/reads kandel

some interesting therapies under development include:

- a few drugs that modulate neurotransmitter levels, in hopes of improving cognitive symptoms
- a drug that decreases the level of secretases that turn APP into amyloid peptides
- immunization against amyloid peptides
- immunization against tau

variants of the APOE gene carry different risks of developing late-onset alzheimer's.

diagnosis of even mild dementia due to alzheimer's is now pretty accurate, using MRI to check for cortical thinning and ventricular enlargement, and PET to label and visualize amyloid plaque and aggregated tau.

there was a debate (between "baptists" and "tauists"!) about whether the amyloid plaques or hyperphosphorylated tau tangles were the main cause of alzheimer's.

we now think amyloid plaque accumulation somehow drives tau aggregation, and abnormal tau spreads between cells in a prion-like manner.

the amyloid precursor protein (APP) gene sits on chromosome 21. people with down's syndrome, who have an extra copy of 21, all develop alzheimer's by age 50–a pretty strong signal that excessive APP production is a cause.

one of the genes that causes early-onset alzheimer's also encodes APP.

unlike normal aging, alzheimer's causes extensive neuron death.

like other neurodegenerative diseases, there's abnormal protein buildup both intracellularly (tau-rich tangles) and extracellularly (amyloid plaques).

entorhinal cortex, hippocampus, and basal forebrain are especially affected.

dementia (progressive impairment of memory, language, problem-solving, judgement, and attention) is most commonly caused by alzheimer's.

alzheimer's becomes much more prevalent with age: 2% of people at 70, over 20% at 80. the early-onset variant is often genetic, but most cases are sporadic.

brains shrink over time.

some neurons do die. but in healthy brains, it's mostly structural alteration caused by the loss of myelin, dendritic spines, neurotransmitters, and synapses.

we're starting to look for genetic controls of aging in model organisms. caloric restriction seems to help?

age-related cognitive decline affects people unevenly: most people decline gradually, some decline early and sharply, others apparently don't decline at all.

working memory, spatial reasoning, and verbal fluency are often affected, while vocabulary, knowledge, and comprehension are usually spared.

64. the aging brain

over time, as healthcare and nutrition improve, humans live longer: average life span in the US was only ~50 in 1900, and is ~80 now.

sadly, this means more of us are encountering the cognitive impairments that come with age, including alzheimer's and other dementias.

"chaperone" proteins help other proteins fold properly and prevent accumulation, and there's evidence that they help slow disease progression.

in mice, as long as mutant transgenes are turned off before mass neuron death, dysfunction is reversible, giving hope that the same would be true in humans.

we've learned from animal models of neurodegenerative disease that:

- disease severity depends on how long the mutant protein is, and how much is produced
- mutant proteins accumulate in neurons, which can't break them down fast enough
- some mutants have no effect unless they're in the nucleus

different types of neurons are affected first in each degenerative disease: striatal neurons in huntington's, purkinje cells in the SCAs, and dopaminergic neurons in parkinson's.

this may be because each disease causes a different protein misfolding, which some cells are particularly vulnerable to.

3% of people over 65 have parkinson's, hallmarked by progressive loss of dopaminergic neurons and accumulation of abnormal clumps of protein ("lewy bodies") in the brain.

patients suffer from resting tremor, slow and difficult movement, rigidity, poor balance, and eventually cognitive decline.

most spinocerebellar ataxias (SCAs) and some muscular atrophies are also CAG repeat diseases. all cause difficulties with movement and speech, pointing to dysfunction of cerebellum, spinal cord, brain stem, and possibly PNS.

generally, the longer the CAG repeat, the earlier the onset of disease.

in huntington's, too many CAG repeats leads to the degeneration of striatum, often visible in imaging a decade before symptom onset.

corticostriatal projections are disrupted and cortex thins, manifesting downstream as everything from motor dysfunction to depression to psychosis to severe dementia.

63. genetic mechanisms in neurodegenerative diseases of the nervous system

the late-onset degenerative diseases fall into 2 categories:

- sporadic, i.e. unknown etiology (majority of alzheimer's and parkinson's cases)
- inherited (huntington's, spinocerebellar ataxia, several muscular atrophies)

other ongoing work includes:

- identifying how and when autism-related genes affect the brain (glutamatergic synaptic function? mid-fetal development?)
- finding relevant animal models
- looking for histological abnormalities (that aren't caused by comorbid epilepsy)
- looking for gene therapies!

we don't fully understand the genetics of autism yet, but we've learned:

- de novo mutations in neuroligin genes markedly increase risk, and are correlated with paternal age
- other shaky candidate genes include polymorphisms in (in order of likelihood) CNTNAP2, OXT, MTHFR, BCKDK, NHE9, and HTT 🤷‍♀️

other intellectual / social disabilities include:

- fragile x syndrome (FMR1 gene has way too much CGG, causing overmethylation)
- rett syndrome (MECP2 knockout causes reduced brain-derived neurotrophic factor)
- williams syndrome (missing 27 genes on chromosome 7 causes _increased_ sociability)

autism definitely has a genetic component, with identical twins showing somewhere between 60-90% concordance, depending on if you count partial cases like social impairment only.

ASD isn't monogenic, but some other social disorders are. it has an environmental component as well. it's not vaccines.

other vaguely unsatisfying behavioral markers for autism include lack of flexibility in thinking and generally poor executive function.

there's also a higher-than-average prevalence of special talents in areas like music, memory, art, math, systems thinking, and spatial reasoning, among others.

some brain areas implicated in autism deficits include orbitofrontal cortex, anterior cingulate cortex, amygdala, face areas, and striatum.

there may be a neural mechanism that attends to social stimuli. in eye-tracking experiments, people with ASD ignore eyes in scenes, fixating on mouths instead.

autism spectrum disorder (ASD) affects ~2% of the population. boys are diagnosed more often than girls, but this may be bias.

a common symptom in children is the inability to spontaneously infer mental states of others ("mind blindness"). this can be learned, but usually not to natural fluency.

62. disorders affecting social cognition: autism spectrum disorder

neurodevelopmental disorders can affect perception, general cognition, or, as in autism, social cognition.

autism has 2 defining features:

- impaired social communication
- stereotyped behaviors with highly restricted interests

depression treatments include:

- monoamine-affecting antidepressants, like SSRIs
- ketamine (fast-acting!)
- psychotherapy, like CBT
- electroconvulsive therapy (not terrible if done properly)
- neuromodulation, like TMS or DBS

mania is treated with lithium, anticonvulsants, or antipsychotics.

both depression and stress are associated with a hyperactive HPA axis and high levels of cortisol. chronic stress may lead to depression because of this.

this is likely related to the demonstrated loss of hippocampal volume, as elevated glucocorticoid levels suppress adult hippocampal neurogenesis.

depression and anxiety are associated with an overactive amygdala, possibly due to reduced top-down control by anterior cingulate cortex (ACC), as seen in fMRI studies. this makes ACC a good target for DBS probes.

reward circuitry is also abnormal: suppressed in depression, overactive in mania.

depression and anxiety often co-occur, in people as well as in families, polygenically.

other risk factors are:

- developmental (severe childhood adversity, leading to altered reactivity in hypothalamic-pituitary-adrenal, or HPA, axis)
- environmental (substance use, life transitions, illness)

fear is an appropriate and adaptive response to danger, and typically transient in its activation of the sympathetic nervous system.

but when fear persists for a protracted time period at an intensity disproportionate to the likelihood and severity of threat, it becomes an anxiety disorder.

there's no objective medical test for depression–it's criteria-based. but major depression differs significantly from normal sadness in amplitude, time course, rigidity, and contextual appropriateness.

the same differences, but with positive valence with respect to normal happiness, comprise mania.