The Use of Transcranial Focused Ultrasound for the Treatment of Neurodegenerative Dementias

The purpose of this open label study is to evaluate longer term tolerability and early efficacy of transcranial ultrasound in the treatment of patients with mild cognitive impairment or dementia.

The present study is designed as an open label study of patients with mild cognitive impairment (MCI) or dementia to evaluate longer term tolerability and early efficacy of transcranial ultrasound treatment. Baseline and outcome measures in this study utilize validated tests that are appropriate for repeated measures which are not affected by practice effects. For patients with amnestic predominant cognitive change, the target will be the mesial temporal lobe through a trans temporal scalp window. Targeting will include reference to scalp fiducials based on the obtained MRI and Transcranial Doppler (TCD) waveform confirmation will be obtained because of the ability of TCD to record Doppler signal from the posterior cerebral artery that runs medial to the mesial temporal lobe. On the day of the ultrasound appointment, patients will undergo ten to thirty minutes of transcranial ultrasound treatment. The sonification device will be aimed at the hippocampus or the putamen and substantia nigra, depending on the predetermined condition. Targeting will include reference to scalp fiducials based on the obtained MRI; confirmation of target accuracy will either be obtained by Doppler waveform confirmation or optical tracking technology which co-registers patient neuroimaging with real space. Patients will undergo 8 total sessions of focused ultrasound. Patients will be evaluated at baseline and upon final ultrasound treatment using the same measures obtained upon entry. Safety and any adverse events will be monitored closely.

All patients enrolled will receive transcranial focused ultrasound. Target location is dependent on patient condition.

The FDA has determined the power intensity limits that are safe for clinical use; the proposed equipment works within these parameters. Furthermore, monitoring sessions up to one hour as proposed in this study are routinely used in patients even with acute brain injury at 2 megaHertz without any reports of complications induced by the ultrasound device. No brain heating, cavitation or bleeding has been identified with the proposed equipment and protocol. For each individual safety can be followed by performing a selective mental status exam at each session completion (for example for hippocampal targets, there will be a delayed recall memory test).

The Quick Dementia Rating Scale (QDRS) is an interview-based tool administered by study officials to participants' caregivers used to obtain observations from a consistent source. The QDRS form consists of 10 categorical questions (5 cognitive, 5 functional), each with 5 detailed options depicting the level of impairment as either 0 (normal), 0.5 (mild/inconsistent impairment), 1 (mild/consistent impairment), 2 (moderate impairment), or 3 (severe impairment). Based on the conversion table outlined in Dr. James Galvin's research (2015), total QDRS scores were converted to Clinical Dementia Rating (CDR) scale levels ranging from 0 (normal aging), 0.5 (mild cognitive impairment), 1 (mild dementia), 2 (moderate dementia), and 3 (severe dementia).

RBANS assesses immediate memory, visuospatial skill, language, attention, and delayed memory. Patient performance on each subscale immediate memory, language, attention, visuospatial, and delayed memory are scored relative to validated norms for same-aged peers. A change of 8+ points in the Total Scale score, 11+ points in the Immediate Memory score, 9+ points in the Language score, 4+ points on the Attention score, 14+ points is considered significant for the Visuospatial score, and 10+ points for the Delayed Memory score are considered significant.

RBANS assesses immediate memory, visuospatial skill, language, attention, and delayed memory. Patient performance on each subscale immediate memory, language, attention, visuospatial, and delayed memory are scored relative to validated norms for same-aged peers. A change of 8+ points in the Total Scale score, 11+ points in the Immediate Memory score, 9+ points in the Language score, 4+ points on the Attention score, 14+ points is considered significant for the Visuospatial score, and 10+ points for the Delayed Memory score are considered significant.

The MoCA evaluates frontal-executive functions (e.g., verbal abstraction and mental calculation), language (e.g., confrontation naming, phonemic fluency), orientation (e.g., person, place, date, day of the week, and time), visuospatial construction (e.g., simple figure copy), divided visual attention, and immediate and delayed memory of unstructured information. MoCA scores range from 0-30 possible points; 26 or greater is considered to reflect normal cognitive status.

The MoCA evaluates frontal-executive functions (e.g., verbal abstraction and mental calculation), language (e.g., confrontation naming, phonemic fluency), orientation (e.g., person, place, date, day of the week, and time), visuospatial construction (e.g., simple figure copy), divided visual attention, and immediate and delayed memory of unstructured information. MoCA scores range from 0-30 possible points; 26 or greater is considered to reflect normal cognitive status.

The Quick Dementia Rating Scale (QDRS) is an interview-based tool administered by study officials to participants' caregivers used to obtain observations from a consistent source. The QDRS form consists of 10 categorical questions (5 cognitive, 5 functional), each with 5 detailed options depicting the level of impairment as either 0 (normal), 0.5 (mild/inconsistent impairment), 1 (mild/consistent impairment), 2 (moderate impairment), or 3 (severe impairment). Based on the conversion table outlined in Dr. James Galvin's research (2015), total QDRS scores were converted to Clinical Dementia Rating (CDR) scale levels ranging from 0 (normal aging), 0.5 (mild cognitive impairment), 1 (mild dementia), 2 (moderate dementia), and 3 (severe dementia).

Inclusion Criteria: CDR stage of at least 0.5 (mild cognitive impairment) At least one pathognomic imaging biomarker of a neurodegenerative process. Exclusion Criteria: Cognitive decline clearly related to an acute illness Subjects unable to give informed consent Subjects with scalp rash or open wounds on the scalp (for example from treatment of squamous cell cancer) Advanced terminal illness Advanced kidney, pulmonary, cardiac or liver failure Subjects who would not be able to lay down without excessive movement in a calm environment sufficiently long enough to be able to achieve sleep Subjects with major depressive disorder Subjects with vascular causes of dementia

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