Tackling the global problem of traumatic stress in low-income countries: a pilot clinical trial comparing reconsolidation therapy to paroxetine in Nepal.

BACKGROUND: Traumatic stress is a global mental health problem requiring novel, easily implemented treatment solutions. We compared the effectiveness and efficiency of Reconsolidation Therapy (RT) to the well-established antidepressant paroxetine, in reducing symptoms of traumatic stress among patients from Nepal, a low-income country. METHODS: Forty-six adults with posttraumatic stress disorder (PTSD) were randomized to one of two groups. The reconsolidation blocker propranolol was administered 90 min before briefly recalling a traumatic memory with a therapist, weekly for six consecutive weeks. This was compared to daily paroxetine for 26 weeks. Self-reported PTSD symptoms were assessed blindly at the 7th, 13th, and 26th weeks. RESULTS: An intent-to-treat analysis revealed a robust pre- to post-treatment main effect (ß1 = - 4.83, 95% CI = [- 5.66, - 4.01], p < .001), whereby both groups improved, with Cohen's effect sizes of d = 2.34 (95% CI = [1.57, 3.12]) for paroxetine, and of 2.82 (95% CI = [1.98, 3.66]) for RT after 7 weeks, suggesting treatment effectiveness for both groups in a real-world setting. Three and six-month follow-up yielded further significant improvement in both groups, which did not differ from each other. CONCLUSION: RT also displayed promising efficiency, considering that it had been discontinued weeks earlier while the paroxetine treatment was continued, as recommended. RT could be taught in low-income countries as part of the local therapeutic resources to treat the core symptoms of PTSD, provided that such results are replicated on a broader scale. TRIAL REGISTRATION: ISRCTN34308454 (11/10/2017).

Consolidation and reconsolidation are impaired by oral propranolol administered before but not after memory (re)activation in humans.

Propranolol administered immediately after learning or after recall has been found to impair memory consolidation or reconsolidation (respectively) in animals, but less reliably so in humans. Since reconsolidation impairment has been proposed as a treatment for mental disorders that have at their core an emotional memory, it is desirable to understand how to reliably reduce the strength of pathogenic memories in humans. We postulated that since humans (unlike experimental animals) typically receive propranolol orally, this introduces a delay before this drug can exert its memory impairment effects, which may render it less effective. As a means to test this, in two double-blind placebo-controlled experiments, we examined the capacity of propranolol to impair consolidation and reconsolidation as a function of timing of ingestion in healthy subjects. In Experiment 1, (n=36), propranolol administered immediately after learning or recall failed to impair the consolidation or reconsolidation of the memory of a standardized slideshow with an accompanying emotional story. In Experiment 2 (n=50), propranolol given 60-75min before learning or recall successfully impaired memory consolidation and reconsolidation. These results suggest that it is possible to achieve reliable memory impairment in humans if propranolol is given before learning or before recall, but not after.

Peritraumatic distress and the course of posttraumatic stress disorder symptoms: a meta-analysis.

OBJECTIVE: To examine how peritraumatic distress modulates the severity of posttraumatic stress disorder (PTSD) according to the timing of the PTSD symptom assessments. METHOD: A systematic literature review of English- and French-language studies having administered the Peritraumatic Distress Inventory (PDI) was conducted. Meta-analyses were performed on correlations relating PDI and PTSD symptom scores obtained from the sampled studies. The meta-analyses, which included calculations of regression slopes, took into consideration the time at which PTSD symptoms were assessed following the traumatic event and the timing of the PDI assessment. RESULTS: The literature review yielded a total of 22 studies. The meta-analysis performed over all studies resulted in a pooled correlation coefficient of 0.55 between the PDI and PTSD symptom scores. Meta-regression analyses conducted over all data revealed no apparent decrease in the correlations according to the timing of the PTSD symptom assessments. However, there were numerical or statistically significant declines in regression slopes when the meta-regressions were separately conducted on studies having administered the PDI either within, or following, a 1-month period after a traumatic event. CONCLUSIONS: While PDI or PTSD symptom score correlations remain generally significant, they tend to decline as time elapses between the traumatic event and the PTSD assessment. This suggests there may be factors other than peritraumatic distress that increasingly account for the long-term trajectory PTSD symptoms.

A narrative review of the epigenetics of post-traumatic stress disorder and post-traumatic stress disorder treatment.

Epigenetic research in post-traumatic stress disorder (PTSD) is essential, given that environmental stressors and fear play such a crucial role in its development. As such, it may provide a framework for understanding individual differences in the prevalence of the disorder and in treatment response. This paper reviews the epigenetic markers associated with PTSD and its treatment, including candidate genes and epigenome-wide studies. Because the etiopathogenesis of PTSD rests heavily on learning and memory, we also draw upon animal neuroepigenetic research on the acquisition, update and erasure of fear memory, focusing on the mechanisms associated with memory reconsolidation. Reconsolidation blockade (or impairment) treatment in PTSD has been studied in clinical trials and, from a neurological perspective, may hold promise for identifying epigenetic markers of successful therapy. We conclude this paper by discussing several key considerations and challenges in epigenetic research on PTSD in humans.

Treatment of adjustment disorder stemming from romantic betrayal using memory reactivation under propranolol: A open-label interrupted time series trial.

OBJECTIVES: In a sustained relationship, romantic betrayal is a catastrophic event that can precipitate an adjustment disorder (AD). Surprisingly, there exists no empirically validated treatment for AD, despite its high prevalence in clinical practice. Considering the promise of memory reactivation under propranolol (i.e., reconsolidation interference) for treating posttraumatic stress disorder, we sought to extend this finding to AD, given that in both disorders, symptoms stem from an identified stressor. METHOD: A single-blind interrupted time series design was used to examine the efficacy of memory reactivation under propranolol to alleviate symptoms of AD. After being placed on a 4-week waitlist, sixty-one participants received 5 weekly 25-min treatments during which they recalled the betrayal event, 1 h after having orally ingested the beta-blocker propranolol. RESULTS: Segmented regression analyses on the intent-to-treat sample revealed that AD symptoms significantly decreased during the treatment phase (pre/post Cohen's d = 1.44), compared to the waitlist phase (d = 0.01). Significant pre/post reductions in anxio-depressive symptomatology were also found. Improvement was maintained at the 4-month follow-up on all outcomes. CONCLUSION: Memory reactivation under propranolol shows promise in reducing symptoms of AD. This study provides the theoretical framework and necessary effect sizes to inform larger, double-blind, placebo-controlled clinical trials.

The clinician-administered PTSD Scale for DSM-5 (CAPS-5) structured interview for PTSD: A French language validation study.

The Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) is a structured interview that assesses the frequency and severity of each symptom of posttraumatic stress disorder (PTSD) in relation to a single traumatic stressor over a 1-month period, allowing the trained interviewer to infer a current or lifetime diagnosis congruent with the 5th Edition of the Diagnostic and Statistical Manual of the American Psychiatric Association. This study evaluated the psychometric properties of the original English language CAPS-5 translated to French. Participants (N = 168) were recruited in clinical settings of France, Lebanon, and Canada. The psychometric properties of the measure were found to be excellent, as good-to-strong interitem consistency was found (α = .90; ITC = .52; ICC = .30), while also finding strong convergent validity between the CAPS-5 total score and the severity score of a self-report PTSD measure (r = .82): the PCL-5. The test-retest reliability was excellent, with Cohen's κ = 1.00 and the intraclass coefficient (ICC) = .95. However, no latent factor structure model was deemed a strong fit to the data. Overall, the reliability and validity of the French CAPS-5 and are consistent with those of the original CAPS-5. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Trauma on duty: cognitive functioning in police officers with and without posttraumatic stress disorder (PTSD).

Background: Neuropsychological alterations co-occur with Posttraumatic Stress Disorder (PTSD); yet, the nature and magnitude of such alterations in police officers remains unknown despite their high level of trauma exposure. Objective: The current research sought to examine (1) cognitive functioning among police officers with and without PTSD; (2) the clinical significance of their cognitive performance; and (3) the relationship between PTSD symptoms and cognition. Method: Thirty-one police officers with PTSD were compared to thirty age- and sex-matched trauma-exposed officers without PTSD. Clinical assessment and self-report questionnaires established PTSD status. All participants underwent a neuropsychological evaluation. Results: Police officers with PTSD displayed lower cognitive performance across several domains, notably executive functioning, verbal learning and memory, and lexical access, compared to controls. The neuropsychological decrements in the PTSD group were mild compared to normative data, with average performances falling within normal limits. Among officers with PTSD, higher levels of intrusion symptoms were associated with reduced efficacy in executive functioning, as well as attention and working memory. Moreover, increased intrusion and avoidance symptoms were associated with slower information processing speed. Conclusion: Considering that even mild subclinical cognitive difficulties may affect their social and occupational functioning, it appears important to integrate neuropsychological assessments in the clinical management of police officers diagnosed with PTSD.

Antecedentes: Pueden co-ocurrir alteraciones neuropsicológicas con el trastorno de estrés postraumático (TEPT); sin embargo, la naturaleza y magnitud de tales alteraciones en oficiales de policía aún no se conoce a pesar de su alto nivel de exposición al trauma.Objetivo: La presente investigación buscó examinar (1) el funcionamiento cognitivo entre oficiales de policía con y sin TEPT; (2) la importancia clínica de su rendimiento cognitivo; y (3) la relación entre los síntomas de TEPT y la cognición.Método: Treinta y un oficiales de policía con TEPT fueron comparados a treinta oficiales expuestos a trauma sin TEPT, emparejados por edad y sexo. El estado de TEPT fue establecido mediante evaluación clínica y cuestionarios de auto-reporte. Todos los participantes se sometieron a una evaluación neuropsicológica.Resultados: Los oficiales de policía con TEPT desplegaron un menor rendimiento cognitivo a través de varios dominios, notablemente el funcionamiento ejecutivo, aprendizaje verbal y memoria, y acceso léxico, comparado con los controles. Las mermas neuropsicológicas en el grupo de TEPT fueron leves comparado con los datos normativos, con rendimientos promedio dentro de los límites normales. Entre los oficiales con TEPT, los mayores niveles de síntomas intrusivos se asociaron a una eficacia reducida en el funcionamiento cognitivo, así como también en la atención y en la memoria de trabajo. Más aún, los síntomas de intrusión y evitación aumentados se asociaron con una velocidad de procesamiento de la información más lenta.Conclusión: Considerando que incluso leves dificultades cognitivas subclínicas pueden afectar a su funcionamiento social y ocupacional, parece ser importante integrar evaluaciones neurocognitivas en el manejo clínico de los oficiales de policía diagnosticados con TEPT.

Scales as outcome measures for Alzheimer's disease.

The assessment of patient outcomes in clinical trials of new therapeutics for Alzheimer's disease (AD) continues to evolve. In addition to assessing drugs for symptomatic relief, an increasing number of trials are focusing on potential disease-modifying agents. Moreover, participants with AD are being studied earlier in their course of disease. As a result, the limitations of current outcome measures have become more apparent, as has the need for better instruments. In recognition of the need to review and possibly revise current assessment measures, the Alzheimer's Association, in cooperation with industry leaders and academic investigators, convened a Research Roundtable meeting devoted to scales as outcome measures for AD clinical trials. The meeting included a discussion of methodological issues in the use of scales in AD clinical trials, including cross-cultural issues. Specific topics related to the use of cognitive, functional, global, and neuropsychiatric scales were also presented. Speakers also addressed academic and industry initiatives for pooling data from untreated and placebo-treated patients in clinical trials. A number of regulatory topics were also discussed with agency representatives. Panel discussions highlighted areas of controversy, in an effort to gain consensus on various topics.

Cognitive neuroscience studies of semantic memory in Alzheimer's disease.

Semantic memory is the component of long-term memory that stores our concepts about the world. The disruption of semantic memory as a result of brain damage may have profound negative consequences on an individual's ability to name objects and process concepts. This can be disrupted as a result of many forms of brain damage, particularly Alzheimer's disease (AD). The current paper reviews research demonstrating that semantics deteriorates early in AD, particularly on effortful semantic tasks. There is a "category effect", meaning that AD preferentially affects concepts dealing with living things and abstract concepts compared to non-living objects and verbs/actions. While this pattern of deterioration, specific for AD, may reflect a breakdown within a distributed semantic system (where living things are distinguished by a high rate of inter-correlations between concepts or by a particular mode of being learned), it is equally possible that there is a regional distribution of semantic knowledge, with living things preferentially involving left temporal regions which become damaged early on in AD. Evidence from patients with strokes and semantic dementia, as well as activation studies in normal individuals, implicates the left posterior temporal region in semantic processing for pictures, abstract words, and concrete words. AD individuals, who are impaired in a variety of semantic tasks, show functional deficits in this area, and fail to activate it normally.

Comprehension of grammatical and emotional prosody is impaired in Alzheimer's disease.

Previous research has demonstrated impairment in comprehension of emotional prosody in individuals diagnosed with Alzheimer's disease (AD). The present pilot study further explored the prosodic processing impairment in AD, aiming to extend our knowledge to encompass both grammatical and emotional prosody processing. As expected, impairments were seen in emotional prosody. AD individuals were also found to be impaired in detecting sentence modality, suggesting that impairments in affective prosody processing in AD may be ascribed to a more general prosodic processing impairment, specifically in comprehending prosodic information signaled across the sentence level. AD participants were at a very mild stage of the disease, suggesting that prosody impairments occur early in the disease course.

Reduction of PTSD Symptoms With Pre-Reactivation Propranolol Therapy: A Randomized Controlled Trial.

OBJECTIVE: The authors assessed the efficacy of trauma memory reactivation performed under the influence of propranolol, a noradrenergic beta-receptor blocker, as a putative reconsolidation blocker, in reducing symptoms of posttraumatic stress disorder (PTSD). METHOD: This was a 6-week, double-blind, placebo-controlled, randomized clinical trial in 60 adults diagnosed with long-standing PTSD. Propranolol or placebo was administered 90 minutes before a brief memory reactivation session, once a week for 6 consecutive weeks. The hypothesis predicted a significant treatment effect of trauma reactivation with propranolol compared with trauma reactivation with placebo in reducing PTSD symptoms on both the Clinician-Administered PTSD Scale (CAPS) and the patient-rated PTSD Checklist-Specific (PCL-S) in an intention-to-treat analysis. RESULTS: The estimated group difference in posttreatment CAPS score, adjusted for pretreatment values (analysis of covariance), was a statistically significant 11.50. The within-group pre- to posttreatment effect sizes (Cohen's d) were 1.76 for propranolol and 1.25 for placebo. For the PCL-S, the mixed linear model's estimated time-by-group interaction yielded an average decrease of 2.43 points per week, for a total significant difference of 14.58 points above that of placebo. The pre- to posttreatment effect sizes were 2.74 for propranolol and 0.55 for placebo. Per protocol analyses for both outcomes yielded similar significant results. CONCLUSIONS: Pre-reactivation propranolol, a treatment protocol suggested by reconsolidation theory, appears to be a novel and efficacious treatment for PTSD. Replication studies using a long-term follow-up in various trauma populations are required.

Alzhemed: a potential treatment for Alzheimer's disease.

As a potential disease-modifying treatment for AD, Alzhemed (tramiprosate) is a compound that binds to soluble amyloid-beta peptide (Abeta) and inhibits the formation of neurotoxic aggregates that lead to amyloid plaque deposition in the brain. The safety, tolerability, and pharmacodynamic effects of Alzhemed were assessed in a double-blind study in which 58 individuals with mild-to-moderate AD (MMSE 13-25) were randomized to receive placebo or Alzhemed 50, 100 or 150 mg BID for 3 months. At the end of the double-blind phase, 42 of these subjects entered a 36-month open-label (OL) phase in which they received Alzhemed 150 mg BID. Assessments included plasma and cerebrospinal fluid (CSF) Alzhemed concentrations, CSF levels of Abeta, as well as cognitive (Alzheimer's Disease Assessment Scale-cognitive subscale, Mini-Mental State Examination) and clinical performance (Clinical Dementia Rating scale, Sum-of-Boxes) measures. Alzhemed was safe and well tolerated, crossed the blood-brain barrier, and dose-dependently reduced CSF Abeta(42) levels after 3 months of treatment. Mild AD subjects (MMSE 19-25 at entry) displayed greater reduction of CSF Abeta(42) levels than moderate AD participants (MMSE 13-18 at entry). There was no effect of Alzhemed on the cognitive or clinical measures after 3 months of treatment. The OL follow-up suggested a stabilization of cognitive function especially in mild AD subjects over the 36-month study period. Alzhemed thus appears to be well tolerated with long-term exposure and reduces CSF Abeta(42) levels in mild-to-moderate AD subjects. These findings will be discussed in the context of two large-scale randomized, double-blind, placebo-controlled Phase III clinical trials that are currently being conducted to test the long-term safety and efficacy of Alzhemed.

Atypical categorical perception in autism: autonomy of discrimination?

A diminished top-down influence has been proposed in autism, to account for enhanced performance in low-level perceptual tasks. Applied to perceptual categorization, this hypothesis predicts a diminished influence of category on discrimination. In order to test this hypothesis, we compared categorical perception in 16 individuals with and 16 individuals without high-functioning autism. While participants with and without autism displayed a typical classification curve, there was no facilitation of discrimination near the category boundary in the autism group. The absence of influence of categorical knowledge on discrimination suggests an increased autonomy of low-level perceptual processes in autism, in the form of a reduced top-down influence from categories toward discrimination.

Propranolol's impact on cognitive performance in post-traumatic stress disorder.

BACKGROUND: Propranolol has effectively diminished fear-based emotional memories in posttraumatic stress disorder (PTSD) and this effect has been attributed to traumatic memory reconsolidation blockade. However, propranolol may also exert cognitive effects by modulating stress and arousal. METHOD: Within a randomized double-blind placebo controlled trial, propranolol's impact on cognitive functioning was examined in individuals who were diagnosed with chronic PTSD. Participants received a single dose of 1mg/kg of propranolol (n=20) or placebo (n=21), and completed subtests of the Wechsler Adult Intelligence Scale third edition (WAIS-III). PTSD symptoms were assessed 1 week before and after treatment by the Impact of Event Scale Revised (IES-R). RESULTS: The propranolol group performed significantly better on the Processing Speed composite measure compared to the placebo group. Furthermore, greater heart rate decreases were associated with higher Perceptual Organization performance, within the propranolol group. LIMITATIONS: The generalizability of results may have been reduced as participants were treatment seeking; the sample size was small and included a greater proportion of females.This study could not assess whether pre-existing psychological function influenced cognitive performance, post-trauma. Future studies might consider including a non-PTSD control group to determine if our findings are specific to propranolol's effect on PTSD associated cognitive impairment. CONCLUSIONS: Our preliminary results demonstrated that cognitive functioning improved following propranolol administration in PTSD patients. The implications are discussed with regards to the processing of traumatic events.

Reactivating addiction-related memories under propranolol to reduce craving: A pilot randomized controlled trial.

BACKGROUND: The reconsolidation blocker propranolol abolishes alcohol and drug-seeking behavior in rodents and attenuates conditioned emotional responses to drug-cues in humans in experimental settings. This suggests a role for its use in the treatment of substance dependence. In this translational pilot study, we explored the feasibility and efficacy of this procedure as an adjunct treatment for addiction. We hypothesized that guided addiction-related memory reactivation under propranolol would significantly attenuate tonic craving, a central element in relapse following addiction treatment. METHODS: Seventeen treatment-seeking adults diagnosed with substance dependence were randomized to receive double-blind propranolol (n = 9) or placebo (n = 8) on six occasions prior to reading a personalized script detailing a drug-using experience. The primary outcome measure was self-reported craving intensity. RESULTS: After controlling for baseline craving scores, intent-to-treat analysis revealed a time by group interaction, F(1, 14) = 5.68, p = .03, η(2) = 0.29; craving was reduced in the propranolol-treated group (Cohen's d = 1.40, p < .05) but not in the placebo group (d = 0.06, n.s.). LIMITATIONS: The usual limitations related to small sample size and the lack of a follow-up apply here. CONCLUSION: Drug-related memory reactivation under propranolol can subsequently reduce craving among substance-dependent individuals. Considering the relapse rate among individuals treated for substance dependence, our study highlights the feasibility of, and need for, more comprehensive trials of this treatment approach.

Trauma reactivation plus propranolol is associated with durably low physiological responding during subsequent script-driven traumatic imagery.

OBJECTIVE: In a previous, double-blind, placebo-controlled study, patients with posttraumatic stress disorder (PTSD) showed lower physiological response during script-driven traumatic imagery 1 week after receiving a single dose of propranolol given after the retrieval of a traumatic memory. We hypothesized that this effect would extend beyond 1 week using a modified treatment approach. METHOD: Twenty-eight participants with PTSD read an account of their traumatic event once weekly for 6 consecutive weeks under the influence of open-label propranolol. One week and 4-months later, skin conductance, heart rate, and left corrugator electromyogram responses were measured while participants engaged in script-driven mental imagery of their traumatic event. Results from the 22 study participants were compared with results from treated and untreated participants in a previously published trial. RESULTS: Most participants in our study were classified as non-PTSD cases at posttreatment and follow-up according to a psychophysiological discriminant function analysis. Posttreatment skin conductance and heart rate responses of the current (propranolol-treated) participants were lower than those of placebo participants from the previous study. No difference was observed between physiological responding measured posttreatment and at follow-up. CONCLUSIONS: Low physiological responding during script-driven traumatic imagery after treatment extends up to 4 months, demonstrating the durability of the treatment effect's. Limitations include the absence of a placebo-controlled group and lack of physiological baseline measures. Despite these limitations, results point to the need for future trials examining the clinical efficacy of trauma reactivation plus propranolol, as it has the potential to become a novel, cost- and time-effective treatment for PTSD.

Tramiprosate in mild-to-moderate Alzheimer's disease - a randomized, double-blind, placebo-controlled, multi-centre study (the Alphase Study).

INTRODUCTION: The aim of the study was to assess the clinical efficacy, safety, and disease-modification effects of tramiprosate (homotaurine, ALZHEMED(TM)) in mild-to-moderate Alzheimer's disease (AD). MATERIAL AND METHODS: Double-blind, placebo-controlled, randomized trial in 67 clinical centres across North America. Patients aged ≥ 50 years, with mild-to-moderate AD (Mini-Mental State Examination score between 16 and 26) and on stable doses of cholinesterase inhibitors, alone or with memantine. INTERVENTION: 78-week treatment with placebo, tramiprosate 100 mg or tramiprosate 150 mg BID. MEASUREMENTS: Alzheimer Disease Assessment Scale - cognitive subscale (ADAS-cog) and Clinical Dementia Rating - Sum of Boxes (CDR-SB) assessments were performed at baseline and every 13 weeks. Baseline and 78-week magnetic resonance imaging (MRI) hippocampus volume (HV) measurements were conducted in a subgroup of patients. RESULTS: A total of 1,052 patients were enrolled and 790 (75.1%) completed the 78-week trial. Patient discontinuation and reasons for withdrawal were similar across groups. Planned analyses did not reveal statistically significant between-group differences. Lack of adequate statistical validity of the planned analysis models led to the development of revised predictive models. These adjusted models showed a trend toward a treatment effect for ADAS-cog (P = 0.098) and indicated significantly less HV loss for tramiprosate 100 mg (P = 0.035) and 150 mg (P = 0.009) compared to placebo. The incidence of adverse events was similar across treatment groups. CONCLUSIONS: The primary planned analyses did not show a significant treatment effect, but were confounded by unexplained variance. Post-hoc analyses showed a significant treatment-related reduction in HV loss. However, there was only a trend towards slowing of decline on the ADAS-cog and no slowing of decline on the CDR-SB. These results must be interpreted in consideration of the limitations of clinical and disease-modification outcome measures and their relationship, the heterogeneity of the disease and the impact of confounding demographic and clinical variables.

Cognitive predictors of donepezil therapy response in Alzheimer disease.

OBJECTIVES: To examine whether the presence of domain-specific cognitive impairments would predict a response to donepezil medication in patients with mild-to-moderate Alzheimer disease (AD). METHODS: The protocol was an open-label study of 30 AD subjects (mean age 74 years; education 11 years; Mini-Mental State Exam (MMSE) 23 of 30) beginning a 6-month course of treatment with donepezil. Global response to treatment was determined using a combination algorithm based on changes over 6 months in the ADAS-cog, MMSE and CIBIC. In addition, a set of neuropsychological and experimental cognitive tests designed to test five domains of cognition were administered before beginning therapy in order to determine which domain of testing would be predictive to response to treatment. The tests examined attention, short-term and working memory, learning and memory, visuo-spatial motor skills, and lexical-semantic knowledge. RESULTS: Eighteen of the thirty subjects were rated as having responded (stable or improved scores on the combination algorithm) to the therapy. Responders were significantly less impaired prior to treatment on the following tests: the Clock Drawing Test, a Visual-Spatial Motor Tracking Test, and the Boston Picture Naming Test. No significant initial group differences were noted on the other neuropsychological or experimental cognitive measures. CONCLUSION: The tests that most reliably predicted response to donepezil in AD subjects were in the domains of visual-spatial motor abilities and lexical-semantic functioning.