What This Section Is About

The Cholinergic System (Acetylcholine)

• The brain uses a chemical called acetylcholine to help with memory and thinking.
• In AD, the system that makes and uses acetylcholine breaks down - especially in a region called the basal forebrain.
• This is why drugs called cholinesterase inhibitors (like donepezil) were developed - they try to boost acetylcholine levels.

• Special PET tracers ([¹¹C]PMP and [¹¹C]MP4A) measure the enzyme AChE, which breaks down acetylcholine.
• In AD patients, AChE activity is reduced in the hippocampus, temporal, and parietal lobes - the same regions that show low metabolism on FDG scans.
• Early-onset AD patients lose more AChE activity overall (across the whole brain), while late-onset AD patients lose it mainly in specific cortical spots - suggesting early-onset may benefit more from these drug treatments.

• Another PET tracer, (+)-[¹⁸F]flubatine, measures a type of acetylcholine receptor (nAChR - think of receptors as "docking stations" for the chemical).
• AD patients showed reduced receptor activity in the hippocampus, precuneus, and several frontal/cingulate areas. The biggest losses were in the temporal lobes.
• A second tracer (2-[¹⁸F]FA-85380) found that reduced receptor binding matched the severity of cognitive decline - and importantly, only MCI patients who later got AD showed this reduction, meaning PET might help predict who will progress to full AD.

The Serotonin System

• Serotonin governs mood, sleep, and cognition.
• AD patients show reductions in:
  • 5-HTT (serotonin transporter) - reduced in the striatum even before depression develops
  • 5-HT2A receptors - reduced in temporal and frontal cortex
  • 5-HT1A receptors - reduced mainly in the hippocampus and raphe nuclei

• Reduced 5-HT1A receptor binding in the hippocampus correlates with worsening cognition (MMSE scores) and lower brain metabolism.
• Interestingly, patients with amnestic MCI (a pre-AD stage) showed increased 5-HT1A binding, while full AD patients showed decreased binding - so PET might help tell the two apart.
• The drop in 5-HT2A receptors appears to be an early event in MCI but does NOT seem to predict progression to AD.

The Dopamine System

• This matters because doctors need to distinguish AD from Parkinson's dementia and Lewy body dementia (DLB), which also affect the dopamine system.
• [¹¹C]raclopride PET (measures dopamine D2 receptors) showed reduced hippocampal binding in AD, correlating with memory impairment.
• However, tracers measuring dopamine vesicle storage ([¹⁸F]AV-133) showed mixed results - no clear dopaminergic degeneration in AD.
• A study of MCI patients found that both amyloid buildup AND dopamine terminal loss predicted conversion from MCI to dementia - but PET-based subtype classification only roughly matched clinical diagnosis.

PET in Evaluating AD Treatments

Donepezil (a common AD drug)

• It was assumed donepezil blocked almost all AChE in the brain.
• PET revealed it actually only blocks about 27% of AChE activity - much less than thought.
• Also, AChE inhibitor activity does NOT appear linked to amyloid buildup or cognitive decline.

Anti-Amyloid Vaccines

• A vaccine trial (vanutide cridificar/ACC-001) used PET to measure amyloid plaques before and after.
• Result: No reduction in amyloid, no cognitive improvement - and worryingly, brain volume shrank faster in vaccinated patients.

Aducanumab

• This controversial anti-amyloid antibody was approved by the FDA despite mixed trial results.
• PET was used to track amyloid reduction, but no clear clinical benefit was confirmed.

Lecanemab & Donanemab (newer drugs)

• Trials showed ~27-36% slowing of cognitive decline over 18 months.
• In numbers: lecanemab produced a 0.45-point difference on a clinical scale (CDR-SB); donanemab produced 0.67 points.
• Problem: A clinically meaningful improvement on that scale is considered 1-2 points - so these differences may be too small to matter to real patients.
• Standard (conventional) AD therapy has shown bigger improvements on the same scales.

Focused Ultrasound + Drug Delivery

• A new technique uses focused ultrasound to briefly open the blood-brain barrier, helping drugs reach the brain better.
• PET confirmed amyloid plaques were reduced, but again - no cognitive improvement.

The Bottom Line

1. Diagnose AD earlier
2. Distinguish AD from other dementias
3. Predict disease progression
4. Measure whether treatments are working

How the Dopamine System Tells AD, Parkinson's Dementia (PDD), and Lewy Body Dementia (DLB) Apart

The Key Structure: The Nigrostriatal Pathway

• Station of origin: Substantia nigra (a small region in the brainstem)
• Destination: Striatum (basal ganglia - controls movement and some cognition)
• The trains: Dopamine molecules
• The tracks/loading docks: Dopamine transporters (DAT) on nerve terminals

What Each Disease Does to This Pathway

The "One Big Rule" for DAT Imaging

A normal (preserved) DAT scan = NOT PDD or DLB. It points toward AD.

• Sensitivity: 78-88% for detecting DLB vs. AD
• Specificity: 90-100% for separating DLB from AD
• The FDA approved DaTscan (¹²³I-ioflupane SPECT) specifically for distinguishing DLB from AD
• Kaplan & Sadock's Comprehensive Textbook of Psychiatry: "Dopamine transporter imaging...is abnormal in Parkinson disease, DLB, multisystem atrophy, and PSP."

DLB vs. PDD - The Harder Problem

• Motor symptoms come first (>1 year before dementia) → PDD
• Dementia comes first, or together with motor symptoms → DLB

• Stahl's Essential Psychopharmacology: "The differential diagnosis between DLB and PDD relies mainly on when there is onset of motor symptoms versus when there is onset of dementia."

What Additional PET/Imaging Clues Help?

Why Is This Clinically Important?

1. Antipsychotics (like haloperidol) are commonly used in dementia for hallucinations. In AD, they carry risks but can be used cautiously. In DLB/PDD, they can cause catastrophic and sometimes fatal reactions (severe neuroleptic sensitivity - rigidity, loss of consciousness, rapid decline). DLB patients are listed as having "severe neuroleptic sensitivity" as a core diagnostic feature.
2. Cholinesterase inhibitors (donepezil, rivastigmine) work in all three conditions but work particularly well in DLB for hallucinations.
3. Dopaminergic drugs (like levodopa for Parkinson's motor symptoms) work in PDD and DLB motor features but can worsen hallucinations in DLB.

In Simple Summary

• AD: Dopamine pathway mostly intact → DAT scan normal
• PDD: Dopamine pathway severely damaged → DAT scan abnormal + motor symptoms came first
• DLB: Dopamine pathway severely damaged → DAT scan abnormal + dementia came first or simultaneously
• The DAT scan's biggest clinical job is separating AD (normal scan) from DLB/PDD (abnormal scan)
• Separating PDD from DLB itself relies more on the timeline of symptoms than the scan

Why Is Amyloid PET Variable in PDD and DLB?

The Core Concept: Mixed Pathology

AD = amyloid + tau (defining features) PDD/DLB = alpha-synuclein (defining feature) ± amyloid (optional, variable co-passenger)

Why Do SOME PDD/DLB Patients Have Amyloid and Others Don't?

1. Age Effect

• Amyloid plaques are a normal feature of aging - even healthy elderly people accumulate some.
• PDD and DLB typically affect older patients, so many patients simply acquire amyloid deposits alongside their synuclein disease by coincidence of age, not because amyloid is driving their disease.
• Younger patients with PDD/DLB tend to have less amyloid on PET - hence the variable result.

2. The Alpha-Synuclein / Amyloid Interaction (They Promote Each Other)

• Research shows α-syn and amyloid-β interact synergistically - each protein promotes the aggregation and spread of the other.
• In some patients, this bidirectional feedback loop accelerates amyloid accumulation on top of Lewy body pathology.
• In others (especially younger or genetic cases), synuclein acts largely independently without triggering much amyloid buildup.

3. APOE ε4 Gene - The Key Driver

• APOE ε4 is the strongest known genetic risk factor for amyloid accumulation.
• DLB patients who carry the APOE ε4 allele have much higher rates of amyloid positivity on PET.
• Those without APOE ε4 (especially GBA1 mutation carriers - a different genetic pathway) tend toward "pure" synuclein pathology with little amyloid.
• So two DLB patients can look the same clinically but one is amyloid-positive on PET and the other is not - simply based on their genetics.

4. DLB Has More Amyloid Than PDD (They're Not Equal)

• This is a subtle but important distinction:
  • DLB: >70% of patients have medium-to-high levels of amyloid at autopsy. Amyloid-β plays a more pronounced role in DLB.
  • PDD: Only ~30-40% of PD patients accumulate significant AD co-pathology (amyloid + tau tangles).
• The reason is thought to relate to where Lewy bodies start spreading in the brain - DLB has earlier neocortical involvement, which overlaps more with amyloid-rich territories.
• So amyloid PET is positive more often in DLB than in PDD on a population level - yet both are still "variable."

5. PDD Patients Without Amyloid Still Get Dementia - Via Pure Synuclein

• In PDD, widespread neocortical spread of alpha-synuclein alone (without amyloid) is sufficient to cause dementia.
• So amyloid PET can be entirely negative in a PDD patient with severe cognitive impairment - because it's the synuclein doing the damage, not the amyloid.
• This is why amyloid PET has poor sensitivity for diagnosing PDD - a negative scan does NOT rule it out.

What Does This Mean Clinically? A Summary Table

The Clinical Consequence: Why This Matters

• Shorter interval to dementia onset
• Faster cognitive decline
• Clinical presentation shifts to look more like AD (more memory loss, less prominent tremor)
• Some researchers believe these amyloid-positive PDD patients are actually sitting in the overlap zone between AD and PDD on a disease spectrum

The Bottom Line

1. Amyloid is not the primary disease - synuclein is. Amyloid is a co-traveler.
2. Whether a patient accumulates amyloid depends on age, genetics (APOE ε4 vs GBA1), and the synuclein-amyloid interaction - not all patients have all three.
3. DLB accumulates more amyloid than PDD because of where and how synuclein spreads in the brain.
4. A negative amyloid PET does NOT rule out DLB or PDD - it just means the synuclein is working alone.

¹²³I-MIBG Cardiac Scintigraphy in PDD and DLB - A Detailed Explanation

1. What Is MIBG and What Does This Scan Actually Measure?

2. Why Does the Heart Matter in PDD and DLB?

Alpha-synuclein aggregates
       ↓
Lewy bodies form in peripheral sympathetic ganglia
(especially the stellate ganglion, paravertebral ganglia)
       ↓
Postganglionic cardiac sympathetic axons degenerate
       ↓
Heart muscle loses its sympathetic innervation
       ↓
MIBG cannot bind → reduced uptake on scan

3. How the Scan Is Performed and Read

1. Patient receives potassium iodide orally first (to block the thyroid from absorbing free radioactive iodine)
2. ¹²³I-MIBG is injected IV
3. Gamma camera images are taken at two time points:
   • Early image: ~20 minutes after injection
   • Delayed image: ~3-4 hours after injection

• The Heart (H) - target organ
• The Mediastinum (M) - background reference (chest space between lungs)

4. MIBG in PDD (Parkinson's Disease Dementia)

What Happens:

MIBG Findings in PDD:

• Markedly reduced MIBG uptake, both early and delayed images
• H/M ratio typically 1.4-1.7 (well below normal cutoff of ~2.0)
• Denervation is global - involving the entire cardiac sympathetic plexus
• Reduced uptake correlates with:
  • Severity of autonomic symptoms (orthostatic hypotension, constipation)
  • REM sleep behavior disorder (RBD)
  • Urinary disturbances and rigidity

Diagnostic Performance (PD/PDD):

• Sensitivity: 88% (95% CI 86-90%)
• Specificity: 85% (95% CI 81-88%)
• Area under ROC curve: 0.93 (excellent)

• Sensitivity: 90.2%, Specificity: 81.9%

• Sensitivity: 94.1%, Specificity: 87.4% for delayed H/M ratio

5. MIBG in DLB (Dementia with Lewy Bodies)

What Happens:

MIBG Findings in DLB:

• Markedly reduced uptake in the majority of patients
• H/M ratio typically even lower than in PDD in some studies (H/M ~1.28-1.47 in DLB vs PDD)
• Reduced uptake correlates with:
  • Orthostatic hypotension
  • Nocturia
  • Visual hallucinations (in some studies)
  • Greater autonomic dysfunction overall

Diagnostic Performance (DLB vs AD):

• Sensitivity: 98%, Specificity: 94% (single-center, optimal conditions)
• Multicenter trials (more realistic): Sensitivity ~69%, Specificity ~87-89%
• MIBG is listed as an "indicative biomarker" in the 2017 DLB diagnostic criteria
• MIBG is considered more sensitive than CSF p-tau for distinguishing DLB from AD

• MIBG sensitivity alone: 68.2%
• DAT SPECT sensitivity alone: 80.3%
• Combined MIBG + DAT SPECT: 93.9% - the best diagnostic strategy

6. The Critical Comparison: Can MIBG Tell PDD from DLB Apart?

7. Important Confounders - False Positives (Reduced MIBG Without Lewy Bodies)

8. What MIBG Cannot Distinguish

• PD from PDD from DLB (all abnormal)
• PD from Pure Autonomic Failure (PAF) (all abnormal)
• PD from REM sleep behavior disorder (prodromal - already abnormal)

• Separating PDD/DLB from AD (normal in AD)
• Separating PDD/DLB from MSA (preserved or mildly reduced in MSA, since MSA is a preganglionic disorder)
• Separating PDD/DLB from PSP (relatively preserved)
• Separating PDD/DLB from vascular parkinsonism (normal)

9. The Optimal Clinical Strategy

Summary in Plain Language

The heart's sympathetic nerves are killed by Lewy bodies in both PDD and DLB. MIBG is essentially a radioactive "norepinephrine" that cannot find a home in the heart when those nerves are dead - so the scan shows a dark, cold heart instead of a bright one.

This makes MIBG a powerful tool to confirm Lewy body disease (by separating it cleanly from AD, MSA, PSP, and vascular dementia), but it cannot separate PDD from DLB because both diseases kill the same nerves.

The best diagnostic approach combines MIBG with DAT SPECT for maximum sensitivity (93.9%), and adds clinical timing of symptoms to distinguish PDD from DLB.

• Tang et al., 2024, J Alzheimers Dis - PMID 38848178
• Cardiac MIBG in PD - Comprehensive Review, Brain Sciences 2023
• MIBG in Lewy Body Disorders - Literature Review, J Mov Disord