia = 68, possible dementia = 16 & probable dementia = 16) were examined from a longitudinal cohort of aging individuals with DS. Receiver operating characteristic curves investigated the accuracy of these measures in relation to consensus dementia diagnoses, diagnoses which demonstrated high percent agreement with the examining neurologist's independent diagnostic impression. RESULTS: The SIB and BPT exhibited fair discrimination ability for differentiating no/possible versus probable dementia [area under the curve (AUC) = 0.61 and 0.66, respectively]. The DLD exhibited good discrimination ability for differentiating no versus possible/probable dementia (AUC = 0.75) and further demonstrated better performance of the DLD Cognitive subscale compared with the DLD Social subscale (AUC = 0.77 and 0.67, respectively). CONCLUSIONS: Results suggest that the SIB, BPT and DLD are able to reasonably discriminate consensus dementia diagnoses in individuals with DS, supporting their continued use in the clinical assessment of dementia in DS. The general performance of these measures suggests that further work in the area of test development is needed to improve on the AUCs for dementia status discrimination in this unique population. At present, however, the current findings suggest that the DLD may be the best option for reliable identification of prodromal dementia in this population, reinforcing the importance of including informant behaviour ratings in assessment of cognition for adults with DS.

Self-Reported Memory Complaints: A Comparison of Demented and Unimpaired Outcomes.

BACKGROUND: Subjective memory complaints are common in aged persons, indicating an increased, but incompletely understood, risk for dementia. OBJECTIVE: To compare cognitive trajectories and autopsy results of individuals with subjective complaints after stratifying by whether a subsequent clinical dementia occurred. DESIGN: Observational study. SETTING: University of Kentucky cohort with yearly longitudinal assessments and eventual autopsies. PARTICIPANTS: Among 516 patients who were cognitively intact and depression-free at enrollment, 296 declared a memory complaint during follow-up. Among those who came to autopsy, 118 died but never developed dementia, while 36 died following dementia diagnosis. MEASUREMENTS: Cognitive domain trajectories were compared using linear mixed models adjusted for age, gender, years of education and APOE status. Neuropathological findings were compared cross-sectionally after adjustment for age at death. RESULTS: While the groups had comparable cognitive test scores at enrollment and the time of the first declaration of a complaint, the group with subsequent dementia development had steeper slopes of decline in episodic memory and naming but not fluency or sequencing. Autopsies showed the dementia group had more severe Alzheimer pathology and a higher proportion of subjects with hippocampal sclerosis of aging and arteriolosclerosis, whereas the non-demented group had a higher proportion expressing primary age related tauopathy (PART). CONCLUSIONS: While memory complaints are common among the elderly, not all individuals progress to dementia. This study indicates that biomarkers are needed to predict whether a complaint will lead to dementia if this is used as enrollment criteria in future clinical trials.

Differential reports of pain and depression differentiate mild cognitive impairment from cognitively intact elderly participants.

BACKGROUND: Positive associations between pain and depression in the general population have been well characterized; however, the interplay between pain, depression, and early cognitive decline, characterized as mild cognitive impairment (MCI), is poorly understood. METHODS: The current study examined the association of self-reported pain complaints (measured by the 36-item Short Form Health Survey) and self-reported depressive symptoms (measured by the 30-item Geriatric Depression Scale) in cognitively intact participants (n = 492) and participants with a clinical diagnosis of MCI (n = 83). RESULTS: Depressive symptoms and subjective reports of pain were significantly associated in the entire sample (r = .29; P < .0001). Multiple logistic regression modeling (adjusted for age, education, and APOE4 status as covariates) demonstrated that while depressive symptoms were positively associated with the diagnosis of MCI (P < .001), subjective pain reports were negatively associated with MCI (P < .002). CONCLUSION: While the negative association of subjective pain complaints with MCI might arguably be explained by the development of anosognosia, self-reports of depressive symptoms were actually increased in these participants, suggesting preserved insight into cognitive decline-associated symptoms. It is possible that preferential involvement of limbic circuitry in MCI could explain these findings. Future studies are needed to elucidate the reasons for the dissociation of pain and depressive symptoms in MCI described in the present article.

Attention-deficit/hyperactivity disorder in childhood is associated with cognitive test profiles in the geriatric population but not with mild cognitive impairment or Alzheimer's disease.

The frequency of ADHD in the aging population and its relationship to late-life cognitive decline has not been studied previously. To address this gap in our understanding, the Wender-Utah ADHD Rating scale (WURS) was administered to 310 geriatric subjects with cognitive status ranging from normal cognition to mild cognitive impairment to overt dementia. The frequency of WURS-positive ADHD in this sample was 4.4%. WURS scores were not related to cognitive diagnoses, but did show nonlinear associations with tasks requiring sustained attention. The frequency of ADHD appears stable across generations and does not appear to be associated with MCI or dementia diagnoses. The association of attentional processing deficits and WURS scores in geriatric subjects could suggest that such traits remain stable throughout life. Caution should be considered when interpreting cognitive test profiles in the aging population that exhibit signs and symptoms of ADHD, as attentional deficits may not necessarily imply the existence of an underlying neurodegenerative disease state.

Prodromal clinical manifestations of neuropathologically confirmed Lewy body disease.

The mild cognitive impairment (MCI) stage of dementia with Lewy bodies (MCI-DLB) has not yet been defined, but is likely to differ in the MCI stage of Alzheimer's disease (MCI-AD). To determine whether clinical features distinguish MCI-DLB and MCI-AD, 9 cases of neuropathologically confirmed MCI-DLB and 12 cases of MCI-AD were compared. No significant differences were found between MCI-DLB and MCI-AD cases in age at death, gender, ApoE status, education, time followed while clinically normal, or duration of MCI. MCI-DLB and MCI-AD cases differed clinically in the expression of Parkinsonism (P=0.012), provoked hallucinations or delirium (P=0.042), or the presence of any of these noncognitive symptoms of DLB (P<0.0001). Letter fluency (P=0.007) was significantly lower and Wechsler Logical Memory I (P=0.019) was significantly higher in MCI-DLB compared to MCI-AD cases. These data demonstrate the feasibility of differentiating underlying pathologic processes responsible for cognitive decline in the preclinical disease state and suggest that further refinement in diagnostic criteria may allow more accurate early detection of prodromal DLB and AD.

Relative preservation of MMSE scores in autopsy-proven dementia with Lewy bodies.

BACKGROUND: Recent studies raised questions about the severity of cognitive impairment associated with dementia with Lewy bodies (DLB). However, there have been few analyses of large, multicenter data registries for clinical-pathologic correlation. METHODS: We evaluated data from the National Alzheimer's Coordinating Center registry (n = 5,813 cases meeting initial inclusion criteria) and the University of Kentucky Alzheimer's Disease Center autopsy series (n = 527) to compare quantitatively the severity of cognitive impairment associated with DLB pathology vs Alzheimer disease (AD) and AD+DLB pathologies. RESULTS: Mini-Mental State Examination (MMSE) scores showed that persons with pure DLB had cognitive impairment of relatively moderate severity (final MMSE score 15.6 +/- 8.7) compared to patients with pure AD and AD+DLB (final MMSE score 10.7 +/- 8.6 and 10.6 +/- 8.6). Persons with pure DLB pathology from both data sets had more years of formal education and were more likely to be male. Differences in final MMSE scores were significant (p < 0.01) between pure DLB and both AD+DLB and pure AD even after correction for education level, gender, and MMSE-death interval. Even in cases with extensive neocortical LBs, the degree of cognitive impairment was most strongly related to the amount of concomitant AD-type neurofibrillary pathology. CONCLUSIONS: Dementia with Lewy bodies can constitute a debilitating disease with associated psychiatric, motoric, and autonomic dysfunction. However, neocortical Lewy bodies are not a substrate for severe global cognitive impairment as assessed by the Mini-Mental State Examination. Instead, neocortical Lewy bodies appear to constitute or reflect an additive disease process, requiring Alzheimer disease or other concomitant brain diseases to induce severe global cognitive deterioration.

Clinical features of mild cognitive impairment differ in the research and tertiary clinic settings.

OBJECTIVE: Comparative analysis of subjects with mild cognitive impairment (MCI) diagnosed in a primary research setting and those seen in a tertiary care memory disorders clinic. METHODS: Subjects who received a diagnosis of MCI between July 1, 2005, and December 31, 2006, in a longitudinal research study of normal cognition (n = 48) and patients diagnosed in a tertiary care referral clinic (n = 34) were evaluated using similar methodologies. Comparative analyses of detailed medical, neurological and neuropsychological data are presented. RESULTS: The diagnosis of MCI was not accepted by 13 of 48 subjects (27%) classified as MCI in the primary research setting. Nondegenerative, potentially treatable causes of cognitive decline were found in 3 of 34 subjects (9%) seen in the tertiary referral clinic and in 11 of 35 subjects (31%) identified as MCI in the primary research setting (p = 0.02, Fisher's exact test). MCI subjects identified in the primary research setting were older than those referred to the memory clinic (mean +/- SD, 79.7 +/- 7.0 vs. 71.5 +/- 9.0 years, p < 0.0001, t test) and had more years of education (16.0 +/- 3.2 vs. 13.6 +/- 4.2 years, p < 0.01, t test). MCI subjects in the primary research setting appeared to be in a milder stage of disease, characterized by higher Mini-Mental State Examination scores (28.2 +/- 1.8 vs. 25.7 +/- 1.8, p < 0.0001), and a tendency towards single domain involvement, predominantly memory (mean number of domains involved, 1.0 vs. 2.5, p < 0.0001). More advanced stages of MCI, seen in the tertiary referral population, had additional involvement of attention (p < 0.0001, Fisher's exact test) and visuospatial domains (p < 0.0002, Fisher's exact test). Semiquantitative grading of hippocampal and medial temporal lobe atrophy did not differ between groups (p = 0.81, Mann-Whitney U test). CONCLUSIONS: The diagnosis of MCI may be unwelcome in naïve persons. Remedial causes of MCI should be actively investigated. Demographic and clinical characteristics of MCI differ between research subjects and patients referred to a tertiary care clinic.

Brain structural alterations before mild cognitive impairment.

OBJECTIVE: To determine whether alterations of brain structure in normal aged individuals precede the development of mild cognitive impairment (MCI) or Alzheimer disease (AD). BACKGROUND: Persons with MCI and AD demonstrate cortical volume losses vs asymptomatic aged individuals, particularly in the hippocampus, amygdala, and entorhinal cortex. It is unknown whether these losses or other volumetric changes are present, and to what degree, in cognitively normal individuals before the clinical diagnosis of MCI. METHODS: Structural MRI was performed on a cross-section of 136 longitudinally examined normal aged subjects. All subjects were cognitively normal at the time of their scan, but 23 later developed MCI, and 9 of these 23 went on to an AD diagnosis. Extracted volumes from voxel-based morphometric analysis were combined with clinical data to compare the 23 subjects who eventually developed MCI to 113 subjects who remained cognitively normal over an average follow-up of 5.4 years. RESULTS: Initially normal subjects who eventually developed MCI demonstrated decreased gray matter volumes in the anteromedial temporal lobes bilaterally and left angular gyrus while still cognitively normal. CONCLUSION: Structural brain changes in anatomic areas involved in higher cognitive processes precede clinical signs and symptoms in longitudinally followed normal subjects destined to develop mild cognitive impairment.

cAMP-dependent protein kinase phosphorylations on tau in Alzheimer's disease.

To elucidate the role cAMP-dependent protein kinase (PKA) phosphorylations on tau play in Alzheimer's disease, we have generated highly specific monoclonal antibodies, CP-3 and PG-5, which recognize the PKA-dependent phosphorylations of ser214 and ser409 in tau respectively. The present study demonstrates by immunohistochemical analysis, CP-3 and PG-5 immunoreactivity with neurofibrillary pathology in both early and advanced Alzheimer's disease, but not in normal brain tissue and demonstrates that cAMP-dependent protein kinase phosphorylations on tau precede or are coincident with the initial appearance of filamentous aggregates of tau. Studies using heat-stable preparations demonstrate that neither site appears to be phosphorylated to any appreciable extent in normal rodent or human brain. Further analysis demonstrates that the beta catalytic subunit of PKA (Cbeta), the beta II regulatory subunit of PKA (RIIbeta), and the 79 kDa A-kinase-anchoring-protein (AKAP79), are tightly associated with the neurofibrillary pathology, positioning cAMP-dependent protein kinase to participate directly in the pathological hyperphosphorylation of tau seen in Alzheimer's disease.

Sequence requirements for formation of conformational variants of tau similar to those found in Alzheimer's disease.

Alz-50 and MC-1 monoclonal antibody reactivity is dependent on both the extreme N-terminus of tau (residues 7-9) and a 30-amino acid sequence of tau (amino acids 312-342) in the third microtubule binding domain, suggesting that the specificity of the Alz-50 and MC-1 antibodies for Alzheimer's disease (AD) pathological tau lies in their ability to recognize a specific conformation of the tau molecule in AD. The present study uses deletional and site-directed mutants of tau to further refine the C-terminal (third microtubule binding domain) epitope requirements for Alz-50, MC-1, and several new antibodies that recognize similar epitopes in tau to amino acids 313-322 of tau, and to demonstrate that intervening portions of the tau molecule are not required for the formation of conformational variants of tau similar to those seen in AD. Further analysis of deletional and site-directed mutations of tau demonstrate subtle variations in the epitope requirements for Alz-50, MC-1, CP-1, CP-2, and CP-28, suggesting that these antibodies, albeit different, all recognize a similar pathological conformation of tau. Additional experiments using synthetic peptides demonstrate that the NH2-terminal (amino acids 1-18) and COOH-terminal (amino acids 309-326) portions of the Alz-50, MC-1, CP-1, CP-2, and CP-28 epitopes can interact with high affinity under near physiological conditions.

Altered conformation of recombinant frontotemporal dementia-17 mutant tau proteins.

Recently, a series of both non-coding (intronic) and coding (exonic) mutations in the tau gene have been linked to a family of autosomal dominant dementias referred to as frontotemporal dementia-17. While linkage analysis has demonstrated that these mutations segregate with disease in affected families, it is unclear how mutant tau proteins could lead to the degenerative cascade seen in frontotemporal dementia-17. The present study demonstrates that coding mutations of tau seen in frontotemporal dementia-17 exhibit altered physical and structural characteristics as determined by reverse phase high performance liquid chromatography and circular dichroism spectroscopy. These data suggest that the previously identified mutations in the tau gene seen in frontotemporal dementia-17 are not merely benign polymorphisms, but may have functional consequences for microtubule binding, microtubule polymerization, and the abnormal aggregation of tau seen in a variety of neurodegenerative diseases.

Hierarchical phosphorylation of recombinant tau by the paired-helical filament-associated protein kinase is dependent on cyclic AMP-dependent protein kinase.

Immunoaffinity-purified paired helical filaments (PHFs) from Alzheimer's disease (AD) brain homogenates contain an associated protein kinase activity that is able to induce the phosphorylation of PHF proteins on addition of exogenous MgCl2 and ATP. PHF kinase activity is shown to be present in immunoaffinity-purified PHFs from both sporadic and familial AD, Down's syndrome, and Pick's disease but not from normal brain homogenates. Although initial studies failed to show that the kinase was able to induce the phosphorylation of tau, additional studies presented in this article show that only cyclic AMP-dependent protein kinase-pretreated recombinant tau is a substrate for the PHF kinase activity. Deletional mutagenesis, phosphopeptide mapping, and site-directed mutagenesis have identified the PHF kinase phosphorylation sites as amino acids Thr361 and Ser412 in htau40. In addition, the cyclic AMP-dependent protein kinase phosphorylation sites that direct the PHF kinase have been mapped to amino acids Ser356 and Ser409 in htau40. Additional data demonstrate that these hierarchical phosphorylations in the extreme C terminus of tau allow for the incorporation of recombinant tau into exogenously added AD-derived PHFs, providing evidence that certain unique phosphorylations of tau may play a role in the pathogenesis of neurofibrillary pathology in AD.

Dendritic changes in Alzheimer's disease and factors that may underlie these changes.

It seems likely that the Alzheimer disease (AD)-related dendritic changes addressed in this article are induced by two principally different processes. One process is linked to the plastic response associated with deafferentation, that is, long-lasting transneuronally induced regressive changes in dendritic geometry and structure. The other process is associated with severe alterations of the dendritic- and perikaryal cytoskeleton as seen in neurons with the neurofibrillary pathology of AD, that is, the formation of paired helical filaments formed by hyperphosphorylated microtubule-associated protein tau. As the development of dendritic and cytoskeletal abnormalities are at least mediated by alterations in signal transduction, this article also reviews changes in signal pathways in AD. We also discuss transgenic approaches developed to model and understand cytoskeletal abnormalities.

Alz-50 and MC-1, a new monoclonal antibody raised to paired helical filaments, recognize conformational epitopes on recombinant tau.

Using a series of recombinant tau and FAC1 mutant proteins, this study demonstrates by Western and dot blot analysis that 1) shared epitopes between tau and FAC1 are responsible for Alz-50 binding; 2) Alz-50 reactivity is dependent on two discontinuous portions of the tau molecule; 3) Alz-50 reactivity is most likely the result of a conformational alteration of tau monomers in Alzheimer's disease; and 4) the epitope for MC-1, a novel monoclonal antibody, maps to similar regions of tau but does not react with FAC1. These data raise questions regarding previous studies which have suggested that tau lacks a specific conformation and illustrate the utility of the Alz-50 and MC-1 antibodies in recognizing a distinct pathological conformation of the tau molecule in Alzheimer's disease.

A conformation- and phosphorylation-dependent antibody recognizing the paired helical filaments of Alzheimer's disease.

Hyperphosphorylated tau (PHF-tau) is the major constituent of paired helical filaments (PHFs) from Alzheimer's disease (AD) brains. This conclusion has been based largely on the creation and characterization of monoclonal antibodies raised against PHFs, which can be classified in three categories: (a) those recognizing unmodified primary sequences of tau, (b) those recognizing phosphorylation-dependent epitopes on tau, and (c) those recognizing conformation-dependent epitopes on tau. Recent studies have suggested that the antibodies recognizing primary sequence and phosphorylation-dependent epitopes on tau are unable to distinguish between normal adult biopsy tau and PHF-tau. We now present evidence for a new fourth class of monoclonal antibodies recognizing conformation-dependent phosphoepitopes on tau, typified by TG-3, a monoclonal antibody raised to PHFs from AD brain homogenates. Studies using a series of deletional tau mutants, site-directed tau mutants, and synthetic peptides enable the precise epitope mapping of TG-3. Additional studies demonstrate that TG-3 reacts with neonatal mouse tau and PHF-tau but does not recognize adult mouse tau or tau derived from normal human autopsy or biopsy tissue. Further investigation reveals that TG-3 recognizes a unique conformation of tau found almost exclusively in PHFs from AD brains.

Vacuous jaw movements and feeding deficits in rats with ventrolateral striatal dopamine depletion: possible relation to parkinsonian symptoms.

A series of experiments examined the effects of regional dopamine depletions produced by intrastriatal injections of 6-hydroxydopamine on voluntary and involuntary movements in rats. Depletion of dopamine in the ventrolateral striatum produced a substantial decrease in food intake, from which the animals recovered. Rats with dopamine depletions in anteroventromedial or dorsolateral striatum did not have significant feeding deficits. Rats with ventrolateral dopamine depletions showed no deficits in locomotor activity or rearing behavior; however, depletions of dopamine in dorsolateral striatum significantly reduced rearing. Vacuous jaw movements that resemble chewing were produced by dopamine depletion in the ventrolateral striatum, but not the anteroventromedial or dorsolateral striatum. Systemic administration of haloperidol (0.4 mg/kg) increased vacuous chewing responses in dopamine-depleted and control rats. Thus, vacuous chewing responses can result from reduced functional activity of striatal dopamine, and these responses share some characteristics with human parkinsonian symptoms. In addition, these data support the notion that the neostriatum is functionally heterogeneous and that the ventrolateral region is particularly important for oral motor control.