Zachary Miller loves talking to his patients about their childhood. He believes that the clues to some neurodegenerative diseases have roots in a person’s early years of life. Did your mother have a normal pregnancy? Were you born on time? Did you enjoy reading? Were you ever tutored in math? Are you left-handed? And on and on it goes, patching together dozens of bits of life history to make sense of why an aging brain may be more vulnerable to specific types of dementia.

There is growing evidence the neurologist may be right. For instance, he’s shown that non-right-handedness (left-handedness, ambidexterity, and forced-right-handedness but for simplicity sake, we’ll just call it left-handedness) and learning disabilities in childhood inform where a dementia takes root. And location in the brain is everything when it comes to a person’s symptoms. His evidence comes from looking at the records of almost 200 people diagnosed with progressive primary aphasia, a dementia that affects many aspects of language. There are three specific variants of PPA and each is associated with a specific pathology. He dove into the history of patients with primary progressive aphasia seen at the Memory and Aging Center to see whether there was an association between early life events and the symptoms that had altered their lives many decades later.

Zac Miller, a behavioral neurologist, arrived at the MAC in 2009 with a thirst to understand brain diseases and creativity. His life seemed to be a mix of both: he loved science and his visual impulses were always in overdrive. He entered Haverford College with a double major in fine arts (sculpture) and molecular biology. A seizure disorder that began at ten and finally diagnosed and treated at 16 led him into the puzzle of neurology. He also stood apart from 90 percent of his peers in school: he was a lefty. It was his life as a southpaw and early loves of visual arts and sciences that got him interested in studying creativity and art. There were just so many more left-handed creative people in the world and back in the 1980s one of his heroes, neurologist Norman Geschwind, proposed that in addition to musical, mathematical, and visuospatial giftedness, left-handedness was also linked to an increased prevalence of learning disabilities, stuttering, immune diseases, and migraine headaches.

Zac Miller loved all things Geschwind and his equal passion for art and the brain led him to UCSF, where neurologist Bruce Miller (no relation) had been publishing on people with dementias who would develop a new penchant and talent for art during their diagnostic journey. Bruce Miller, director of the MAC, and an academic “grandson” of Norman Geschwind, believed that damage in one area of the brain could somehow ignite circuits in other areas that are linked to creative expression. Zac came across a finding in one of Bruce Miller’s seminal works suggesting that over a third of these newly artistic dementia patients were left-handed.

That idea got him fired up and ready to go. During his first week of work, Bruce Miller asked him whether he’d be interested in co-authoring a book chapter on dementia and art in the brain. So, the left-handed neurologist from Rockville, Maryland began doing what he always wanted to do: merge his two main passions into a single career. Inspired by the rhetoric of disease susceptibility that another MAC neurologist – Bill Seeley – had pioneered, right away, Zac started thinking about how handedness might influence creativity as well as vulnerability to neurologic disease. In short order, he dug into the files of the first 10,000 people seen at the MAC research system investigating handedness and found, well, nothing. He tried separating out handedness in the different neurodegenerative conditions and again, nothing. It was only when he separated out the three different forms of primary progressive aphasia that he hit pay dirt.

One of the conditions – semantic variant primary progressive aphasia – stood out right of normal. Eighteen percent of the semantic variant patients were left-handed. By comparison, ten percent of the general population is left-handed. There was something else: something BIG. Only four percent of people with nonfluent variant PPA were left-handed, too few, while ten percent of people with logopenic variant, the type most often associated with Alzheimer’s, were left-handed. “This was my Goldilocks moment,” the neurologist told me, “one group was too little, one too big, and the other… just right.” He made the discovery in his first year but it would be another four years of work before he figured out how to incorporate the group that was “just right” into a unified model of neurodevelopmental disease vulnerability within the language network.

Timing is always an interesting phenomenon at the MAC. While mulling over how to fit logopenic variant into a model of neurodegenerative disease, he’d often return to the charts to dig even deeper until finally he found himself on the very road paved by Norman Geschwind. If semantic variant PPA patients were more left-handed, what was the underlying vulnerability responsible for their disease susceptibility? Was it a structural difference? Left-handed brains in general are structurally more symmetrical than their right-handed counterparts. Or was it something else? A fact that he kept pondering over was an observation that of all the FTD syndromes, semantic PPA was the least likely to run in families. He learned this from work done by Columbia University’s Jill Goldman, a genetic counselor who used to work at the MAC and looked at the various FTD syndromes here and saw that semantic variant was the least heritable of these conditions.

So, Zac wondered if maybe he should investigate environmental associations. After all, he proudly offers, his father was a founding member of the Environmental Protection Agency. He went back to the history in the records of the research patients seen at the MAC and discovered a link between select autoimmune diseases and this particular language form of frontotemporal dementia. But it went much deeper. Semantic variant PPA shares pathology with ALS. Immune abnormalities had been controversially linking to Lou Gehrig’s disease and, Zac picked up immune signals across all the FTD spectrum diseases that shared this same pathology. He’s been doggedly pursuing this association to launch clinical trials aimed at modulating the immune system with MAC neurologists Bruce Miller and Adam Boxer, the director of the MAC clinical trials group, and believes that this year will be the year.

But back to our logopenic puzzle. It was during grand rounds on an early Friday morning when a talk on dyslexia opened with a slide of a brain scan. Lit up on the scan was the area where the brain changes occur in young dyslexic readers. There it was: the answer, the Goldilocks trifecta. The anatomy of developmental dyslexia happened to be the same exact anatomy where logopenic variant PPA starts.

Zac gives credit to Northwestern University neurologist Marsel Mesulam who wrote a seminal paper in 2008 identifying a higher frequency of learning abilities, most notably dyslexia) in their PPA patients, and to his mentor Dr. Maria Luisa Gorno Tempini, who in 2004 first described the condition logopenic variant PPA. Logopenic PPA is caused by the same proteins found in the brains of people with the more common amnestic AD but the plaques and tangles accumulate in an area of the brain that governs language. People with logopenic PPA have problems naming objects, while retaining understanding of those objects. Conversely, people with semantic variant PPA have problems understanding meaning, a disorder of concept knowledge. Those with non-fluent/agrammatic PPA have trouble with the production of sounds and organizing them into words and into meaningful sentences, and they lose an understanding of grammar.

Zac realized that the original study on learning differences in PPA had never been performed splitting the PPA patients into their respective subtypes, and suddenly, “all of the pieces of the puzzle that shape the vulnerability of the networks to these disorders fell into place,” he said. It was neurodevelopment, hand preference and learning disability shaping the susceptibility of an individual to neurodegenerative disease some 50–60 years later.

The year 2013 also heralded the publication of his findings on the autoimmune disease association. The neurodevelopmental story came out about six months later. Since Zac first arrived at the MAC over eight years ago, he’s never taken his gaze off neurodevelopment and autoimmune disease, and believes now more than ever that the guy he loved but never met outside of his ideas on paper – Norman Geschwind – was right. These two hits are interconnected. He believes that these factors are key to understanding these early onset atypical dementias and may even be the key to unlocking the mysteries of learning disabilities, autoimmune disease, and most importantly, left-handedness.

His mantra: “The life you live and how you live matters.”


Jamie Talan is an Atlantic Fellow in the Global Brain Health Institute, a collaboration between UCSF and Trinity College in Dublin. She has spent six months at UCSF writing about the inner workings of the brain and giving voice to patients and the doctors, nurses, psychologists, geneticists and researchers involved in building the foundation for a whole body of non-Alzheimer dementias that are often missed, lost or ignored.