The Malfunctioning Mind: Degenerative Diseases of the Brain Andrea Mejia. Spring 2017

Defining: Normal aging Declining abilities Cognitive processing speed Fluid intelligence Divided attention Learning efficiency Source memory Visuoperceptual functioning Stable (improved?) abilities Crystallized intelligence = learned knowledge and experiences Age related cognitive decline (ARCD) –ARCD is used interchangeable with “normal aging”. Those with ARCD are coined as the “worried well”. Applies to the clinical situation where an older person is worried about their memory – to the degree they complain to their PCP therefore prompting a referral – but there is no objective evidence of memory impairment.

Defining: Dementia Loss of intellectual capacity and/or personality Due to loss and/or damage of neurons Reversible Infection, autoimmune, toxic, metabolic Nonreversible Static: stroke, Korsakoff’s, head injury Degenerative: Alzheimer's, Lewy Bodies, vascular, frontotemporal

Degenerative Dementia Intrinsic to the nervous system and affect certain neural systems selectively Presumed to have a degree of genetic transmission Alzheimer’s, Parkinson’s, frontotemporal dementia, etc.

Nondegenerative Dementia Diverse etiologies, including vascular, endocrine, inflammatory, nutritional deficiency, and toxic conditions Infectious dementia (AIDS dementia), demyelinating dementia (multiple sclerosis), chronic alcohol or drug abuse (Korsakoff’s syndrome), etc.

Alzheimer’s Disease: Diagnostic Criteria and Associated Features Gradual onset Worsening of cognition One of two categories must be present Amnestic presentation – most common E.g. learning impairment and of recall of recently learned information Nonamnestic presentations Language, most common word-finding Visual, most common spatial cognition Executive dysfunction, most common reasoning, judgment, problem solving Onset of months to years, not sudden over hours or days Worsening of condition by report of observation Visual – also object agnosia, impaired face recognition

Alzheimer’s Disease: Epidemiology Most common dementia Increasing prevalence Higher prevalence With age Developing nations Women African Americans, Hispanics Survival 2-20 years from diagnosis 1/3 seniors dies with Alzheimer or other dementia 2/3 of americans with Alzheimer’s disease are women In the U.S. someone develops Alzheimer’s ever 66 seconds

Alzheimer’s Disease: Genetic Factors Family history = risk factor Esp. with early onset Three identified genes…still many ?s Having a gene doesn’t mean you will acquire Alzheimer’s...or vice versa But there are three genes that will cause someone to invariably develop AD Down syndrome Neuropathological changes consistent with AD By age 40 in most - For the 3 genes – all 3 causative gene mutations are associated with an early age of onset (occurring before the age of of 65)

Alzheimer’s Disease: Neuropathology Neuronal loss with cortical neuronal shrinkage Correlates with dementia severity Generalized cortical atrophy Sulcal widening, gyral atrophy Increased ventricular size Neurodegenerative changes begin in the medial temporal lobe Spread to frontal, temporal, and parietal lobes

Alzheimer’s Disease: Neurocognitive Profile Memory Episodic memory impairment Begins with recent memories Language Word-finding difficulties Grammar and syntax less and less complex Visuospatial functioning Disorientation in familiar places Object misplacement

Alzheimer’s Disease: Neurocognitive Profile In later stages: Executive dysfunction Planning, sequencing, abstracting Agnosia Recognizing objects Apraxia Learned motor acts

Alzheimer’s Disease: Other symptoms Depression Apathy and agitation Anxiety and delusions (often paranoid) Later stages Visual hallucinations Very advanced stages

Neuropsychological Testing of Alzheimer’s Patients Digit Symbol Block design Clock drawing Object naming Memory Deficits on tests of both left and right hemisphere function Maybe demonstrate if you would like

Alzheimer’s Disease: Neuroimaging Structural neuroimaging (MRI, CT) Cortical atrophy Esp. temporal structures (e.g., Hippocampus) Problem: Overlap with other dementias, normal aging

Alzheimer’s Disease: Neuroimaging Functional neuroimaging (fMRI, PET, SPECT) Reduced activation of multiple regions Temporal Parietal

Alzheimer’s Disease: Treatment Other treatment strategies besides medications Manage depression, anxiety, sleep, psychosis Basic schedules, notebooks, calendars Mixed rehabilitation showed improvement in individuals with MCI, but not early AD Caregiver education and support http://www.youtube.com/watch?v=q1BkfV2h09g MCI – stage before getting dementia and after normal aging - speaks to importance of early, or preclinical diagnosis.

Dementia with Lewy Bodies: Diagnostic Criteria Central feature Progressive dementia interfering with social or occupational function Memory impairment Deficits on tests of attention, executive function, and visuospatial Core features Fluctuating attention, visual hallucinations, parkinsonism Depression Additional features REM sleep-behavior disorder, depression, delusions, autonomic dysfunction (hypotension, urinary incontinence), repeated falls and syncope Memory impairment may not occur in early stages, but is evident with progression Deficits on tests of attention, executive function, and Visuospatial ability may be especially prominent Spontaneous features of parkinsonism Additional features – some are “suggestive” meaning, 1 or more must be present in the presence of one or more core features, a diagnosis of probable DLB can be made. Some are “supportive” features, meaning commonly present but not proven to have diagnostic specificity

Dementia with Lewy Bodies: Epidemiology Found in about 20-35% of elderly with dementia Second most common cause of neurodegenerative dementia Prevalence does not increase with advancing age 2nd, following AD Unlike AD, prevalence does not increase with age... MORE COMMON IN MEN Clinical presentation is often striking not only for the parkinsonism, but also for dramatic fluctuations in patients’ level of arousal, the vivid hallucinations and the histories of dream enactment behavior during sleep

Dementia with Lewy Bodies: Neuropathology Cortical DLB Limbic (e.g. amygdala) and temporal regions, with lesser involvement of frontal and posterior cortical regions Subcortical DLB Hypothalamus, basal forebrain, midbrain Tegmentum Overlap with AD AD pathology at autopsy common Other brain regions for subcortical DLB - Overlap with AD Dementias of DLB and AD are similar in onset and progressive course Prior to autopsy many patients with Lewy body diesease had been given the diagnosis of AD

Dementia with Lewy Bodies: Genetics No genes have been identified for DLB

Dementia with Lewy Bodies: Neuropsychological Profile Compared to AD, DLB patients have greater deficits in attention, letter fluency, visual perceptual organization, and visual constructional skills Significant visual spatial deficits Mild memory difficulties (in comparison to AD) - Prominent clinical presentation involves deficits in attention and concentration and problems in complex visual perceptual processing

Dementia with Lewy Bodies: Treatment Cholinesterase inhibitors More severe deficits than in AD patients Attention, psychiatric, hallucinations Many will show remarkable improvement Dopaminergic agents Levodopa  motor function, alertness Typically responsive, but some adverse reactions AVOID ANTIPSYCHOTICS Severe reactions Risk displaying neuroleptic malignant syndrome *Cholinesterase – profound cholinergic neuronal loss and severe depletion occurs early in DLB, unlike AD until late stages. Neuronal loss and depletion affects attention, and visual disturbances, and does not impair memory Therefore cholinesterase inhibitors are more successful with DLB then AD Thus cholinergic depletion is a critical factor in the symptom manifestation of early DLB but appears to be less so in AD This finding highlights the importance of differentiating btw early versus late stages of different dementias since patients with advance AD may have similar clinical features to those with early DLB* **** may be too specific but shows they are different or treated different although there are many similarities with AD and DLB