Diagnosis of Early Alzheimer's Disease: Clinical Practice in 2021.

Alzheimer's disease is a progressive, irreversible neurodegenerative disease impacting cognition, function, and behavior. Alzheimer's disease progresses along a continuum from preclinical disease, to mild cognitive and/or behavioral impairment and then Alzheimer's disease dementia. Recently, clinicians have been encouraged to diagnose Alzheimer's earlier, before patients have progressed to Alzheimer's disease dementia. The early and accurate detection of Alzheimer's disease-associated symptoms and underlying disease pathology by clinicians is fundamental for the screening, diagnosis, and subsequent management of Alzheimer's disease patients. It also enables patients and their caregivers to plan for the future and make appropriate lifestyle changes that could help maintain their quality of life for longer. Unfortunately, detecting early-stage Alzheimer's disease in clinical practice can be challenging and is hindered by several barriers including constraints on clinicians' time, difficulty accurately diagnosing Alzheimer's pathology, and that patients and healthcare providers often dismiss symptoms as part of the normal aging process. As the prevalence of this disease continues to grow, the current model for Alzheimer's disease diagnosis and patient management will need to evolve to integrate care across clinical disciplines and the disease continuum, beginning with primary care. This review summarizes the importance of establishing an early diagnosis of Alzheimer's disease, related practical 'how-to' guidance and considerations, and tools that can be used by healthcare providers throughout the diagnostic journey.

Rationale for Early Diagnosis of Mild Cognitive Impairment (MCI) Supported by Emerging Digital Technologies.

Disease-modifying pharmacotherapies for Alzheimer's Disease (AD) are currently in late-stage clinical development; once approved, new healthcare infrastructures and services, including primary healthcare, will be necessary to accommodate a huge demand for early and large-scale detection of AD. The increasing global accessibility of digital consumer electronics has opened up new prospects for early diagnosis and management of mild cognitive impairment (MCI) with particular regard to AD. This new wave of innovation has spurred research in both academia and industry, aimed at developing and validating a new "digital generation" of tools for the assessment of the cognitive performance. In light of this paradigm shift, an international working group (the Global Advisory Group on Future MCI Care Pathways) convened to elaborate on how digital tools may be optimally integrated in screening-diagnostic pathways of AD The working group developed consensus perspectives on new algorithms for large-scale screening, detection, and diagnosis of individuals with MCI within primary medical care delivery. In addition, the expert panel addressed operational aspects concerning the implementation of unsupervised at-home testing of cognitive performance. The ultimate intent of the working group's consensus perspectives is to provide guidance to developers of cognitive tests and tools to facilitate the transition toward globally accessible cognitive screening aimed at the early detection, diagnosis, and management of MCI due to AD.

Early Detection of Mild Cognitive Impairment (MCI) in Primary Care.

Mild cognitive impairment (MCI) is significantly misdiagnosed in the primary care setting due to multi-dimensional frictions and barriers associated with evaluating individuals' cognitive performance. To move toward large-scale cognitive screening, a global panel of clinicians and cognitive neuroscientists convened to elaborate on current challenges that hamper widespread cognitive performance assessment. This report summarizes a conceptual framework and provides guidance to clinical researchers and test developers and suppliers to inform ongoing refinement of cognitive evaluation. This perspective builds upon a previous article in this series, which outlined the rationale for and potentially against efforts to promote widespread detection of MCI. This working group acknowledges that cognitive screening by default is not recommended and proposes large-scale evaluation of individuals with a concern or interest in their cognitive performance. Such a strategy can increase the likelihood to timely and effective identification and management of MCI. The rising global incidence of AD demands innovation that will help alleviate the burden to healthcare systems when coupled with the potentially near-term approval of disease-modifying therapies. Additionally, we argue that adequate infrastructure, equipment, and resources urgently should be integrated in the primary care setting to optimize the patient journey and accommodate widespread cognitive evaluation.

Early Detection of Mild Cognitive Impairment (MCI) in an At-Home Setting.

Emerging digital tools have the potential to enable a new generation of qualitative and quantitative assessment of cognitive performance. Moreover, the ubiquity of consumer electronics, such as smartphones and tablets, can be harnessed to support large-scale self-assessed cognitive screening with benefit to healthcare systems and consumers. A wide variety of apps, wearables, and new digital technologies are either available or in development for the detection of mild cognitive impairment (MCI), a risk factor for dementia. Two categories of novel methodologies may be considered: passive technologies (which monitor a user's behavior without active user input) and interactive assessments (which require active user input). Such examinations can be self-administered, supervised by a caregiver, or conducted by an informant at home or outside of a clinical setting. These direct-to-consumer tools have the potential to sidestep barriers associated with cognitive evaluation in primary care, thus improving access to cognitive assessments. Although direct-to-consumer cognitive assessment is associated with its own barriers, including test validation, user experience, and technological concerns, it is conceivable that these issues can be addressed so that a large-scale, self-assessed cognitive evaluation that would represent an initial cognitive screen may be feasible in the future.

Identifying Better Outcome Measures to Improve Treatment of Agitation in Dementia: A Report from the EU/US/CTAD Task Force.

For the second time in the past 3 years, the EU-US CTAD Task Force addressed challenges related to designing clinical trials for agitation in dementia, which is one of the most disruptive aspects of the condition for both patients and caregivers. Six recommendations emerged from the Task Force meeting: 1 - Operationalizing agitation criteria established by the IPA; 2 - Combining clinician- and caregiver-derived outcomes as primary outcome measures; 3 - Using global ratings to define clinically meaningful effects and power studies; 4 - Improving the accuracy of caregiver reports by better training and education of caregivers; 5 - Employing emerging technologies to collect near real-time behavioral data; and 6 - Utilizing innovative trial designs and increasing the use of biomarkers to maximize the productivity of clinical trials for neuropsychiatric symptoms.

Clinical Effects of Tramiprosate in APOE4/4 Homozygous Patients with Mild Alzheimer's Disease Suggest Disease Modification Potential.

BACKGROUND: Alzheimer's Disease (AD) patients homozygous for the APOE4 allele (APOE4/4) have a distinct clinical and biological phenotype with high levels of beta amyloid (Aß) pathology and toxic Aß oligomers. Tramiprosate, an oral agent that inhibits Aß monomer aggregation into toxic oligomers, was evaluated in two Phase 3 Mild to Moderate AD studies which did not show efficacy in the overall population. Re-analyses of these trials showed the most consistent clinical benefits in APOE4/4 patients. We analyzed efficacy in the APOE4/4 patients with Mild disease. OBJECTIVES: To determine the optimal stage of AD for future trials in APOE4/4 homozygotes. DESIGN: Two randomized, double-blind, placebo-controlled parallel-arm multi-center studies of 78-weeks duration. SETTING: Academic Alzheimer's disease centers, community-based memory clinics, and neuropsychiatric research sites. PARTICIPANTS: Participants included 2,025 AD patients with MMSE 16-26. Approximately 13-15% had APOE4/4 genotype (N= 147 and 110 per study), mean age 71.1 years, 56% females. Almost all were on stable symptomatic drugs. INTERVENTION: Randomized subjects received oral placebo, 100mg BID, or 150mg BID of tramiprosate. MEASUREMENTS: Co-primary outcomes were change from baseline in the ADAS-cog11 and CDR-SB. Disability assessment for dementia (DAD) was a secondary outcome. RESULTS: In APOE4/4 homozygotes receiving 150mg BID tramiprosate, efficacy in the traditional Mild AD patients (MMSE 20-26) was higher than the overall group (MMSE 16-26) and efficacy in the Mild patients (MMSE 22-26) was highest. Tramiprosate benefits compared to placebo on ADAS-cog, CDR-SB, and DAD were 125%, 81% and 71%, respectively (p<0.02). The Mild subgroup (MMSE 22-26) showed cognitive stabilization with no decline over 78 weeks, both ADAS-cog and DAD effects increased over time. Tramiprosate safety in APOE4/4 patients was favorable. Most common adverse events were nausea, vomiting, depression and decreased weight. CONCLUSIONS: The Mild subgroup of APOE4/4 AD patients (MMSE 22-26) showed larger benefits on the high dose of tramiprosate than the overall Mild and Moderate group. Consistent with its preclinical effects on Aß oligomers, tramiprosate seemed to stabilize cognitive performance, supporting its disease modification potential. Confirmatory studies using ALZ-801, an improved pro-drug formulation of tramiprosate, will target APOE4/4 patients with Mild AD.

Clinical Benefits of Tramiprosate in Alzheimer's Disease Are Associated with Higher Number of APOE4 Alleles: The "APOE4 Gene-Dose Effect".

BACKGROUND: Tramiprosate is an oral amyloid anti-aggregation agent that reduces amyloid oligomer toxicity in preclinical studies and was evaluated in two 78-week trials in North America and Western Europe that enrolled 2,025 patients with Mild to Moderate Alzheimer's Disease. The completed North American study did not achieve its efficacy objectives, but a pre-specified subgroup analysis suggested potential efficacy in apolipoprotein E4 (APOE4) carriers. To further explore this observation, we analyzed tramiprosate Phase 3 clinical data based on the number of APOE4 alleles. OBJECTIVES: To analyze tramiprosate efficacy, safety, and occurrence of vasogenic edema in the three APOE4 subgroups: homozygous, heterozygous and non-carriers. DESIGN: Randomized, double-blind, placebo-controlled parallel-arm multi-center studies. SETTING: Academic Alzheimer's disease and dementia centers, community-based dementia and memory clinics, and neuropsychiatric clinical research sites. PARTICIPANTS: Subjects included 2,025 patients, 50 years of age or older, with approximately 60% having APOE4 carrier status (10-15% homozygotes and 45-50% heterozygotes), and mild to moderate disease. All subjects were on stable symptomatic drugs. INTERVENTION: Randomized subjects received placebo, 100 mg BID, or 150 mg BID of tramiprosate. MEASUREMENTS: Co-primary outcomes in both studies were change from baseline in the ADAS-cog11 and CDR-SB assessment scales. RESULTS: Highest efficacy was observed in APOE4/4 homozygotes receiving 150 mg BID of tramiprosate, showing statistically significant effects on ADAS-cog and positive trends on CDR-SB (respectively, 40-66% and 25-45% benefit compared to placebo). APOE4 heterozygotes showed intermediate efficacy, and non-carriers showed no benefit. In 426 patients with MRI scans, no cases of treatment-emergent vasogenic edema were observed. In the three subgroups, the most common adverse events were nausea, vomiting, and decreased weight. CONCLUSIONS: The "APOE4 Gene-Dose effect" is likely explained by the high prevalence of amyloid pathology in symptomatic APOE4 carriers. In APOE4/4 Alzheimer's disease patients, the high dose of tramiprosate showed favorable safety and clinically meaningful efficacy in addition to standard of care.

A phase 2 randomized trial of ELND005, scyllo-inositol, in mild to moderate Alzheimer disease.

OBJECTIVE: This randomized, double-blind, placebo-controlled, dose-ranging phase 2 study explored safety, efficacy, and biomarker effects of ELND005 (an oral amyloid anti-aggregation agent) in mild to moderate Alzheimer disease (AD). METHODS: A total of 353 patients were randomized to ELND005 (250, 1,000, or 2,000 mg) or placebo twice daily for 78 weeks. Coprimary endpoints were the Neuropsychological Test Battery (NTB) and Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale. The primary analysis compared 250 mg (n =84) to placebo (n =82) after an imbalance of infections and deaths led to early discontinuation of the 2 higher dose groups. RESULTS: The 250 mg dose demonstrated acceptable safety. The primary efficacy analysis at 78 weeks revealed no significant differences between the treatment groups on the NTB or ADCS-ADL. Brain ventricular volume showed a small but significant increase in the overall 250 mg group (p =0.049). At the 250 mg dose, scyllo-inositol concentrations increased in CSF and brain and CSF Aßx-42 was decreased significantly compared to placebo (p =0.009). CONCLUSIONS: Primary clinical efficacy outcomes were not significant. The safety and CSF biomarker results will guide selection of the optimal dose for future studies, which will target earlier stages of AD. CLASSIFICATION OF EVIDENCE: Due to the small sample sizes, this Class II trial provides insufficient evidence to support or refute a benefit of ELND005.

The Neuropsychiatric Inventory-Clinician rating scale (NPI-C): reliability and validity of a revised assessment of neuropsychiatric symptoms in dementia.

BACKGROUND: Neuropsychiatric symptoms (NPS) affect almost all patients with dementia and are a major focus of study and treatment. Accurate assessment of NPS through valid, sensitive and reliable measures is crucial. Although current NPS measures have many strengths, they also have some limitations (e.g. acquisition of data is limited to informants or caregivers as respondents, limited depth of items specific to moderate dementia). Therefore, we developed a revised version of the NPI, known as the NPI-C. The NPI-C includes expanded domains and items, and a clinician-rating methodology. This study evaluated the reliability and convergent validity of the NPI-C at ten international sites (seven languages). METHODS: Face validity for 78 new items was obtained through a Delphi panel. A total of 128 dyads (caregivers/patients) from three severity categories of dementia (mild = 58, moderate = 49, severe = 21) were interviewed separately by two trained raters using two rating methods: the original NPI interview and a clinician-rated method. Rater 1 also administered four additional, established measures: the Apathy Evaluation Scale, the Brief Psychiatric Rating Scale, the Cohen-Mansfield Agitation Index, and the Cornell Scale for Depression in Dementia. Intraclass correlations were used to determine inter-rater reliability. Pearson correlations between the four relevant NPI-C domains and their corresponding outside measures were used for convergent validity. RESULTS: Inter-rater reliability was strong for most items. Convergent validity was moderate (apathy and agitation) to strong (hallucinations and delusions; agitation and aberrant vocalization; and depression) for clinician ratings in NPI-C domains. CONCLUSION: Overall, the NPI-C shows promise as a versatile tool which can accurately measure NPS and which uses a uniform scale system to facilitate data comparisons across studies.

Effects of a gamma-secretase inhibitor in a randomized study of patients with Alzheimer disease.

LY450139 dihydrate, a gamma-secretase inhibitor, was studied in a randomized, controlled trial of 70 patients with Alzheimer disease. Subjects were given 30 mg for 1 week followed by 40 mg for 5 weeks. Treatment was well tolerated. Abeta(1-40) in plasma decreased by 38.2%; in CSF, Abeta(1-40) decreased by 4.42 +/- 9.55% (p = not significant). Higher drug doses may result in additional decreases in plasma Abeta concentrations and a measurable decrease in CSF Abeta.

Pharmacologic therapy for behavioral symptoms of Alzheimer's disease.

Behavioral signs and symptoms in dementia are common, morbid, classifiable, and treatable. The current state-of-the-art approach is to evaluate carefully for social or environmental causes, intercurrent medical conditions, or other triggers of the behavior and attempt to deal with those directly. When these conservative steps fail, there may be a role for medication. A rational approach typically hinges on matching the most dominant behavioral target symptoms to the most relevant medication class, the key information of which is summarized.

Placebo-controlled study of divalproex sodium for agitation in dementia.

The authors assessed the efficacy, tolerability, and safety of divalproex sodium for the treatment of agitation associated with dementia in a 6-week, randomized study of 56 nursing home patients with agitation and dementia treated with either placebo or individualized doses of divalproex sodium. Participants were blinded to treatment except for a physician-monitor and a pharmacist. When several covariates were taken into account, the drug/placebo difference in Brief Psychiatric Rating Scale Agitation scores became statistically significant (P=0.05). Sixty-eight percent of patients on divalproex were rated as showing reduced agitation on the Clinical Global Impression scale, vs. 52% on placebo (P=0.06 in the adjusted analysis). Side effects occurred in 68% of the divalproex group vs. 33% of the placebo group (P=0.03) and were generally rated as mild. This placebo-controlled study, despite some limitations, suggests possible short-term efficacy, tolerability, and safety of divalproex for agitation in dementia and supports further placebo-controlled studies.

Second generation anticonvulsant medications: their use in children.

The pharmacotherapy of seizure disorders has long relied on a few standard medications such as phenobarbital, phenytoin (Dilantin), valproate (Depakote), and others that represent the "first generation" of anticonvulsants. This article reviews the newer, "second-generation" anticonvulsants that were developed in the last decade. The addition of these second-generation agents has doubled the number of therapies available for the treatment of seizure disorders. They include felbamate (Felbatol), gabapentin (Neurontin), lamotrigine (Lamictal), levetiracetam (Keppra), oxcarbazepine (Trileptal), tiagabine (Gabitril), topiramate (Topamax), and zonisamide (Zonegran). This article describes the known side effects of the second-generation agents and reviews the adverse reactions of the first generation of anticonvulsants as a guide to potential toxicities. Reference tables are included that note usual dosages, available dosage forms, and tablet imprint. In addition, this article describes monitoring parameters and gives specific information regarding the use of these agents.

Suicide and alcoholism. Distinguishing alcoholic patients with and without comorbid drug abuse.

Psychological autopsy data were used to test the hypothesis that alcoholic patients with comorbid drug use disorders who committed suicide (A + D; n = 26) are distinguishable from alcoholic suicide victims without a comorbid drug use disorder (A; n = 35). Dependent variables included demographics, suicidal behavior; psychiatric symptoms, and medical illness burden. The A group were older, white, and tended to be living alone. Analyses that controlled for age and sex indicated that As were more likely to have had a comorbid major depression and less likely to tell someone they were contemplating suicide. Scores on a measure of illness burden increased with age among the A group but not the A + D group, though the latter were more likely to be under a physician's care with increasing age. These differences should be considered when designing preventive measures.

An open trial of valproate for agitation in geriatric neuropsychiatric disorders.

The authors assessed the efficacy, tolerability and safety of open valproate administration in a group of elderly patients with agitation and neuropsychiatric disorders (N = 13), most of whom had dementia (n = 12). Dosing was individualized according to the response of target symptoms and side effects. Clinical Global Impression of Change (vs. baseline) measured efficacy. This open treatment suggested that valproate reduced agitated behaviors in some patients, and is well tolerated; thus, results warrant a larger, randomized, placebo-controlled study.

Treating Alzheimer's disease. Pharmacologic options now and in the near future.

Treatment of Alzheimer's disease has in the past been limited to empirical trials of psychotropics for relief of behavioral complications. At present, tacrine and doneprezil are the only FDA-approved antidementia agents available. In the very near future, however, other cholinesterases inhibitors (e.g., ENA 713, metrifonate, long-acting physostigmine) are expected to be approved for clinical use. The evidence at this point suggests that they have modest but meaningful clinical effects and possible long-term benefits. Clinical use of the newer agents is likely to be influenced by their side-effect profiles, which consist largely of cholinergic effects, although without the hepatotoxic effects associated with tacrine. To what extent these agents are accepted by patients and physicians remains to be seen. On the one hand, benefits are modest; on the other, these medications are increasingly safe. Continuing research is clarifying the role of cholinergic therapy in relieving behavioral symptoms, as well as the possible side effects on rates of illness progression, institutionalizaton, and even mortality. In the not-too-distant future, physicians can expect to see a variety of medications, now in early stages of development, that are intended to affect cholinergic systems in other ways. Further down the road, a host of mechanism-based therapeutic strategies, which hope to deal with the first cause of this devastating illness, will have been assessed in clinical trials.

Treatment of agitation in dementia.

Agitation occurs commonly in patients with dementia. Before symptomatic pharmacotherapy is undertaken, it is imperative to perform a sequence of evaluations and interventions to establish whether simpler and safer, nonpharmacologic approaches will be beneficial. When psychotropic medications are used they should be used judiciously, in the lowest effective doses and for the shortest period of time necessary. Ineffective medications should be stopped, and even effective medications should be empirically tapered in most patients to learn whether treatment is still necessary. Antipsychotics probably show the greatest benefit for agitation associated with psychotic features; they have less demonstrated efficacy for agitation not associated with psychotic features. The side effects of typical agents are legion; data are pending regarding atypical agents. The available evidence regarding nonneuroleptic medications ranges from case reports to well-designed, double-blind, placebo-controlled, randomized, parallel group studies. Literature exists describing the use of anticonvulsants, anxiolytics, serotonergic antidepressants, and other agents to manage agitation. Carbamazepine and divalproex sodium (valproate) have demonstrated efficacy in uncontrolled studies, whereas the use of carbamazepine has produced negative results in one small controlled study and positive results in two larger controlled studies. Buspirone has shown benefit in some open trials. Encouraging early findings have been reported for trazodone, including from one controlled trial. Varying results have been obtained using selective serotonin reuptake inhibitors, but with consistently encouraging anecdotes. In the aggregate, the evidence suggests but does not prove that alternatives to traditional antipsychotics exist. Again, none of these agents has yet been approved for this purpose by the FDA. As more studies become available we will have a better idea about which classes of agents are most efficacious. It is likely that there may be a role for "rational" polypharmacy in the management of this distressing complication of dementia. However, no studies that we know of address combination therapy, so the clinician must contemplate this option on a case-by-case basis. Clinical trials data are pending from studies with divalproex sodium, carbamazepine, haloperidol versus trazodone versus placebo, risperidone, olanzapine, quetiapine, donepezil, xanomeline, tacrine, buspirone, and sertraline, at the very least. These data will undoubtedly have a major impact on how we care for our patients and lead to revisions of current practice guidelines.

Thyroid evaluation of hospitalized psychiatric patients: the role of TSH screening for thyroid dysfunction.

The incidence and pattern of changes in thyroid function tests were studied in acutely hospitalized psychiatric patients and the cost effectiveness of a systematic screening program for thyroid dysfunction was estimated. Thyroid testing was performed on 1275 of 1424 (90%) admissions to the psychiatric wing of Strong Memorial Hospital between April 1, 1993 and March 30, 1994. Discharge samples were obtained in 232 patients who were hospitalized at least 2 days; 163 patients were admitted multiple times. Psychiatric diagnosis was coded using DSM-III-R criteria. TSH, T4, free T4, and T3 levels were measured within 48 h of admission. TSH values were most frequently abnormal (7.8%) and free T4 the least (1.3%). Admission and discharge thyroid tests were similar. Significant differences in the four parameters of thyroid function were present among the psychiatric groups. By analysis of variance every 1 microU/mL increase in TSH levels was associated with a 2.5% increase in length of stay (LOS) (95% confidence intervals: 0.21%, 4.75%), holding psychiatric diagnosis, age, and gender constant. For patients with elevated TSH levels, the average LOS was increased by 10.7 days (95% confidence intervals: 2.8, 18.7 days). It is concluded that patients hospitalized for psychiatric illness have an incidence of thyroid dysfunction at or slightly higher than the general population. However, patients with elevated TSH levels are hospitalized longer than those with normal or suppressed values.