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Browsing by Author "Cummings, Jeffrey L."
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Item A framework for translating tauopathy therapeutics: Drug discovery to clinical trials(Wiley, 2024) Feldman, Howard H.; Cummings, Jeffrey L.; Boxer, Adam L.; Staffaroni, Adam M.; Knopman, David S.; Sukoff Rizzo, Stacey J.; Territo, Paul R.; Arnold, Steven E.; Ballard, Clive; Beher, Dirk; Boeve, Bradley F.; Dacks, Penny A.; Diaz, Kristophe; Ewen, Colin; Fiske, Brian; Gonzalez, M. Isabel; Harris, Glenn A.; Hoffman, Beth J.; Martinez, Terina N.; McDade, Eric; Nisenbaum, Laura K.; Palma, Jose-Alberto; Quintana, Melanie; Rabinovici, Gil D.; Rohrer, Jonathan D.; Rosen, Howard J.; Troyer, Matthew D.; Kim, Doo Yeon; Tanzi, Rudolph E.; Zetterberg, Henrik; Ziogas, Nick K.; May, Patrick C.; Rommel, Amy; Medicine, School of MedicineThe tauopathies are defined by pathological tau protein aggregates within a spectrum of clinically heterogeneous neurodegenerative diseases. The primary tauopathies meet the definition of rare diseases in the United States. There is no approved treatment for primary tauopathies. In this context, designing the most efficient development programs to translate promising targets and treatments from preclinical studies to early-phase clinical trials is vital. In September 2022, the Rainwater Charitable Foundation convened an international expert workshop focused on the translation of tauopathy therapeutics through early-phase trials. Our report on the workshop recommends a framework for principled drug development and a companion lexicon to facilitate communication focusing on reproducibility and achieving common elements. Topics include the selection of targets, drugs, biomarkers, participants, and study designs. The maturation of pharmacodynamic biomarkers to demonstrate target engagement and surrogate disease biomarkers is a crucial unmet need. HIGHLIGHTS: Experts provided a framework to translate therapeutics (discovery to clinical trials). Experts focused on the "5 Rights" (target, drug, biomarker, participants, trial). Current research on frontotemporal degeneration, progressive supranuclear palsy, and corticobasal syndrome therapeutics includes 32 trials (37% on biologics) Tau therapeutics are being tested in Alzheimer's disease; primary tauopathies have a large unmet need.Item Early behavioural changes in familial Alzheimer's disease in the Dominantly Inherited Alzheimer Network(Oxford University Press, 2015-04) Ringman, John M.; Liang, Li-Jung; Zhou, Yan; Vangala, Sitaram; Teng, Edmond; Kremen, Sarah; Wharton, David; Goate, Alison; Marcus, Daniel S.; Farlow, Martin R.; Ghetti, Bernardino; McDade, Eric; Masters, Colin L.; Mayeux, Richard P.; Rossor, Martin N.; Salloway, Stephen; Schofield, Peter R.; Cummings, Jeffrey L.; Buckles, Virginia; Bateman, Randall J.; Morris, John C.; Dominantly Inherited Alzheimer Network; Department of Neurology, IU School of MedicinePrior studies indicate psychiatric symptoms such as depression, apathy and anxiety are risk factors for or prodromal symptoms of incipient Alzheimer's disease. The study of persons at 50% risk for inheriting autosomal dominant Alzheimer's disease mutations allows characterization of these symptoms before progressive decline in a population destined to develop illness. We sought to characterize early behavioural features in carriers of autosomal dominant Alzheimer's disease mutations. Two hundred and sixty-one persons unaware of their mutation status enrolled in the Dominantly Inherited Alzheimer Network, a study of persons with or at-risk for autosomal dominant Alzheimer's disease, were evaluated with the Neuropsychiatric Inventory-Questionnaire, the 15-item Geriatric Depression Scale and the Clinical Dementia Rating Scale (CDR). Ninety-seven asymptomatic (CDR = 0), 25 mildly symptomatic (CDR = 0.5), and 33 overtly affected (CDR > 0.5) autosomal dominant Alzheimer's disease mutation carriers were compared to 106 non-carriers with regard to frequency of behavioural symptoms on the Neuropsychiatric Inventory-Questionnaire and severity of depressive symptoms on the Geriatric Depression Scale using generalized linear regression models with appropriate distributions and link functions. Results from the adjusted analyses indicated that depressive symptoms on the Neuropsychiatric Inventory-Questionnaire were less common in cognitively asymptomatic mutation carriers than in non-carriers (5% versus 17%, P = 0.014) and the odds of experiencing at least one behavioural sign in cognitively asymptomatic mutation carriers was lower than in non-carriers (odds ratio = 0.50, 95% confidence interval: 0.26-0.98, P = 0.042). Depression (56% versus 17%, P = 0.0003), apathy (40% versus 4%, P < 0.0001), disinhibition (16% versus 2%, P = 0.009), irritability (48% versus 9%, P = 0.0001), sleep changes (28% versus 7%, P = 0.003), and agitation (24% versus 6%, P = 0.008) were more common and the degree of self-rated depression more severe (mean Geriatric Depression Scale score of 2.8 versus 1.4, P = 0.006) in mildly symptomatic mutation carriers relative to non-carriers. Anxiety, appetite changes, delusions, and repetitive motor activity were additionally more common in overtly impaired mutation carriers. Similar to studies of late-onset Alzheimer's disease, we demonstrated increased rates of depression, apathy, and other behavioural symptoms in the mildly symptomatic, prodromal phase of autosomal dominant Alzheimer's disease that increased with disease severity. We did not identify any increased psychopathology in mutation carriers over non-carriers during the presymptomatic stage, suggesting these symptoms result when a threshold of neurodegeneration is reached rather than as life-long qualities. Unexpectedly, we found lower rates of depressive symptoms in cognitively asymptomatic mutation carriers.Item Effects of Oral Rivastigmine on Cognitive Domains in Mild-to-Moderate Alzheimer’s Disease(Sage, 2010) Farlow, Martin R.; Cummings, Jeffrey L.; Olin, Jason T.; Meng, Xiangyi; Neurology, School of MedicineRivastigmine has beneficial effects on cognitive functioning in Alzheimer's disease (AD). Effects of cholinesterase inhibitors, particularly rivastigmine, on AD Assessment Scale-cognitive subscale (ADAS-cog) domains and individual items have rarely been analyzed. Results from 4 randomized, double-blind, placebo-controlled, 26-week rivastigmine capsule trials in patients with mild-to-moderate AD were pooled and ADAS-cog domains and individual items were evaluated. Data were available from 878, 1053, and 863 patients in the 1 to 4 mg/d, 6 to 12 mg/d, and placebo groups, respectively. Rivastigmine-treated groups were superior to placebo on total ADAS-cog and memory domain scores (P < or = .0001). Rivastigmine 6 to 12 mg/d was also significantly better versus placebo on language (P < .001) and praxis (P < .001); greatest treatment responses were seen on memory items (P < .0001). Although rivastigmine was associated with dose-dependent improvements in all cognitive domains, largest effects were on memory items. Evaluation of ADAS-cog domain scores provides insight into test items most likely to respond to treatment.Item National Institute of Neurological Disorders and Stroke Consensus Diagnostic Criteria for Traumatic Encephalopathy Syndrome(Wolters Kluwer, 2021) Katz, Douglas I.; Bernick, Charles; Dodick, David W.; Mez, Jesse; Mariani, Megan L.; Adler, Charles H.; Alosco, Michael L.; Balcer, Laura J.; Banks, Sarah J.; Barr, William B.; Brody, David L.; Cantu, Robert C.; Dams-O’Connor, Kristen; Geda, Yonas E.; Jordan, Barry D.; McAllister, Thomas W.; Peskind, Elaine R.; Petersen, Ronald C.; Wethe, Jennifer V.; Zafonte, Ross D.; Foley, Éimear M.; Babcock, Debra J.; Koroshetz, Walter J.; Tripodis, Yorghos; McKee, Ann C.; Shenton, Martha E.; Cummings, Jeffrey L.; Reiman, Eric M.; Stern, Robert A.; Psychiatry, School of MedicineObjective: To develop evidence-informed, expert consensus research diagnostic criteria for traumatic encephalopathy syndrome (TES), the clinical disorder associated with neuropathologically diagnosed chronic traumatic encephalopathy (CTE). Methods: A panel of 20 expert clinician-scientists in neurology, neuropsychology, psychiatry, neurosurgery, and physical medicine and rehabilitation, from 11 academic institutions, participated in a modified Delphi procedure to achieve consensus, initiated at the First National Institute of Neurological Disorders and Stroke Consensus Workshop to Define the Diagnostic Criteria for TES, April, 2019. Before consensus, panelists reviewed evidence from all published cases of CTE with neuropathologic confirmation, and they examined the predictive validity data on clinical features in relation to CTE pathology from a large clinicopathologic study (n = 298). Results: Consensus was achieved in 4 rounds of the Delphi procedure. Diagnosis of TES requires (1) substantial exposure to repetitive head impacts (RHIs) from contact sports, military service, or other causes; (2) core clinical features of cognitive impairment (in episodic memory and/or executive functioning) and/or neurobehavioral dysregulation; (3) a progressive course; and (4) that the clinical features are not fully accounted for by any other neurologic, psychiatric, or medical conditions. For those meeting criteria for TES, functional dependence is graded on 5 levels, ranging from independent to severe dementia. A provisional level of certainty for CTE pathology is determined based on specific RHI exposure thresholds, core clinical features, functional status, and additional supportive features, including delayed onset, motor signs, and psychiatric features. Conclusions: New consensus diagnostic criteria for TES were developed with a primary goal of facilitating future CTE research. These criteria will be revised as updated clinical and pathologic information and in vivo biomarkers become available.