James F. Paskavitz

Efficacy of a Vitamin/Nutriceutical Formulation for Moderate-stage to Later-stage Alzheimer's disease: A Placebo-controlled Pilot Study

Recent studies demonstrated efficacy of a vitamin/ nutriceutical formulation (folate, vitamin B12, alpha-tocopherol, S-adenosyl methionine, N-acetyl cysteine, and acetyl-L-carnitine) for mild to moderate Alzheimers disease. Herein, we tested the efficacy of this formulation in a small cohort of 12 institutionalized patients diagnosed with moderate-stage to later-stage Alzheimers disease. Participants were randomly separated into treatment of placebo groups. Participants receiving the formulation demonstrated a clinically significant delay in decline in the Dementia Rating Scale and clock-drawing test as compared to those receiving placebo. Institutional caregivers reported approximately 30% improvement in the Neuropyschiatric Inventory and maintenance of performance in the Alzheimers Disease Cooperative Study—Activities of Daily Living for more than 9 months. This formulation holds promise for delaying the decline in cognition, mood, and daily function that accompanies the progression of Alzheimers disease, and may be particularly useful as a supplement for pharmacological approaches during later stages of this disorder. A larger trial is warranted.

Efficacy of a Vitamin/Nutriceutical Formulation for Early-stage Alzheimer's Disease: A 1-year, Open-label Pilot Study With an 16-Month Caregiver Extension

We examined the efficacy of a vitamin/nutriceutical formulation (folate, vitamin B6, alpha-tocopherol, S-adenosyl methionine, N-acetyl cysteine, and acetyl-L-carnitine) in a 12-month, open-label trial with 14 community-dwelling individuals with early-stage Alzheimers disease. Participants improved in the Dementia Rating Scale and Clock-drawing tests (Clox 1 and 2). Family caregivers reported improvement in multiple domains of the Neuropsychiatric Inventory (NPI) and maintenance of performance in the Alzheimers Disease Cooperative Study—Activities of Daily Living (ADL). Sustained performance was reported by caregivers for those participants who continued in an 16-month extension. Performance on the NPI was equivalent to published findings at 3 to 6 months for donepezil and exceeded that of galantamine and their historical placebos. Participants demonstrated superior performance for more than 12 months in NPI and ADL versus those receiving naproxen and rofecoxib or their placebo group. This formulation holds promise for treatment of early-stage Alzheimers disease prior to and/or as a supplement for pharmacological approaches. A larger, placebo-controlled trial is warranted.

Neuroanatomical correlates of malingered memory impairment: Event-related fMRI of deception on a recognition memory task

Primary objective: Event-related, functional magnetic resonance imaging (fMRI) data were acquired in healthy participants during purposefully malingered and normal recognition memory performances to evaluate the neural substrates of feigned memory impairment. Methods and procedures: Pairwise, between-condition contrasts of neural activity associated with discrete recognition memory responses were conducted to isolate dissociable neural activity between normal and malingered responding while simultaneously controlling for shared stimulus familiarity and novelty effects. Response timing characteristics were also examined for any association with observed between-condition activity differences. Outcomes and results: Malingered recognition memory errors, regardless of type, were associated with inferior parietal and superior temporal activity relative to normal performance, while feigned recognition target misses produced additional dorsomedial frontal activation and feigned foil false alarms activated bilateral ventrolateral frontal regions. Malingered response times were associated with activity in the dorsomedial frontal, temporal and inferior parietal regions. Normal memory responses were associated with greater inferior occipitotemporal and dorsomedial parietal activity, suggesting greater reliance upon visual/attentional networks for proper task performance. Conclusions: The neural substrates subserving feigned recognition memory deficits are influenced by response demand and error type, producing differential activation of cortical regions important to complex visual processing, executive control, response planning and working memory processes.

FMRI correlates of the WAIS–III Symbol Search subtest

Functional magnetic resonance imaging (FMRI) experiments frequently administer substantially adapted cognitive tests. This study was designed to identify FMRI correlates of a well-standardized clinical measure presented with minor adaptations. We administered the WAIS-III Symbol Search (SS) and a visuospatial control task to fifteen adults during FMRI. SS-related brain activity was identified, followed by analyses of activity related to performance level. Compared to the control task, SS was associated with greater activity in bilateral medial occipital, occipitoparietal, occipitotemporal, parietal, and dorsolateral prefrontal cortices (DLPFC). Across both tasks, slower processing speed was also related to greater activity in these areas, except right DLPFC. Greater activity in left DLPFC was specifically related to slower processing speed during SS. Performance was consistent with education levels. Findings suggest that SS performance involves regions associated with executive and visual processing. Furthermore, slower SS performance was related to greater recruitment of left hemisphere regions associated with executive function in other studies.

Recruitment and Stabilization of Brain Activation Within a Working Memory Task; an fMRI Study

Seventeen subjects underwent functional magnetic resonance imaging (fMRI) performing a 2-Back verbal working memory (VWM) task alternating with a control task to characterize the temporal dynamics of the specific brain regions involved in VWM. Serial sampling of 2-Back sub-blocks revealed many small areas of activation that grew and merged over time. Significant temporal effects for volume recruitment were seen in specific brain regions known to be involved in VWM, including the bilateral dorsolateral prefrontal (DLPFC), medial frontal (MFC), posterior parietal (PPC) cortices and also some extra-cortical and subcortical regions of interest (ROIs). Signal intensity increased over time in most ROIs recruited early in the task, including the DLPFC, MFC, and PPC but excluding dorsal premotor areas. MFC intensity increased rapidly then stabilized with time. The uniqueness of the MFC response raises the possibility that it drives the recruitment process. Increases in intensity and volume were associated with worsening VWM performance over time, suggesting that recruitment of brain resources is necessary in attempting to sustain difficult tasks. Worsening of performance over sub-blocks despite stable task demands reinforces this temporal “load effect”.

Clock drawing and frontal lobe behavioral effects of memantine in Alzheimer's disease: a rater-blinded study.

Caregivers of Alzheimer’s disease patients treated with memantine have reported improved frontal lobe behaviors. The present study examined these possible improvements in executive functioning using rater-blinded scoring of a clock-drawing test. Fifty-one Alzheimer’s disease patients were treated with open-label memantine for 10 weeks. Clock drawing and Mini-Mental State Examination data were collected before and after treatment. Clock drawing improved significantly with treatment, whereas Mini-Mental State Examination data did not. Twenty-seven patients judged as improved in frontal lobe behaviors by caregivers demonstrated a statistically significant improvement in clock drawing to command, whereas 24 patients judged to be unchanged or worse with memantine in their frontal lobe behaviors had no change in their clock drawing and had worsening on their Mini-Mental State Examination. The current findings suggest that memantine improves frontal lobe behavior in some Alzheimer’s disease patients and that clock drawing to command may be sensitive to these improvements.

The Clock-Drawing Test: Time for a Change?

Clock-drawing tests are simple and rapid screening devices for dementia. It was observed that individuals <60 years of age showed similar performance with a digital prompt (“ . . .make the clock read 12:45”) or an analog prompt (“ . . .quarter to 1”), whereas individuals >70 years of age showed improved performance with an analog prompt. The digital prompt has routinely been used to force participants to recode the prompt via conceptualization. Differential scoring across a range of ages has likely derived from the advent and increase of digital clocks with the younger segment of the population. This implies the need for as-yet undetermined alteration in the nature of prompts to force recoding as the current younger population ages.