%0 Journal Article %J J Alzheimers Dis %D 2023 %T Multi-Site Cross-Site Inter-Rater and Test-Retest Reliability and Construct Validity of the MarkVCID White Matter Hyperintensity Growth and Regression Protocol. %A Bahrani, Ahmed A %A Abner, Erin L %A DeCarli, Charles S %A Barber, Justin M %A Sutton, Abigail C %A Maillard, Pauline %A Sandoval, Francisco %A Arfanakis, Konstantinos %A Yang, Yung-Chuan %A Evia, Arnold M %A Schneider, Julie A %A Habes, Mohamad %A Franklin, Crystal G %A Seshadri, Sudha %A Satizabal, Claudia L %A Caprihan, Arvind %A Thompson, Jeffrey F %A Rosenberg, Gary A %A Wang, Danny J J %A Jann, Kay B %A Zhao, Chenyang %A Lu, Hanzhang %A Rosenberg, Paul B %A Albert, Marilyn S %A Ali, Doaa G %A Singh, Herpreet %A Schwab, Kristin %A Greenberg, Steven M %A Helmer, Karl G %A Powel, David K %A Gold, Brian T %A Goldstein, Larry B %A Wilcock, Donna M %A Jicha, Gregory A %X

BACKGROUND: White matter hyperintensities (WMH) that occur in the setting of vascular cognitive impairment and dementia (VCID) may be dynamic increasing or decreasing volumes or stable over time. Quantifying such changes may prove useful as a biomarker for clinical trials designed to address vascular cognitive-impairment and dementia and Alzheimer's Disease.

OBJECTIVE: Conducting multi-site cross-site inter-rater and test-retest reliability of the MarkVCID white matter hyperintensity growth and regression protocol.

METHODS: The NINDS-supported MarkVCID Consortium evaluated a neuroimaging biomarker developed to track WMH change. Test-retest and cross-site inter-rater reliability of the protocol were assessed. Cognitive test scores were analyzed in relation to WMH changes to explore its construct validity.

RESULTS: ICC values for test-retest reliability of WMH growth and regression were 0.969 and 0.937 respectively, while for cross-site inter-rater ICC values for WMH growth and regression were 0.995 and 0.990 respectively. Word list long-delay free-recall was negatively associated with WMH growth (p < 0.028) but was not associated with WMH regression.

CONCLUSIONS: The present data demonstrate robust ICC validity of a WMH growth/regression protocol over a one-year period as measured by cross-site inter-rater and test-retest reliability. These data suggest that this approach may serve an important role in clinical trials of disease-modifying agents for VCID that may preferentially affect WMH growth, stability, or regression.

%B J Alzheimers Dis %V 96 %P 683-693 %8 2023 Nov 07 %G eng %N 2 %R 10.3233/JAD-230629 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Multiple Neurodegenerative Pathologies in an Alzheimer's Disease Patient Treated with Fornical Deep Brain Stimulation. %A White, Bartholomew %A Lyketsos, Constantine G %A Rosenberg, Paul B %A Oh, Esther S %A Chen, Liam %X

As an established treatment for movement disorders, deep brain stimulation (DBS) has been adapted for the treatment of Alzheimer's disease (AD) by modulating fornix activity. Although it is generally regarded as a safe intervention in patients over 65 years of age, the complex neurophysiology and interconnection within circuits connected to the fornix warrants a careful ongoing evaluation of the true benefit and risk potential of DBS on slowing cognitive decline in AD patients. Here we report on a patient who died long after being implanted with a DBS device who donated her brain for neuropathologic study. The autopsy confirmed multiple proteinopathies including AD-related change, diffuse neocortical Lewy body disease, TDP-43 proteinopathy, and a nonspecific tauopathy. We discuss the possible mechanisms of these overlapping neurodegenerative disorders and caution that future studies of DBS for AD will need to take these findings into consideration.

%B J Alzheimers Dis %V 80 %P 1383-1387 %8 2021 Apr 20 %G eng %N 4 %R 10.3233/JAD-201415 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Deep Brain Stimulation Targeting the Fornix for Mild Alzheimer Dementia (the ADvance Trial): A Two Year Follow-up Including Results of Delayed Activation. %A Leoutsakos, Jeannie-Marie S %A Yan, Haijuan %A Anderson, William S %A Asaad, Wael F %A Baltuch, Gordon %A Burke, Anna %A Chakravarty, M Mallar %A Drake, Kristen E %A Foote, Kelly D %A Fosdick, Lisa %A Giacobbe, Peter %A Mari, Zoltan %A McAndrews, Mary Pat %A Munro, Cynthia A %A Oh, Esther S %A Okun, Michael S %A Pendergrass, Jo Cara %A Ponce, Francisco A %A Rosenberg, Paul B %A Sabbagh, Marwan N %A Salloway, Stephen %A Tang-Wai, David F %A Targum, Steven D %A Wolk, David %A Lozano, Andres M %A Smith, Gwenn S %A Lyketsos, Constantine G %X

BACKGROUND: Given recent challenges in developing new treatments for Alzheimer dementia (AD), it is vital to explore alternate treatment targets, such as neuromodulation for circuit dysfunction. We previously reported an exploratory Phase IIb double-blind trial of deep brain stimulation targeting the fornix (DBS-f) in mild AD (the ADvance trial). We reported safety but no clinical benefits of DBS-f versus the delayed-on (sham) treatment in 42 participants after one year. However, secondary post hoc analyses of the one-year data suggested a possible DBS-f benefit for participants≥65 years.

OBJECTIVE: To examine the long-term safety and clinical effects of sustained and delayed-on DBS-f treatment of mild AD after two years.

METHODS: 42 participants underwent implantation of DBS-f electrodes, with half randomized to active DBS-f stimulation (early on) for two years and half to delayed-on (sham) stimulation after 1 year to provide 1 year of active DBS-f stimulation (delayed on). We evaluated safety and clinical outcomes over the two years of the trial.

RESULTS: DBS-f had a favorable safety profile with similar rates of adverse events across both trial phases (years 1 and 2) and between treatment arms. There were no differences between treatment arms on any primary clinical outcomes. However, post-hoc age group analyses suggested a possible benefit among older (>65) participants.

CONCLUSION: DBS-f was safe. Additional study of mechanisms of action and methods for titrating stimulation parameters will be needed to determine if DBS has potential as an AD treatment. Future efficacy studies should focus on patients over age 65.

%B J Alzheimers Dis %V 64 %P 597-606 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29914028?dopt=Abstract %R 10.3233/JAD-180121 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Psychometric Properties of Apathy Scales in Dementia: A Systematic Review. %A Mohammad, Dana %A Ellis, Courtney %A Rau, Allison %A Rosenberg, Paul B %A Mintzer, Jacobo %A Ruthirakuhan, Myuri %A Herrmann, Nathan %A Lanctôt, Krista L %X

Apathy is a prevalent and problematic neuropsychiatric symptom in those with dementia that is emerging as a treatment target, necessitating accurate assessment. While many apathy scales are available, not all have been developed for use exclusively in dementia, and psychometric properties may vary across different populations. This systematic review aimed to provide an overview of the psychometric properties of apathy scales used in Alzheimer's disease (AD) and related dementias, as well as rate the methodological quality of supporting studies. In addition, for those scales identified, performance in clinical trials was reviewed. A search was conducted through Medline, Psychinfo, Embase, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews. Articles that reported psychometric properties of an apathy scale in an AD or mixed dementia population were included. Of 15 articles, the methodological quality ratings of the studies ranged from adequate to excellent. Three clinical trials and two pooled analyses of clinical trials were included that used apathy scales evaluated in this review. Three scales emerged. The Neuropsychiatric Inventory apathy subscale (NPI-apathy) and the Apathy Evaluation Scale (AES) had the greatest number of studies evaluating psychometric properties and were also used in the clinical trials and have shown sensitivity to change. The Dementia Apathy Interview and Rating demonstrated excellent values of internal consistency, validity, and reliability for use in an AD population. Future research should address comparative scale performance and assess ability to distinguish subtypes of apathy. Validation may include evaluation of performance against specific imaging defined deficits.

%B J Alzheimers Dis %V 66 %P 1065-1082 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30400094?dopt=Abstract %R 10.3233/JAD-180485 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Mild Behavioral Impairment Checklist (MBI-C): A Rating Scale for Neuropsychiatric Symptoms in Pre-Dementia Populations. %A Ismail, Zahinoor %A Agüera-Ortiz, Luis %A Brodaty, Henry %A Cieslak, Alicja %A Cummings, Jeffrey %A Fischer, Corinne E %A Gauthier, Serge %A Geda, Yonas E %A Herrmann, Nathan %A Kanji, Jamila %A Lanctôt, Krista L %A Miller, David S %A Mortby, Moyra E %A Onyike, Chiadi U %A Rosenberg, Paul B %A Smith, Eric E %A Smith, Gwenn S %A Sultzer, David L %A Lyketsos, Constantine %X

BACKGROUND: Mild behavioral impairment (MBI) is a construct that describes the emergence at ≥50 years of age of sustained and impactful neuropsychiatric symptoms (NPS), as a precursor to cognitive decline and dementia. MBI describes NPS of any severity, which are not captured by traditional psychiatric nosology, persist for at least 6 months, and occur in advance of or in concert with mild cognitive impairment. While the detection and description of MBI has been operationalized in the International Society to Advance Alzheimer's Research and Treatment - Alzheimer's Association (ISTAART-AA) research diagnostic criteria, there is no instrument that accurately reflects MBI as described.

OBJECTIVE: To develop an instrument based on ISTAART-AA MBI criteria.

METHODS: Eighteen subject matter experts participated in development using a modified Delphi process. An iterative process ensured items reflected the five MBI domains of 1) decreased motivation; 2) emotional dysregulation; 3) impulse dyscontrol; 4) social inappropriateness; and 5) abnormal perception or thought content. Instrument language was developed a priori to pertain to non-demented functionally independent older adults.

RESULTS: We present the Mild Behavioral Impairment Checklist (MBI-C), a 34-item instrument, which can easily be completed by a patient, close informant, or clinician.

CONCLUSION: The MBI-C provides the first measure specifically developed to assess the MBI construct as explicitly described in the criteria. Its utility lies in MBI case detection, and monitoring the emergence of MBI symptoms and domains over time. Studies are required to determine the prognostic value of MBI for dementia development, and for predicting different dementia subtypes.

%B J Alzheimers Dis %V 56 %P 929-938 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28059789?dopt=Abstract %R 10.3233/JAD-160979 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Changes in Neuropsychiatric Inventory Associated with Semagacestat Treatment of Alzheimer's Disease. %A Rosenberg, Paul B %A Lanctôt, Krista L %A Herrmann, Nathan %A Mintzer, Jacobo E %A Porsteinsson, Anton P %A Sun, Xiaoying %A Raman, Rema %X

BACKGROUND: In a recent report, 76 weeks' treatment with a gamma-secretase inhibitor (semagacestat) was associated with poorer cognitive outcomes in Alzheimer's disease (AD).

OBJECTIVE: We sought to examine the effect of semagacestat treatment on neuropsychiatric symptoms (NPS).

METHODS: 1,537 participants with mild to moderate AD were randomized to 76 weeks' treatment with placebo versus two doses of semagacestat. NPS were assessed with the Neuropsychiatric Inventory (NPI-Total and subdomains). Cognition was assessed with the Alzheimer's Disease Assessment Scale-Cognitive (first 11 items, ADAS11). Mixed-Model Repeated Measures was used to compare the effects of treatment assignment on change in NPI-total and subdomains over time. Survival analysis was used to assess the treatment effect on time to first worsening of NPS (NPI-Total ≥10 or NPI subdomain ≥4) for subjects with no or minor NPS at baseline.

RESULTS: Participants on high dose semagecestat (140 mg) had greater increase in NPI-Total and greater risk of incident first worsening in NPI-Total and in subdomains of aberrant motor behavior, appetite, depression/dysphoria, and sleep. ADAS11 increased more in participants whose NPI-Total increased.

CONCLUSION: In participants with mild to moderate AD, high dose semagacestat treatment was associated with greater severity and faster worsening of NPS in a pattern resembling an agitated depression. Increased NPS was associated with cognitive decline regardless of treatment assignment. These findings suggest that greater NPS may be the result of gamma-secretase treatment and emphasize the importance of monitoring NPS as potential adverse events in trials of novel treatments for AD.

%B J Alzheimers Dis %V 54 %P 373-81 %8 2016 Aug 10 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567808?dopt=Abstract %R 10.3233/JAD-151113 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Phase II Study of Fornix Deep Brain Stimulation in Mild Alzheimer's Disease. %A Lozano, Andres M %A Fosdick, Lisa %A Chakravarty, M Mallar %A Leoutsakos, Jeannie-Marie %A Munro, Cynthia %A Oh, Esther %A Drake, Kristen E %A Lyman, Christopher H %A Rosenberg, Paul B %A Anderson, William S %A Tang-Wai, David F %A Pendergrass, Jo Cara %A Salloway, Stephen %A Asaad, Wael F %A Ponce, Francisco A %A Burke, Anna %A Sabbagh, Marwan %A Wolk, David A %A Baltuch, Gordon %A Okun, Michael S %A Foote, Kelly D %A McAndrews, Mary Pat %A Giacobbe, Peter %A Targum, Steven D %A Lyketsos, Constantine G %A Smith, Gwenn S %X

BACKGROUND: Deep brain stimulation (DBS) is used to modulate the activity of dysfunctional brain circuits. The safety and efficacy of DBS in dementia is unknown.

OBJECTIVE: To assess DBS of memory circuits as a treatment for patients with mild Alzheimer's disease (AD).

METHODS: We evaluated active "on" versus sham "off" bilateral DBS directed at the fornix-a major fiber bundle in the brain's memory circuit-in a randomized, double-blind trial (ClinicalTrials.gov NCT01608061) in 42 patients with mild AD. We measured cognitive function and cerebral glucose metabolism up to 12 months post-implantation.

RESULTS: Surgery and electrical stimulation were safe and well tolerated. There were no significant differences in the primary cognitive outcomes (ADAS-Cog 13, CDR-SB) in the "on" versus "off" stimulation group at 12 months for the whole cohort. Patients receiving stimulation showed increased metabolism at 6 months but this was not significant at 12 months. On post-hoc analysis, there was a significant interaction between age and treatment outcome: in contrast to patients 

CONCLUSION: DBS for AD was safe and associated with increased cerebral glucose metabolism. There were no differences in cognitive outcomes for participants as a whole, but participants aged≥65 years may have derived benefit while there was possible worsening in patients below age 65 years with stimulation.

%B J Alzheimers Dis %V 54 %P 777-87 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567810?dopt=Abstract %R 10.3233/JAD-160017 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Depression and Suicidal Ideation During Two Psychosocial Treatments in Older Adults with Major Depression and Dementia. %A Kiosses, Dimitris N %A Rosenberg, Paul B %A McGovern, Amanda %A Fonzetti, Pasquale %A Zaydens, Hana %A Alexopoulos, George S %X

BACKGROUND: Depression is prevalent in dementia and contributes to poor outcomes for patients and their families. Antidepressants have limited efficacy in older adults with major depression and dementia, and psychosocial interventions are under-investigated.

OBJECTIVE: To examine the course, predictors and moderators of depression and suicidal ideation during 12 weeks of home-delivered Problem Adaptation Therapy (PATH) versus Supportive Therapy for Cognitively Impaired Older Adults (ST-CI) in 39 older adults with major depression and dementia.

METHODS: Thirty-nine older adults with major depression, mild or moderate dementia, and disability participated in a randomized controlled trial that compared the efficacy of PATH versus ST-CI. Depression and suicidal ideation were assessed with Cornell Scale for Depression in Dementia Total Score and Suicide Item.

RESULTS: PATH participants had significantly greater reduction in depression than ST-CI participants over 12 weeks of treatment. PATH participants with high social support had the greatest reduction in depression. Both treatments had comparable reduction in suicidal ideation.

CONCLUSION: PATH is more effective in reducing depression in older adults with major depression and dementia compared to ST-CI. These results are clinically significant as antidepressants have limited efficacy in this population. Home-delivered psychosocial treatments may reduce suicidal ideation in this population.

%B J Alzheimers Dis %V 48 %P 453-62 %8 2015 Sep 9 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26402009?dopt=Abstract %R 10.3233/JAD-150200